The ADHD Drug Epidemic, Amphetamines and Methylphenidate

The ADHD Drug Epidemic, Amphetamines and Methylphenidate

Today we are in the midst of a second iatrogenic amphetamine epidemic. Most people do not know we went through this same thing in the 1960’s. Notice in the above chart, the current amphetamine peak is as high as previous peak in1969 (Green ellipse and arrows). The 1969 peak was due solely to amphetamines, whereas the current peak is a combination of methylphenidate (Ritalin) and amphetamines. Both iatrogenic epidemics occurred because drug marketing by the pharmaceutical industry convinced doctors the drugs are innocuous, meaning safe and effective, and can be handed out freely without concern for adverse side effects. The medical profession and the public have been persuaded by fraudulent and deceptive industry sponsored research seeded into the medical literature, thus creating a block-buster drug used as a “mood booster and pick-me-up”. (1)

Above chart Fig 1. courtesy of Rasmussen, Nicolas. “America’s first amphetamine epidemic 1929–1971: a quantitative and qualitative retrospective with implications for the present.” American journal of public health 98.6 (2008): 974-985.

Starting in 1933

Amphetamine was first patented in 1933 by Smith, Kline and French (SKF) and marketed as Benzedrine Inhaler for over-the-counter sale.  Harvard psychiatrist Dr. Abraham Myerson, who incidentally received funding from SKF, was instrumental in gaining acceptance by psychiatrists and neurologists for Amphetamines as treatment for depression, called “anhedonia” at the time. Thus Amphetamines were the first mass-market “antidepressant”. There was extensive use of Amphetimaines, Benzedrine and Dexedrine by the military during World War Two without any regulation or oversight. Tablets were handed out freely. About this same time, amphetamines were also commonly used as a weight loss treatment. In late 1950’s, SKF introduced Dexamyl, a combination of dextro-amphetamine and amobaritol, a barbiturate sedative, sold as anti-depressant, and weight loss remedy.  At its peak in 1969, amphetamine production was 8 billion 10 mg. doses per year. Obvious problems started to emerge in the 1960’s with recognition of amphetamine psychosis, and amphetamine addiction, the two most disturbing problems.

Amphetamine Psychosis and Addiction

Amphetamine induced psychosis was easily identified by the symptoms of paranoia, evil voices heard arising from toilet bowls and ventilation ducts, or the patient reports being followed by government spies waiting around every corner, etc. Once the drug is stopped, recovery follows one or two weeks later, revealing the psychosis was drug induced.

1971 End of First Epidemic

By 1970, there were about 10 million amphetamine users in the U.S. and roughly one million people either addicted or dependent on the drug.  The amphetamine epidemic came to an end in 1971 when the DEA reclasified amphetamines and methylphenidate as Shedule II drugs. This restrictive classification caused prescription sales to plummet by 60 per cent. By the late 1970’s amphetamines had been replaced by cocaine on the street as the drug abuser’s choice. (1-3)

Today’s Amphetamine Epidemic – Widely Accepted as Safe

Today’s iatrogenic amphetamine epidemic is made possible by the return of “medical normalization”, the result of drug company advertising to  convince the medical profession and the public that amphetamines are safe, even for small children (for ADHD).  As recorded in the first amphetamine epidemic in the 1960’s, these drugs are not safe for adults nor children. In 2008,  Nicolas Rasmussen writes:

Today, amphetamines are widely accepted as safe even for small children, and this return of medical normalization inevitably undermines public health efforts to limit amphetamine abuse…the pharmaceutical industry’s “multihundred million dollar advertising budgets, frequently the most costly ingredient in the price of a pill, have pill by pill, led, coaxed and seduced post–World War II generations into the ‘freaked out’ drug culture” plaguing the nation. Any effort to deal harshly with methamphetamine users today in the name of epidemic control, without touching medical stimulant production and prescription, is as impossible practically as in 1970—and given historical experience, even more hypocritical. (1)

The Etiology of the ADHD Drug Epidemic

These Are Merely Normal Children

I proposed two different explanations of the ADHD Drug Epidemic. The first is that the diagnosis of ADHD has no actual biological tests or markers. Rather, ADHD is a list of behaviors in the classroom recognized by the teacher who refers the child to the school psychologist for evaluation. These behaviors are listed as inattention, hyperactivity, and impulsivity. The child may be disruptive in class, boistrous and defiant to authority, emotional outbursts, or perhaps the child may have learning difficulties. Many dissenting health professionals take the position these are behaviors found in normal children, who do not have a disease, and do not require Schedule II additive drug treatment with amphetamines. In short, these are normal children whose behaviors are given the ADHD label, leading to the required treatment with brain damaging drugs to suppress their behavior.

ADHD is an ESSENCE DIsorder  (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations)

As discussed in the previous PART ONE article on Hypervaccination, Autism, ADHD and Neurodevelopmental Disorders, medical science has no known c ause for Autism and ADHD. However, new studies over the last decade on the ESSENCE disorders shows that both Autism and ADHD are the result of immune dysregulation and brain inflammation caused by hypervaccination. In other words, the ever expanding childhood vaccination program is the most likely cause of our ADHD/Amphetamine Epidemic. Of course, this is an inconvenient truth which must be suppressed, and not to be mentioned in public. If accepted as true, this means the ADHD drug epidemic is an iatrogenic medical catastrophe of monumental proportions. The vaccination program has creating three generations of brain damaged children with with various neuropsychiatric and neurodevelopmental disorders. To compound this tragic mistake, these same children are then treated with ADHD drugs, adding to the brain damage.

2 Minute Video on Mechanism of ADHD Drugs

Methylphenidate and Amphetamine are the two most commonly used ADHD drugs. Here is a 2 minute video explaining the mechanism of action. Methylphenidate increases the quantity of dopamine and norepinephrine at the synaptic cleft by blocking DAT (Dopamine Transporter) which is involved in reuptake of dopamine and norepinephrine terminal ending. Since re-uptake is blocked, dopamine and norepinephrine accumulate in the synaptic space (or cleft). Dopamine and norepinephrine are called neurotransmitters because they transmit the nerve impulse signal from one neuron to the next one:

Mechanism of Action of Methylphenidate:

MPH [Methylphenidate] is a stimulant that blocks the transporters that reuptake dopamine and norepinephrine into the presynaptic neuron following their release. This action prolongs the availability of these neurotransmitters in synapses to exert effects on postsynaptic neurons. (73)

Dr. Peter Breggin on the Safety and Efficacy of ADHD Drugs

Dr. Peter Breggin is an integrative adult and child psychiatrist who has extensive experience treating ADHD children. In 1999, Dr. Peter Breggin MD discusses the effects of ADHD drugs on children, stating we must “reclaim our children from the drug companies and their advocates in the medical profession”:

Millions of children in North America are diagnosed with attention deficit/hyperactivity disorder and treated with psychostimulants such as methylphenidate, dextroamphetamine, and methamphetamine. These drugs produce a continuum of central nervous system toxicity that begins with increased energy, hyperalertness, and overfocusing on rote activities. It progresses toward obsessive/compulsive or perseverative activities, insomnia, agitation, hypomania, mania, and sometimes seizures. They also commonly result in apathy, social withdrawal, emotional depression, and docility. Psychostimulants also cause physical withdrawal, including rebound and dependence. They inhibit growth, and produce various cerebral dysfunctions, some of which can become irreversible. The “therapeutic” effects of stimulants are a direct expression of their toxicity. Animal and human research indicates that these drugs often suppress spontaneous and social behaviors while promoting obsessive/compulsive behaviors. These adverse drug effects make the psychostimulants seemingly useful for controlling the behavior of children, especially in highly structured environments that do not attend to their genuine needs.(25)

Psychotic Episodes

One of the adverse effects of ADHD drug is induction of psychotic episodes. When the parent recognized the child is having a psychotic episode and brings the child back to the doctor for help, this only leads to a second tragedy. Instead of stopping the amphetamine drug, the child is given additional anti-psychotic or antidepressants drugs, leading to polypharmacy. In 1999, Drs. Cherland and Fitzpatrick found psychotic episodes in about  9-10 percent of children on ADHD drugs. In 2000, Dr. Peter Breggan  writes

Until recently, no studies have systematically examined the rate of psychotic symptoms caused by routine treatment with stimulant drugs such as methylphenidate (Ritalin) and amphetamine (Dexedrine, Adderall). Doctors who prescribe stimulant drugs often seem oblivious to the fact that they can cause psychoses, including manic-like and schizophrenic-like disorders. Without providing a scientific basis, the literature often cites rates of 1% or less for stimulant-induced psychoses (reviewed in [1,2]). Recently on television I debated a well-known expert in child psychiatry who took the position that prescribed stimulants “never” cause psychoses in children.

The rate of psychotic symptoms that first appear during stimulant treatment has recently been investigated in a 5-year retrospective study of children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) [5]. Among 192 children diagnosed with ADHD at the Canadian clinic, 98 had been placed on stimulant drugs, mostly methylphenidate. Psychotic symptoms developed in more than 9% of the children treated with methylphenidate. According to Cherland and Fitzpatrick, (1999) “The symptoms ceased as soon as the medication was removed” [5, p. 812]. No psychotic symptoms were reported among the children with ADHD who did not receive stimulants. The psychotic symptoms caused by methylphenidate included hallucinations and paranoia. The authors conclude that, due to poor reporting, the rate of stimulant-induced psychosis and psychotic symptoms was probably much higher. In my practice of psychiatry, I am frequently consulted about children who are taking three, four, and sometimes five psychiatric drugs, including medications that are FDA-approved only for the treatment of psychotic adults. The drug treatment typically began when the children developed conflicts with adults at home or at school. In retrospect, the conflicts could easily have been resolved by interventions such as family counseling or individualized educational approaches. Usually under pressure from a school, the parents instead acquiesced to put their child on stimulants prescribed by psychiatrists, family physicians, or pediatricians. When these children developed depression, delusions, hallucinations, paranoid fears and other drug-induced reactions while taking stimulants, their physicians mistakenly concluded that the children suffered from “clinical depression”, “schizophrenia” or “bipolar disorder” that had been “unmasked” by the medications. Instead of removing the child from the stimulants, these doctors mistakenly prescribed additional drugs, such as antidepressants, mood stabilizers, and neuroleptics. Children who were put on stimulants for “inattention” or “hyperactivity” ended up taking multiple adult psychiatric drugs that caused severe adverse effects, including psychoses and tardive dyskinesia. It is time to recognize that the supposedly increasing rates of “schizophrenia”, “depression”, and “bipolar disorder” in children in North America are often the direct result of treatment with psychiatric drugs. They should be classified as adverse drug reactions, not as primary psychiatric disorders. Doctors need to become more expert at identifying these adverse drug reactions in children and more aware of how and why to taper children from psychiatric medications [4]. When parents are willing to take a fresh approach to disciplining and caring for their children, or when the children’s school situation can be improved, it is usually possible to taper them off of all psychiatric medications. The parents are then relieved and gratified to see their children increasingly improve with the removal of each drug. What is the answer to this widespread, unwarranted use of medication in the treatment of children? As long as we respond to the signals of conflict and distress in our children by subduing them with drugs, we will not address their genuine needs. As parents, teachers, therapists, and physicians we need to retake responsibility for our children [3].We must reclaim them from the drug companies and their advocates in the medical profession. At the same time, we must address the needs of our children on an individual and societal level. On the individual level, children need more of our time and energy. Nothing can replace the personal relationships that children have with us as their parents, teachers, counselors, or doctors. On a societal level, our children need improved family life, better schools, and more caring communities. (26) (18-20)

The Success of Drug Marketing – A Marketable Brand Driven by Economic Interests

In 2023, Dr. Laura Batstra asks what is driving the increased ADHD diagnosis and treatment rates ? The global market for ADHD drugs is 30 billion dollars in 2022, and expected to reach 45 billion dollars in 2027, writing that we should be thinking of ADHD as a “marketable brand driven by economic and guild interests”:

If the science supporting ADHD diagnosis and treatments is weak and has not advanced significantly since 1980; What is driving increased ADHD diagnosis and treatment rates?…With the global ‘ADHD therapeutics market’ estimated to be worth US $29.56 billion in 2022—and expected to reach US $45.68 billion by 2027 (10)—perhaps the answer lies in thinking differently about ADHD. Instead of regarding it as an illness requiring medical intervention, it may be more insightful to understand ADHD as a marketable brand driven by economic and guild interests. (15)

More Adverse Drug Reactions

In 2010, Dr. Sean Patrick Hatt an Integrative Psychologist describes the additional adverse effects of stimulant drugs:

Adverse drug reactions in stimulant formulas include impaired growth, insomnia, agitation, hypomania, mania, seizures, physical withdrawal, rebound effects, dependence, and even psychosis. (27)

All Stimulants Produce Effects Similar to Cocaine Use

In 2014, Dr David A. Gorelick and Michael H. Baumann, PhD discuss the effects of stimulant drugs used to treat ADHD, amphetamines, methampetamines and methylphenidate, writing they all produce effects similar to cocaine. (35):

All stimulants produce a similar range of psychological, behavioral, and physiologic effects, with the intensity and duration depending on potency, dose, route of administration, and duration of useThe initial effects—usually desired— include increased energy, alertness, and sociability; elation or euphoria; and decreased fatigue, need for sleep, and appetite . The intense pleasurable feeling has been described as a “total body orgasm” . These effects may occur after 5 to 20 mg of oral amphetamine, methamphetamine, or methylphenidate; 100 to 200 mg of oral cocaine; 40 to 100 mg of intranasal cocaine; or 15 to 25 mg of IV or smoked cocaine (122,123). Such single oral doses of stimulants improve cognitive and psychomotor performance in subjects whose performance has been impaired by fatigue, sleep deprivation, or alcohol, especially in tasks that require focused and sustained attention (vigilance) (35)

Animal Studies Show Chronic Methylphenidate Use has Long-Term Neurodegenerative Consequences.

In 2012, Dr. Shankar Sadasivan studied the effects of Methylphenidate on the basal ganglia in mice, finding a twenty percent loss of dopaminergic neurons in the basal ganglia as well as activation of microglia (an inflammatory response) at doses “spanning the therapeutic range in humans” . Dr. Shankar Sadasivan concluded in the mouse model, “chronic Methyphenidate use has long-term neurodegenerative consequences…[stimulant] drugs shown to increase the levels of dopamine in the synaptic cleft can contribute to degenerative changes in the basal ganglia”. writing:

Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia…Through the use of stereological counting methods, we observed a significant reduction (∼20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc….Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. ..We also found an increase in mRNA levels of the pro-inflammatory genes IL-6 and TNF-alpha in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing…Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.a recent epidemiological study that showed that long-term amphetamine usage, which like MPH [methylphenidate] results in higher levels of striatal dopamine in the synaptic cleft, results in a significantly higher risk for developing Parkinson’s disease…Taken together, our results suggest that chronic administration of methylphenidate in mice, at doses that approximate those at the higher therapeutic range in humans, results in a reduced expression of neurotrophic factors, increased neuroinflammation, and a small, but significant loss of SNpc [Substantia Nigra] dopamine neurons … this work supports studies that demonstrate that drugs shown to increase the levels of dopamine in the synaptic cleft can contribute to degenerative changes in the basal ganglia. (36) (80)

Enduring Changes in Neuro Glial Network

In 2023, Dr. Carlo Cavaliere studied Methylphenidate in a mouse animal model, finding long-term changes in the neuroglial network in the brains of mice, including an increase in dendritic spines in the striatum, writing:

Repeated exposure to psychostimulant drugs induces complex molecular and structural modifications in discrete brain regions of the meso-cortico-limbic system. This structural remodeling is thought to underlie neurobehavioral adaptive responses. Administration to adolescent rats of methylphenidate (MPH), commonly used in attention deficit and hyperactivity disorder (ADHD), triggers alterations of reward-based behavior paralleled by persistent and plastic synaptic changes of neuronal and glial markers within key areas of the reward circuits. By immunohistochemistry, we observe a marked increase of glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expression and a down-regulation of glial glutamate transporter GLAST in dorso-lateral and ventro-medial striatum. Using electron microscopy, we find in the prefrontal cortex a significant reduction of the synaptic active zone length, paralleled by an increase of dendritic spines (involved in long-term memory). We demonstrate that in limbic areas the MPH-induced reactive astrocytosis affects the glial glutamatergic uptake system that in turn could determine glutamate receptor sensitization. These processes could be sustained by NO production and synaptic rearrangement and contribute to MPH neuroglial induced rewiring.(37-38) (42)

Exposure ot Methylphenidate in Juvenile Mice Decreases Adult Neurogenesis in the Hippocampus

In 2006, Dr. Diane Lagace found that administration of methylphenidate to juvenile mice attenuates hippocampal neurogenesis at the stage of adult mice, Methyphenidate exposure impairs the normal ability of the adult mouse brain to regenerate, concluding:

Early-life exposure to MPH [Methylphenidate] inhibits the survival of adult-generated neurons in the temporal hippocampus …  These findings suggest that decreased adult neurogenesis is an enduring consequence of early-life exposure to MPH and are discussed for their relevance to humans. (39)

Prolonged ADHD medication use at higher doses is significantly associated with smaller hippocampus volumes in specific subregions.

Methylphenidate Use in Children Shrinks the Hippocampus, Involved in Brain Regeneration

In 2021, Dr. Nellie Fotopoulos did neuroimaging studies in children treated with ADHD stimulant drugs finding smaller hippocampus volumes. The hippocampus and the neurotrophic factor BDNF (brain derived neurotopic factor) are involved with brain regeneration, writing:

Structural neuroimaging studies comparing ADHD children to neurotypical children identified group differences in cortical and subcortical brain regions (Albajara Saenz, Villemonteix, & Massat, 2018). A landmark study by Shaw et al. 2007 reported a delay in peak cortical maturation of 3.5 years in children with ADHD, most apparent in prefrontal regions (Shaw et al., 2007). A mega-analysis by Hoogman et al. 2017 reported reduced volumes in the accumbens, amygdala, hippocampus, putamen, and overall brain in comparison to control children (Hoogman et al., 2017). However, there is considerable variability across neuroimaging studies in ADHD, as one meta-analysis found that only 25–50% of published reports had reproducible results (Frodl & Skokauskas, 2012). Since pharmacological agents are commonly used to treat ADHD symptoms, it is important to assess their impact on brain structure. If exposure to ADHD medication significantly alters brain structure measurements, it might provide partial explanation for the varying results across ADHD imaging studies…Taken together, these studies do not provide evidence for abnormal brain development following exposure to ADHD medication. Rather, they highlight the confusing state of the literature where medication is reported as having either no effect on brain structure or as having a normalizing effect brain structure…studies have reported hippocampus volume reductions in adults with ADHD who had, during childhood, been treated with ADHD medication (Frodl and Skokauskas, 2012, Onnink et al., 2014). These findings were not observed in stimulant-naïve adults with ADHD. Frodl and Skokauskas (2012) have suggested that changes in smaller regions, such as the hippocampus, may go undetected as large threshold corrections for the whole brain are typically used (Frodl & Skokauskas, 2012). Moreover, in the relatively few studies that have included the hippocampus when assessing medication effects, no studies have sought to investigate subregions…The number of independent prescriptions for ADHD medication per child was one (n = 7), two (n = 34), three (n = 21), four (n = 18) and five (n = 21). A total of 315 prescriptions were included: Ritalin® (35.2%), Biphentin® (32.4%), Concerta® (22.6%), Vyvanse® (5.7%), Strattera® (2.5%) and Adderall® (1.6%)…Conclusions Although this study is cross-sectional, the results found within this sample of children show that prolonged ADHD medication use at higher doses is significantly associated with smaller hippocampus volumes in specific subregions.(40)

Study Using MRI Spectroscopy to Measure GABA Levels in Prefrontal Cortex

Methylphenidate May Induce Long-Lasting Alterations in the adult GABAergic System in Prefrontal Cortex when Treatment Started in Childhood.

In 2017, Dr. Michelle Solleveld studied 44 ADHD patients, finding Methylphenidate induces age-dependent long lasting effects on their GABAergic systems in the PFC (prefrontal cortex) of the brain when given to children. These changes are not found when MPH is given to adults, writing:

First stimulant exposure [with Methylphenidate] at a young age is thus associated with lower baseline levels of GABA+ and increased responsivity in adulthood. This effect could not be found in patients that started treatment at an adult age. Hence, while adult stimulant treatment seems to exert no major effects on GABA+ levels in the mPFC [prefrontal cortex], MPH may induce long-lasting alterations in the adult mPFC GABAergic system when treatment was started at a young age.In conclusion, our results demonstrate that MPH effects on GABA+ levels in ADHD patients are influenced by whether a subject had first started stimulant treatment in childhood or in adulthood. Our data thus suggest that long-lasting alterations may have occurred in GABAergic neurotransmission in the mPFC [prefrontal cortex], selectively in subjects who had been first exposed to stimulant treatment early during childhood, but not in those who started medication only from later in their lives onward. (43)(77)

Methylphenidate Behavioral Study in Juvenile Mice –  Changes Endure into Adulthood

In 2003, Dr. William Carlezon Jr. studied early developmental exposure to methylphenidate and cocaine in juvenile mice, finding enduring behavioral effects, writing:

Methylphenidate (MPH) is a stimulant prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulant drugs can cause enduring behavioral adaptations, including altered drug sensitivity, in laboratory animals. We examined how early developmental exposure to stimulants affects behavior in several rodent models…Rats received MPH or cocaine during preadolescence. Behavioral studies began during adulthood. We compared how early exposure to MPH and cocaine affects sensitivity to the rewarding and aversive properties of cocaine using place conditioning. We also examined the effects of early exposure to MPH on depressive-like signs using the forced swim test, and habituation of spontaneous locomotion, within activity chambers…In place-conditioning tests, early exposure to MPH or cocaine each made moderate doses of cocaine aversive and high doses less rewarding. Early MPH exposure also caused depressive-like effects in the forced swim test, and it attenuated habituation to the activity chambers…Conclusions: Early exposure to MPH causes behavioral changes in rats that endure into adulthood. Some changes (reduced sensitivity to cocaine reward) may be beneficial, whereas others (increases in depressive-like signs, reduced habituation) may be detrimental. The effects of MPH on cocaine-related behaviors may be a general consequence of early stimulant exposure. (45)

=========== Amphetamines ========

Amphetamines in Monkey Studies

In 2007, Dr. Lynn Selemon gave amphetamines to monkeys, finding altered dendritic morphology in prefrontal cortical pyramidal neurons. Dr. Selemon found reduced dendritic branching and 22 percent reduced spine density, resembling the brain alterations found in schizophrenia, writing:

Amphetamine (AMPH) sensitization in the nonhuman primate induces persistent aberrant behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, psychomotor depression, and profound cognitive impairment. The present study examined whether AMPH sensitization induces similarly long-lasting morphologic alterations in prefrontal cortical pyramidal neurons. Three to 3½ years postsensitization, sensitized, and AMPH-naïve control monkeys were killed. Blocks of prefrontal cortex were Golgi-impregnated for elucidation of pyramidal dendritic morphology in layers II/superficial III (II/IIIs), deep III, and V/VI. In AMPH-sensitized animals as compared to AMPH-naïve controls, pyramidal dendrites in layer II/IIIs exhibited reduced overall dendritic branching and reduced peak spine density (22%) on the apical trunk. Across all layers, the distance from soma to peak spine density along the apical trunk was decreased (126.38±7.65 μm in AMPH-sensitized compared to 162.98±7.26 μm in AMPH-naïve controls), and basilar dendritic length was reduced (32%). These findings indicate that chronic dopamine dysregulation, consequent to AMPH sensitization, results in enduring, atrophic changes in prefrontal pyramidal dendrites that resemble the pathologic alterations described in patients with schizophrenia and may contribute to the persistence of schizophrenia-like behavioral changes and cognitive dysfunction associated with sensitization. These findings may also provide key insights into the etiologic origin of the pronounced behavioral disturbances and cognitive dysfunction associated with schizophrenia. (50)

Amphetamines in Mouse Study – Loss of Neurons and Behavioral Changes

In 2021, Dr. Arroyo-García gave amphetamines (AMPH) to 58 mice over 5 days, and then studied with behavioral testing 38 days later. After this, the animals were sacrificed to study brain morphology. Compared to controls, the authors found alteration of neuron morphology neurons in the hippocampus as well as alterations in memory and learning behaviors in the mice, writing:

An increase in the dopaminergic tone caused by AMPH [amphetamine] sensitization generates oxidative stress, neuronal death, and morphological changes in the hippocampus that affect cognitive behaviors like short- and long-term memories. (51)

Above image Fig. 2: Neuronal density after 35 days of chronic amphetamine (AMPH) administration. Courtesy of  Arroyo-García,(2021) . (51)

In 2022, Dr. Hiram Tendilla-Beltrán discussed the various effects of amphetamines on neuronal morphology, the reward system, behavioral sensitization, hypertrophy of dendritic arborization, increased dendritic spines, and memory and learning disturbances, writing in the book, Amphetamine and the Biology of Neuronal Morphology:

Amphetamines are widely used psychostimulants for both therapeutic and recreational purposes. These drugs enhance monoaminergic neurotransmission. Amphetamines increase dopamine, noradrenaline, and serotonin availability in the synaptic cleft, mainly by the reverse action of the monoamine transporters (MATs), which in physiological conditions are the main mechanism for monoamine recapture. Moreover, monoamines are closely related to the reward system, which is an ensemble of corticolimbic structures that hierarchizes sensory information according to motivation or pleasure. It has been widely studied the increased motor behavioral effects after repeated and intermittent amphetamine exposure, described as behavioral sensitization, which is part of the complex addictive behavior. Interestingly, amphetamines have neuroplasticity effects, since chronic exposure to these drugs hypertrophies the dendritic arbor and increases the number of dendritic spines in neurons of the corticolimbic system. Also, amphetamines induce oxidative stress. These neuronal impairments can be related to the memory and learning disturbances and ultimately to the behavioral sensitization induced by amphetamine exposure. (52)

Damage to Dopaminergic Nerve Endings in Striatum

It was known as early as 2005 that amphetamines used for ADHD damage the dopaminergic nerve ending in the ventral striatum of the brain (caudate nucleus and putamen). In 2005, Dr. George A Ricaurte studied amphetamines in monkeys finding damage effects to the dopaminergic nerve endings in the striatum. Dosage was similar to that used for ADHD in humans, writing:

Here we demonstrate that amphetamine treatment, similar to that used clinically for adult ADHD, damages dopaminergic nerve endings in the striatum of adult nonhuman primates. Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity in nonhuman primates are on the order of those reported in young patients receiving amphetamine for the management of ADHD. These findings may have implications for the pathophysiology and treatment of ADHD. (53)

Chronic Amphetamine Use Reduces BDNF (Brain Dereived Neurotrophic Factor)

In 2007, Dr Francesco Angelucci iusing mice, found chronic amphetamine use reduced two brain growth factors, NGF and BDNF, writing:

Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia. (55)

No Long Term Clinical Trials to Assess Safety or Efficacy

In 2014, Dr. Florence Bourgeois reviewed 32 clinical trials conducted for the approval of 20 ADHD drugs, finding none of them assessed long-term safety and efficacy, writing:

Clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events or long-term safety and efficacy.

Reduction in Height and Weight

In 2022, Dr. Konstantin Mechler foundADHD stimulant drug treatment resulted in a “statistically significant reduction in height and weight gain”, and that long term outcomes of the drugs have not been studied and are unknown, writing:

While short-term efficacy and safety of both stimulants and non-stimulants have been soundly demonstrated in various clinical trials, a comparable extent of systematic assessments for longer-term outcomes is not yet available. (58)

In 2015, Dr. Armanda Teixeira-Gomes reviewed the neurotoxicity of amphetamines during the adolescent period, finding recent studies in young adults and during adolescence clearly indicating brain damage or behavioural changes, suggesting ADHD drugs have long-term neurotoxic effects when used in children and adolescents. The age of maturity is important. Dr. Armanda Teixeira-Gomes writes:

Amphetamine-type psychostimulants (ATS), such as amphetamine (AMPH), 3,4-Methylene Dioxy Meth Amphetamine (MDMA), and methamphetamine (METH) are psychoactive substances widely abused, due to their powerful central nervous system (CNS) stimulation ability. Young people particularly use ATS as recreational drugs. Moreover, AMPH [Amphetamine] is used clinically, particularly for attention deficit hyperactivity disorder, and has the ability to cause structural and functional brain alterations. ATS are known to interact with monoamine transporter sites and easily diffuse across cellular membranes, attaining high levels in several tissues, particularly the brain. Strong evidence suggests that ATS induce neurotoxic effects, raising concerns about the consequences of drug abuse. Considering that many teenagers and young adults commonly use ATS, our main aim was to review the neurotoxic effects of amphetamines, namely AMPH, MDMA, and METH, in the adolescence period of experimental animals. …The susceptibility to the neurotoxic effects of ATS seems roughly located in the early adolescent period of animals. Many authors report that the age of exposure to ATS is crucial for the neurotoxic outcome, showing that the stage of brain maturity has a strong importance. Moreover, recent studies have been undertaken in young adults and/or consumers during adolescence that clearly indicate brain or behavioural damage, arguing for long-term neurotoxic effects in humans. There is an urgent need for more studies during the adolescence period, in order to unveil the mechanisms and the brain dysfunctions promoted by ATS. (59)

Lithium Neuroprotective

In 2009, Dr. Irina Krasnova reviewed methamphetamine (METH) neuro-toxicity, finding patterns of brain degeneration very similar to other ATS (Amphetamine Typre Stimulants), namely METH-induced damage to [dopaminergic] monoaminergic terminals, the combination with the neuro-protective mineral, Lithium, might be useful in prevention of neurotoxicity, writing:

Methamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, loss of gray matter accompanied by hypertrophy of the white matter and microgliosis in different brain areas. In the present review, we summarize data on the animal models of METH neurotoxicity which include degeneration of monoaminergic terminals and neuronal apoptosis. In addition, we discuss molecular and cellular bases of METH-induced neuropathologies. The accumulated evidence indicates that multiple events, including oxidative stress, excitotoxicity, hyperthermia, neuroinflammatory responses, mitochondrial dysfunction, endoplasmic reticulum stress converge to mediate METH-induced terminal degeneration and neuronal apoptosis. …In summary, the brains of human METH addicts, who abuse large doses of the drug, are characterized by a variety of neuropathological changes. These include degeneration of monoaminergic terminals, dysregulation of energy metabolism, evidence of oxidative stress, as well as microgliosis and reactive astrogliosis. The deleterious effects of the drug have been consistently replicated in animal models. These studies have helped to identify some of the pathways that form the mechanistic substrates for METH-induced damage to monoaminergic terminals. Similarly, recent investigations have clarified the bases for neuronal apoptosis caused by METH exposure in various regions of the mammalian brain… The combination of anti-addictive agents with the anti-manic drug, lithium, that has been shown to have neuroprotective properties (Chuang, 2004), might be a fruitful approach to the treatment of METH abusers. (60)

Motaghinejad, Majid, et al. “The neuroprotective effect of lithium against high dose methylphenidate: Possible role of BDNF.Neurotoxicology 56 (2016): 40-54.  Lithium has the potential to act as a neuroprotective agent against MPH induced toxicity in rat brain and this might be mediated by BDNF expression in hippocampus of rats.

Ghanaatfar, Fateme, et al. “Is lithium neuroprotective? An updated mechanistic illustrated review.” Fundamental & Clinical Pharmacology 37.1 (2023): 4-30.

Mehrafza, Shafagh, et al. “Pharmacological evidence for lithium-induced neuroprotection against methamphetamine-induced neurodegeneration via Akt-1/GSK3 and CREB-BDNF signaling pathways.Iranian Journal of Basic Medical Sciences 22.8 (2019): 856.

Neurotoxicity 2011

In 2011, Dr. Thomas Steinkellner reviewed the neurotoxicity of amphetamines:  (MDMA,‘Ecstasy’), methamphetamine and D-amphetamine. , finding:

Amphetamines exert their acute effects both in the central nervous system (CNS) and in peripheral tissues. The acute clinical outcome is dependent upon the dose administered and typically includes positively prescribed subjective effects such as an increased state of arousal, euphoria, increased energy and talkativeness, but also negative emotions including anxiety, paranoia or auditory and visual hallucinations (Baylen and Rosenberg 2006; Cruickshank and Dyer, 2009)… he peripheral effects of amphetamines are primarily mediated by its interaction with the noradrenaline transporter (NAT) and are associated with an increase in extracellular noradrenaline (NA) concentrations. These effects include increases in heart rate, blood pressure, respiration rate, body temperature, psychomotor activation and reduced appetite (Boenisch and Bruess, 2006; Cruickshank and Dyer, 2009). It is the sympathomimetic stimulating effect of amphetamines which renders them attractive as doping agents (Docherty, 2008)…Amphetamines also increase locomotor activity, an effect which can be enhanced by the repeated administration of the drug. This hyperactivity is referred to as ‘behavioural sensitisation’ and is neurochemically correlated with an increase in striatal DA release. It can persist for several months following the last drug administration, thereby mimicking the sensitised states of human psychostimulant abusers (Paulson and Robinson, 1995; Pierce and Kalivas, 1997)…Taken together, these observations are consistent with a cellular model where amphetamine action in mesocorticolimbic dopaminergic neurons is the fundamental mechanism contributing to their reinforcing and addictive properties (Nestler, 2005; Kalivas, 2007)…Chronic METH abuse leads to the degeneration of monoaminergic terminals (Davidson et al., 2001; Krasnova and Cadet, 2009) and reduced DAT [Dopamine Transporter] and DA [Dopamine] levels in the striatum of mice, rats and monkeys (Anderson and Itzhak, 2006; Graham et al., 2008; Melega et al., 2008). Similar effects have been reported in people subjected to positron emission tomography (PET) (Volkow et al., 2001).

Amphetamines and psychotic episodes: One of the prime findings in amphetamine abuse is the induction of psychotic episodes that are almost indistinguishable from the positive symptoms seen in schizophrenic patients (Ujike and Sato, 2004; Hermens et al., 2009). This supports the conjecture that there might be a link between amphetamine abuse and the psychopathic traits observed in schizophrenia…psychostimulants such as d-AMPH or METH can increase the susceptibility of users to psychotic symptoms either during acute amphetamine abuse or during withdrawal (Ujike and Sato, 2004; Hermens et al., 2009)…It has been recently shown that impulsive antisocial behaviours (a possible ‘negative symptom’ that can occur in schizophrenia) correlates with an increase in amphetamine-induced DA release in the NAc measured by [18F]fallypride PET and functional magnetic resonance imaging. These observations provide evidence for an association between substance abuse and psychopathic traits (Buckholtz et al., 2010). To obtain an animal model for the psychotic symptoms of schizophrenia, animals are subjected to amphetamine-induced sensitisation and observed during withdrawal periods after the sensitisation regimen (Paulson and Robinson, 1995; Peleg-Raibstein et al., 2009). Sensitised animals show an increase in subsequent amphetamine-induced DA release in the striatum and an increase in locomotor activity (Paulson and Robinson, 1995; Iwata et al., 1997). Thus, sensitisation is not only a model for addiction but also for psychosis (Gainetdinov et al., 2001).

Conclusions and future perspectives: Amphetamines are the second most commonly abused drugs in Europe after cannabis (EMCDDA, 2009) and the devastating effects of METH addiction are obvious in many parts of the world (Karila et al., 2010). All three drugs (METH, d-AMPH and MDMA) have been reported to induce psychotic episodes or ‘seizures’ in humans (Ujike and Sato, 2004; Karlsen et al., 2008). Furthermore, the loss of nigrostriatal dopaminergic neurons observed following repeated METH administration in animals has been associated with the pathogenesis of PD [Parkinson’s Disease] (Sonsalla et al., 1996; Harvey et al., 2000; Granado et al., 2010). These unintended (‘side’) effects should be carefully assessed when considering the long-term effects of amphetamine abuse on mental health and well-being…Conversely, both d-AMPH [Amphetamines} and METH [Methamphetamines] are used in the treatment of ADHD, narcolepsy and obesity. Likewise, MDMA abuse has been implicated in both the origin and treatment of PD (Morton, 2005; Sotnikova et al., 2005). Moreover, MDMA has even been suggested as a therapeutic aid in post-traumatic stress disorder (Morton, 2005). Long-term amphetamine administration has been shown to induce ample neurodegenerative side effects in animal models, thus rendering this the main cause for concern in humans following chronic amphetamine abuse. (61)

2022 Methamphatamine Toxicity

In 2022, Dr. Amber Edinoff reviewed the adverse effects and related toxicities of Methamphetamine use, writing:

Methamphetamine use increased four-fold from 2015 to 2016. Due to this increase in methamphetamine use and its associated medical complications, the mortality rate associated with methamphetamine use has doubled over the past ten years. Cardiopulmonary symptoms include chest pain, palpitations, and shortness of breath. Methamphetamine-related myocardial infarction can also occur. Central nervous system symptoms include agitation, anxiety, delusions, hallucinations, and seizures. Methamphetamine-induced psychosis may unmask underlying psychiatric disorders. It can also cause cerebral vasculitis, which elicits cortical blindness and ischemic strokes. Methamphetamine-induced neurotoxicity in serotonergic systems is more diffuse, involving the striatum, hippocampus, septum, amygdala, and hypothalamus leading to mood changes, psychosis, and memory impairment.(62)

Possible Antidotes to Amphetamine Neurotoxicity

Neuroprotective Effects of Berberine

In 2023, Dr. Fahimeh Mohseni studied 32 mice after inhaling methamphetamine [METH] for 14 days, finding neuroprotective effects of a plant alkaloid, Berberine.  Immunofluorescence staining in the hippocampus after mice were sacrificed at 37 days showed increased BDNF and GDNF, brain and glial derived neurotrophic factor, both associated with improvement in cognition. Dr. Fahimeh Mohseni writes:

Activation of neurotrophic factors after administration of Berberine BER resulted in improvement of METH-induced cognitive deficits. Methamphetamine (METH) use is a serious risk factor for the development of cognitive problems. Severe cognitive deficits occur in at least 27% of users of ecstasy, an amphetamine derivative (). Previous studies indicate that regular amphetamine use leads to learning and memory deficits and impairs decision-making (). In addition, patients with chronic METH use perform poorly on tests of cognitive flexibility (, ). Moreover, METH use is related to dysfunction in attentional set-shifting (), executive function (), verbal recall, and recognition domains (). In a recent study to screen for cognitive impairment in METH users, all cognitive sub-scores, including memory, attention, visuospatial functions, and verbal fluency were significantly impaired in the sample (). The results of this study confirm the adverse effects of METH use on all domains of cognitive performance….For instance, Bisagno et al. (2002) () and Schröder et al. (2003) () show that repeated administration of METH within a single day leads to profound deficits in a nonspatial task of recognition memory. Moreover, repeated moderate doses of METH damage monoaminergic terminals in the forebrain and non monoaminergic cells in the somatosensory cortex and impair performance in a novelty preference object recognition task (). The essential forebrain structure for cognitive function is the hippocampus, which is highly sensitive to amphetamine derivatives (). It is well known that dysfunction or damage to the hippocampal formation is closely associated with deficits in recognition memory (). For example, amphetamine-induced cognitive impairment is accompanied by neurotrophic deficiency in the hippocampus (). In addition, reports suggest that cognitive deficit related to amphetamine neurotoxicity may be associated with changes in brain-derived neurotrophic factor (BDNF) in the hippocampus in the METH-induced model of mania in rats ()…In other experimental studies, brain-derived neurotrophic factor (BDNF) was shown to decrease after repeated METH administration and to increase 30 and 90 days after psychostimulant withdrawal (). In addition, another report shows that chronic amphetamine can decrease the concentration of glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) in the hippocampus (, )…METH abusers may exhibit severe neurotrophic dysfunction and impaired neuroprotective function after repeated use of METH…One of the interesting protective properties of BER is the up-regulation of neurotrophic agents and their receptors by a yet unknown mechanism in the central nervous system ()…A plant-based isoquinoline alkaloid, Berberine hydrochloride (BER), shows memory and cognition enhancement properties…we found that BER-induced improvement in recognition memory after consumption of METH was related to the raised expression of BDNF and GDNF in the hippocampus. In general, neurotrophins are one of the known biomarkers with widespread cognition-enhancing properties (, )…. In the current study, we found that activation of neurotrophic factors after administration of BER resulted in improvement of METH-induced cognitive deficits.(64)

Alpha Lipoic Acid and Lithium Reverse Amphetamine Toxic Effects, on Locomotor Activity and BDNF.

In 2012, Dr. DS MAcedo studied amphetamine-induced mania in mice, finding finding that supplements Alpha Lipoic Acid ALA and Lithium Li prevented and reversed the AMPH [Amphetamine] -induced increase in locomotor activity, and reversed AMPH-induced decreases in BDNF [Brain Derived Neurotrophic Factor] and GSH [glutathione] in the HC [Hippocampus], writing:

Conclusions: Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA’s possible antimanic effect.(65)

Low-Dose Nutritional Lithium for ADHD James Greenblatt, MD

In 2017, in his book, “Finally Focused”, Dr. James Greenblatt, who is an integrative child psychiatrist advocates for the use of Lithium in the treatment of ADHD, claiming lithium has neuroprotective properties, restores attention, minimizes hyperactivity, and helps eliminate ADHD drug side effects. Dr. James Greenblatt writes:

I continue to prescribe low-dose nutritional lithium to my patients. I use the treatment to stabilize mood. To help with addictions. To slow or stop memory loss in seniors. And I use it to effectively ease or erase irritability, anger, and aggression in children with ADHD…

A 4-year-old boy, Peter, had severe ADHD. Even at this young age, he was shunned by other children, and his parents were asked to remove him from preschool. It was easy to observe his aggressive behaviors in my office. A trace mineral analysis from a hair sample revealed no detectable lithium. I prescribed 250 mcg of lithium [daily] in liquid form. Peter’s annoying aggressiveness diminished. He became able to make friends, and eventually he began to participate cooperatively with other children in a new preschool…

Shawn at age 8 was often in trouble for bullying. Although he had been diagnosed with ADHD, stimulants had not been helpful. His trace mineral analysis showed no detectable lithium. On 2 mg of lithium orotate, he showed significant improvement, and he lost interest in bullying other children. (28) (66-68)

Dr. James Greenblatt recommends another supplment for ADHD kids called OPCs (Pycnogenol) derived from French Maritime pine bark, writing:

In over three decades of using OPCs to treat patients with ADHD, we have never observed any negative side effects associated with OPC supplementation. Instead, we have observed patients whose thinking becomes progressively clearer once they start taking OPCs. Count- less patients have also reported an improved ability to concentrate and maintain focus, a steady improvement in their ability to read, write, and listen, and parents of patients have shared anecdotal stories about improvements in behaviors at home and performance in school. (69)  Note: OPC= Oligomeric Proanthocyanidins.

Buy Lithium Orotate 1 mg Capsules: Lithium (orotate) 1 mg from Pure Encapsulations. Dosage is 1-2 mg/ day which is similar to average dietary intake

Buy Pycnogenol  Pure Encapsulations: Pycnogenol (OPC) proanthocyanidin extract, maritime pine bark.

Dr Breggin ADHD Drugs / ADHD Kids

Watch the video below: (70)
Peter Breggin, MD – ADHD Kids – A Lifelong Road to Tragedy.
Simple Truths about Psychiatry Vol. 8

Partial Transcript of the above video:

I am  Peter Beggin, I am a psychiatrist and this is one in my series of simple truths about psychiatry. I have already talked to you about stimulant drugs for children and now I want to talk to you about ADHD or attention deficit disorder but first remember that stimulant drugs don’t cure anything they don’t fix anything they don’t improve anything they cause biochemical imbalances in the brain that make children docile that take away their spontaneity and make them obsessively focus on things that they don’t care about . There’s no evidence that stimulant drugs improve anything past the first few weeks when they subdue behavior, there’s no improvement in academic performance, social life, how people feel about themselves, sports. These drugs should not be given to children. That’s the vast weight of scientific evidence that you can find in my books like psychiatric drug withdrawal and brain disabling treatments in psychiatry but now let’s go on to what is ADHD.

i want you to imagine you know maybe in your late twenties or thirties that you went back to school. Was it fun ? Do you remember going back to school and thinking, “wow it was great”? Not too many of us think like that. In fact, let’s suppose somebody said you could have a six-figure salary for 20 years and retire and all you would have to do is everything you did in school. You would just sit all day long in hard chairs with a desk in front of you. You would have one person teaching you all day long. You would have to raise your hand to go to the bathroom you wouldn’t be able to socialize. Would you do that for 20 years even for a good retirement ? You see ADHD is about what we’re trying to make our children do that they’re not comfortable willing or able to do. if you look in the diagnostic manual for what are the criteria for ADHD, they are about kids who are uncomfortable in class. The criteria include things like fidgeting in chairs, squirming in chair, cutting off the teacher to answer questions before she’s finished asking them, not standing in line, being too active.

What happened is that the drug companies actually created the diagnosis ADHD to sell it to teachers and say we have a medication that will get rid of all your difficulties in your classroom. They held workshops. They work to the department of education to do it. Now, is adhd a disease?  Well it can’t be a disease because, think about it, what might make a child fidget in class or be hyperactive in class or interrupt the teacher?  Why it could be almost anything. It could be that the child’s behind in class and uneasy and anxious because they can’t keep up it might be that the child’s the opposite of that that the child’s way ahead of class that the child’s thinking about things far beyond what’s going on in the classroom and is bored it could be that the teacher is boring.  Well maybe the teacher’s been depressed for years. Maybe the teacher doesn’t know how to have moral authority, get the kids to quiet down, and listen to her or maybe the child’s going through a divorce at home and is just anxious and fidgety and nervous and needy or maybe the child’s malnourished maybe the child has an underlying problem like head injury from sports. Because that can give you all the same kinds of activities. In other words, this list of behaviors doesn’t mean anything. In my experience it means the parents aren’t disciplining the child properly and within minutes in my office the child’s quiets down because I am giving intense attention really caring about the child. I am interested in what the child has to say and the parents learn how to engage a child right in front of their eyes or the child doesn’t have any problem at all but school is boring i’ve even seen children turn around overnight with a change of teacher.

So adhd is not a disease. It is not a disorder. But once you start giving a child drugs for ADHD you create all kinds of diseases and disorders children get depressed on the drugs, they get psychotic on the drugs. they lose weight, get skinny, weakened and fatigued on the drugs they lose interest in socializing on the drugs which is one of the main effects that the teachers often see as positive because the kid’s not trying to socialize in class anymore. Let me say in a word there is no disorder, there’s no disease. The drugs just flatten behavior. The great news is is that if your child has ADHD like symptoms your child is almost certainly either perfectly normal and bored in school or needs his parents to learn to discipline him better while also providing unconditional love. Read my book, Talking Back to Ritalin or the Ritalin Factbook and you will find everything I am saying is documented with dozens of references and you’ll find better approaches to helping your child be the normal kid he really is thank you.  (70)

71) Dr Breggin ADHD drugs PART ONE: watch you tube video

Partial Transcript of the Above Video:

Dr. Peter Breggin: Stimulant Drugs like Ritalin, Adderal and Concerta have a whole range of devastating effects. It is easier to show how bad they are than it is to show how good they are. First of all, they all suppress growth. And they do it not just by spoiling appetite like some doctors think, They do it by suppressing normal growth hormone cycles. That means the entire growth process of the child is disrupted by stimulants, so much so, that if you do a blood test, and the hormonal levels of growth hormone are normal, the kid is not taking his drug. That means every organ in the body including the brain is not growing normally in any child taking these drugs. Even if your kid is 5 foot 10, may your kid should have been 6 ft 4 inches. The point is we know from systematic studies without a doubt any more, the drugs suppress overall human growth.

Now, they are also highly addictive. They are Schedele II of the DEA which is reserved for the drugs that are most addictive in medicine. They are in the same category, according to the DEA, as morphine, cocaine. That not only means these drugs are addicitive, it also means these drug impact heavily on the brain.

The drugs change the brain. Studies in animals show persistant and probably permanent damage from drugs like ADDeral and Ritalin. The amphetamines and methylphenidate cause drastic biochemical changes that are long range.

In addition to these physical effects, these drugs are devastating from a psychiatric viewpoint. If you read the label for this drug, it will tell you do not give this medication to a child who is agitated or anxious, yet some doctors treat agitation and anxiety with these drugs. Many children become depressed on these drugs. [Depreesion in children is a tip off of the opposite effects of stimulants in children compared to adults where, in adults, amphetamines were the first mass marketed antidepressant in the 1940’s]

Children also develop insomnia and anxiety, obsessive compulsive disorder on these drugs. Your average pediatrician, internist or psychiatrist doesnt know and really isnt interested in all these side effects.  Instead of recognizing that these are drug effects, like apathy and anxiety, depression, even suicidality, the average doctor attibutes these symptoms to the child’s problems. So let us say you start your child on Ritalin or Adderal becasue you want your kid to get better grades, then your kid gets insomnia, so the doctor puts the child on Klonidine, which should never be given to children, never given with Adderal or ritalin, becasue it may cause heart attacks, but the doctor does it anyway. Now the kid is on two psych drugs, sleeping mediaciotn and stimulant medication, causing apathy and indifference. The kid is now depressed, so is then put on an antidepressant. There is powerful evidence that SSRI antidepressants cause suicide in kids. Black box warning for suicidality. Now the kid is on an anti-psychotic drug becasue stimulant drugs cause psychosis. (71)

Summary:

1) ADHD drugs suppress over all human growth, suppressing growth hormone cycles, brain is not growing normally

2) ADHD drugs are highly addictive: schedule II DEA same as morphine, cocaine, fentanyl.

3) ADHD Drugs changes the brain: animal studies show peristent, permanent brain damage.

4) Drug Label says do not give to child who is agitated or depressed.

5) Adverse effects of ADHD drugs: many children become depressed,  start having Insomnia, anxiety, OCD disorder.

6) The average pediatriciian does not recognize these adverse effects.

==========================

Part 2. Dr Breggin on ADHD Drugs

Partial Transcript, Dr. Peter Breggin on ADHD Drugs Part Two:

Dr. Peter Breggin: Stimulant drugs like Ritalin, Adderal and Concerta have a whole range of devastating effects. It is easier to show how bad they are than it is to show how good they are. First of all, they all suppress growth. And they do it not just by spoiling appetite like some doctors think, They do it by suppressing normal growth hormone cycles. That means the entire growth process of the child is disrupted by stimulants, so much so , that if you do a blood test, and the hormonal levels of growth hormone are normal, the kid is not taking his drug. That means every organ in the body including the brain is not growing normally in any child taking these drugs. Even if your kid is 5 foot 10, may your kid should have been 6 ft 4 inches.  The point is we know from systematic studies without a doubt any more, the drugs suppress overall human growth.

Now, they are also highly addictive. They are Schedele II of the DEA which is reserved for the drugs that are most addictive in medicine. They are in the same category, according to the DEA, as morphine, cocaine. That not only means these drugs are addictive, it also means these drug impact heavily on the brain.  The drugs change the brain. Studies in animals show persistant and probably permanent damage from drugs like Adderal and Ritalin. The amphetamines and methylphenidate cause drastic biochemical changes that are long range.

In addition to these physical effects, these drugs are devastating from a psychiatric viewpoint.
If you read the label for this drug, it will tell you do not give this medication to a child who is agitated or anxious, yet some doctors treat agitation and anxiety with these drugs. Many children become depressed on these drugs. [tip off of the opposite effects in children compared to adults where amphetamines were the first mass marketed antidepressant in the 1940’s]. They also develop insomnia and anxiety, obsessive compulsive disorder on these drugs. Your average pediatrician, internist or psychiatrist doesnt know and really isnt interested in all these side effects.
Instead of recognizing that these are drug effects, like apathy and anxiety, depression, even suicidality, the average doctor attibutes these symptoms to the child’s problems. So, let us say you start your child on Ritalin or Adderal becasue you want your kid to get better grades, then your kid gets insomnia, so the doctor puts the child on Clonidine, which should never be given to children, never given with Adderal or ritalin, becasue it may cause heart attacks, but the doctor does it anyway. Now the kid is on two psych drugs, sleeping medication and stimulant medication, causing apathy and indifference. The kid is now depressed, so is then put on an antidepressant. There is powerful evidence that SSRI antidepressants cause suicide in kids. SSRI drugs have a Black Box Warning for suicidality. Now the kid is on an anti-psychotic drug because stimulant drugs cause psychosis.

What is ADHD?  If you look at the list of symptoms contained in the official diagnostic manual, they are divided up into three groups:

1) hyperactivity (kid will not sit still in chair, gets up out of chair, wont stand on line)

2) inattention (kid does not pay attention to the board, doesnt hear the teacher talk, his mind wanders, writing peotry in his head instead of listening in class,

3) impulsivity, that contains my favorite one, interrupts the techer when she is asking a question before the question is even finished. I do that all the time when I am doing radio shows. I know what they are goind to ask me. I interrupt and give the answer.

What do all these things have in common?

They do not have in common an underlying disease preocess. They don’t spring from a common biological source. [I would add here that we now have an underlying process, namely hypervaccination with brain inflammation and immune dysregulation as an underlying cause of ADHD]

A List of Behaviors That Make Trouble for the Teacher

ADHD is actually a list of behaviors that actually make trouble for teachers, that cause teachers to have to pay attention to the child. What psychologists did was to look at all the minor behaviors in the classroom that cause a problem, talking out of turn, interrupting, not writing everything down, talking to your neighbor, all the minor stuff. And in order to sell drugs, they convinced teachers that this was a disorder. Now, when they give the drug, it doesnt matter what it is, Ritalin , Adderal, Stattera, Concerta, behavior is suppressed, lo and behold, next day in class, one dose, and little Johnny isnt doing much any more. Little Johnny is easier to be around. In fact, Little Johnny isnt there as much as he used to be becasue his brain has now been suppressed by the psych drug. [this is what research by Kimberly Urban found, stimulants have a paradoxical effect in children compared to adults, In adults they are stimulants. In children, they depress the prefrontal cortex activity].

We have a lot of scientific information proving how Ritalin and Adderal work. Thinks of a chimpanzee, because we do a lot of studies on chimps. They are like children. They like to groom, They like to play, to explore. They even hug and kiss. And if you put them in a cage, they want to get out. Now what happens when you give a chimp one of these psych drugs? They stop grooming each other. They stop playing . They stop smiling. They stop hugging and kissing, and they stop trying to escape. They become good caged animals. And, that is what we do to our children when we give them stimulant drugs. We make them good caged children. The effect may be subtle, or in some cases, and this is described in the medical literature, the child becomes “zombie-like”.

So you have a whole spectrum of behavior, but one of the things you can really see is, “the sparkle goes” , the spirit is diminished in its expression by these drugs. END  (72)

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Features of ADHD: hyperactivity, inattention, impulsivity. There is no common disease process. ADHD is a list of behaviors that make trouble to teachers. ADHD Drugs include:

Amphetamine Group- amphetamines block dopamine transporters and also increase vesicular release of dopamine into synaptic space.
amphetamine
dextroamphetamine
lisdexamfetamine

Brand names :
Adderall XR (generic available)
Dexedrine (generic available)
Dyanavel XR
Evekeo
ProCentra (generic available)
Vyvanse

Methamphetamine (Desoxyn) – highly addictive street drug used in ADHD

Methylphenidate Group – blocks the reuptake of norepinephrine and dopamine, increasing both at the synaptic space, amplyfying post synaptic signal.

Aptensio XR (generic available)
Metadate ER (generic available)
Concerta (generic available)
Daytrana – transdermal patch Methylphenidate
Ritalin (generic available)
Ritalin LA (generic available)
Methylin (generic available)
QuilliChew
Quillivant – liquid form of methylphenidate

Methylphenidate and the Developing Brain

In 2017, David Tonen writes about the Good, Bad and Ugly of “Smart Drugs” like methylphendate writing:

there’s no way to measure optimal levels of these neurotransmitters. So dosing methylphenidate (or any other stimulant) is mostly guess work…Methylphenidate is particularly popular in high schools and college campuses right around exam time. MPH helps you stay awake. And even helps with cognition and memory.[ix]

But there is growing evidence that methylphenidate plays havoc with the developing young brain.  Your prefrontal cortex is the region in your brain at the center for judgement control, behavior inhibition and control, emotion, logical thinking, working memory and decision making.  And continues to develop through to your late 20’s and early 30’s.[x] Studies show that using MPH early in life can alter circadian rhythms, increase anxiety that persists into adulthood, and even cause problems with object-recognition memory….[MPH researchers] were able to change the locomotor diurnal rhythm patterns, which suggests that these MPD [MPH] doses exerts long-term effects. (73-74)

In 2009, Dr. Min Lee studies repeated injection of methylphenidate (MPH) in female adolescent mice, finding long term effects, writing:

Adolescence is a time of critical brain maturation and development, and the drug exposure during this time could lead to lasting changes in the brain that endure into the adulthood. Circadian rhythms are 24 hour rhythms of physiological processes that are synchronized by the master-clock, the suprachiasmatic nucleus, to keep the body stable in a changing environment.  The obtained data showed that repeated administrations of 2.5 mg/kg and 10 mg/kg MPD were able to change the locomotor diurnal rhythm patterns, which suggests that these MPD doses exerts long-term effects. (74)

In 2020, Dr. York Williams published his book, “An Exploration of ADHD and Comorbidity With Substance Abuse and Brain Development. Dr. York Williams writes in Chapter 16:

Recent human and animal studies suggest MPH [Methylphenidate] alters the dopaminergic system with long-term effects beyond termination of treatment. (75)

In 2022, Dr.Javier Quintero reviewed the molecular characterisation of the mechanism of action of stimulant drugs lisdexamfetamine and methylphenidate on ADHD neurobiology, writing:

ADHD pathophysiology is largely unknown. (81)

In 2017 Dr. Felipe Schmitz studied chronic methylphenidate (MPH) given to juvenile mice, finding behavioral impairments and neuron and astrocyte loss in the hippocampus, the area involved in brain regeneration. The exploratory activity and object recognition memory of the mice were impaired by methylphenidate. Markers of microglial activation were increased, while BDNF (Brain Derived Neurotrophic Factor) was decreased, writing:

Results showed that chronic methylphenidate administration
caused loss of astrocytes and neurons in the hippocampus
of juvenile rats. BDNF and pTrkB immunocontents and NGF levels were decreased, while TNF-α and IL-6 levels, Iba-1 and caspase 3 cleaved immunocontents (microglia marker and active apoptosis marker, respectively) were increased…Both exploratory activity and object recognition memory were impaired by methylphenidate. These findings provide additional evidence that early-life exposure to methylphenidate can have complex effects, as well as provide new basis for understanding of the biochemical and behavioral consequences associated with chronic use of methylphenidate during central nervous system development ADHD is a complex neuropsychiatric disease characterized mainly by high levels of inattention, hyperactivity, and impulsivity [1–3]. However, recent studies have reported a large increase in the incidence of MPH misuse among young adults and students who do not meet the criteria for ADHD, in search of cognitive enhancement, in preschool children with 2–4 years of age. (82)

Articles with Related Interest:

ADHD Drugs, the Good, Bad and Ugly

Hypervacccination Autism and ADHD

Jeffrey Dach MD
750 Griffin Road Suite 180/190
Davie, Florida 33314
954 792 4663
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References:

1) Rasmussen, Nicolas. “America’s first amphetamine epidemic 1929–1971: a quantitative and qualitative retrospective with implications

2) Rasmussen, Nicolas. “Maurice Seevers, the stimulants and the political economy of addiction in American biomedicine.” BioSocieties 5 (2010): 105-123.

3) Rasmussen, Nicolas. “Weight stigma, addiction, science, and the medication of fatness in mid‐twentieth century America.” Sociology of health & illness 34.6 (2012): 880-895.

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14) Volkow, Nora D., et al. “Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder.” Journal of neuroscience 32.3 (2012): 841-849. Fig 1 shows decreased acitivity in ventral striatum after methylphenidate infusion (ivMP on right), indicating increased dopamine release at synaptic clefts

2023

15) Batstra, Laura, Martin Whitely, and Sami Timimi. “ADHD: Science and Society.” Frontiers in Psychiatry 13 (2023): 1129728.

If the science supporting ADHD diagnosis and treatments is weak and has not advanced significantly since 1980; What is driving increased ADHD diagnosis and treatment rates?

With the global ‘ADHD therapeutics market’ estimated to be worth US$29.56 billion in 2022—and expected to reach US$45.68 billion by 2027 (10)—perhaps the answer lies in thinking differently about ADHD. Instead of regarding it as an illness requiring medical intervention, it may be more insightful to understand ADHD as a marketable brand driven by economic and guild interests.

2017
16) Harding, Blake. “The Field Guide to ADHD: What They Don’t Want You to Know. Psychiatry–Theory, Applications and Treatments.” Online Submission (2017).

In the The Field Guide to ADHD: What They Don’t Want You to
Know, Harding confronts with unusual candor and painstaking effort one of the most alarming and perilous crises of our time: ADHD. In confronting this crisis, Harding forces us to reconsider the assumptions underlying ADHD and how we think about medical diagnoses, disability, health and authority. Harding unwraps these bewildering and conflicting ADHD issues while investigating the spiraling amount of overdiagnosed cases of ADHD, many often highly medicated and taught to conform rather than to thrive, no matter the individual or societal cost.

As Harding passionately argues, policy makers, healthcare
professionals, parents and other stakeholders are not only supporting the overdiagnosis of ADHD, but fundamentally thinking about ADHD all wrong.

2018

17) Gaidamowicz, Rima, et al. “ADHD-the scourge of the 21st century?.” Psychiatr Pol 52.2 (2018): 287-307.

Currently, attention deficit hyperactivity disorder (ADHD) is intensively studied by world medical community, its understanding expands, for example, it has now been diagnosed not only in children but also in adults. On the other hand, ADHD raises a number of discussions on the need of its treatment and, if there is a need, how it shall be treated, it is doubtful whether this disorder overall exists, because its “morphological component” has not been identified so far, and all the symptoms of ADHD, including anxiety, concentration difficulties, motor hyperactivity, cognitive disorders or social disadaptation, can be found in a number of mental disorders and somatic diseases. Modern attention, emotional and behavioral changes can be
considered as a result of changing human social portrait. Those who question ADHD existence argue that this disorder is likely temperament and parenting matter, rather than the illness, and that the diagnosis and treatment of this illness can be a matter invented by doctors and pharmacists, the aim of which is to tame individuals disregarding public standards of conduct and get the maximum profit from medicines in the treatment of this illness. Due to the fact that ADHD is diagnosed more often, it is even called the twenty-first-century scourge. In this article we will review the historical aspect of formation of ADHD diagnosis, illness etiology, comorbidity with other mental and somatic diseases as well as treatment necessity and opportunities, paying attention to adult ADHD as well.

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ADHD Drug induced PSYCHOSIS

18) Mosholder, Andrew D., et al. “Hallucinations and other psychotic symptoms associated with the use of attention-deficit/hyperactivity disorder drugs in children.” Pediatrics 123.2 (2009): 611-616.

CONCLUSIONS. Patients and physicians should be aware that psychosis or mania arising during drug treatment of attention-deficit/hyperactivity disorder may represent adverse drug reactions.

19) Shibib, Shatha, and Nevyne Chalhoub. “Stimulant induced psychosis.” Child and adolescent mental health 14.1 (2009): 20-23.

Background: Stimulants are used as a first line option in the treatment of ADHD …The potential for psychotic side effects are well known, but reported as rare.

Method: We are reporting four cases of stimulant induced psychosis which presented over a 2 year period in a small community CAMHS setting.

Results: Our findings suggest that stimulant induced psychosis occurs. The symptoms in the early stages of the psychotic episode mimicked ADHD. Long acting preparations appeared to be a contributory factor to the development of psychotic side effects. Rechallenge with stimulant medication is described.

Conclusion: Psychosis is an important, unpredictable side effect of stimulant medication. Symptoms resolve with discontinuation of treatment. Remergence of ADHD symptoms are rapid and rechallenge is often indicated.

About 9-10 percent of kids treated with Stimulants develope psychosis.

20) Cherland, Esther, and Renée Fitzpatrick. “Psychotic side effects of psychostimulants: a 5-year review.” The Canadian Journal of Psychiatry 44.8 (1999): 811-813.

Of the 98 children treated with stimulant medication, 9 children developed psychotic symptoms (Table 1).

Psychotic symptoms in the chart review appear to cluster in 3
groups: MPH-induced hallucinosis, slower-developing paranoia,
and mood-congruent psychotic symptoms. All 3 kinds
of psychotic side effects have been previously reported in
case reports of children (4,5,8,16).

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Peter Breggin MD   Nov 5, 2023

21) 80% Of Population Takes Psychiatric Drugs and Gets Worse
they end up with “subsequent” “long-term socioeconomic difficulties” “including lower income, unemployment, and increased likelihood to live alone and to be unmarried.” Dr. Peter and Ginger Breggin Nov 5, 2023 SUBSTACK,

Studies in the United States with children started on low doses of Ritalin (methylphenidate) in the 1970s for minimal symptoms of ADHD showed they did very poorly long-term. They had a lifetime decline in quality of life compared to controls, including stunted growth, lower IQ, less education, more psychiatric hospitalizations and imprisonments, obesity, and a shorter lifespan. Ritalin became a gateway to becoming lifelong mental patients on psychiatric drugs of every sort. Other studies have shown brain shrinkage from stimulant drugs given to children. I have reviewed the scientific literature demonstrating these outcomes in: Psychiatric Drug Withdrawal: A Guide for Prescribers, Therapists, Patients, and their Families.2

These long-term catastrophes are primarily caused by drug-induced neurotoxicity 3 but also by the stigmatization and demoralization from doctors telling the children and their parents that the children are genetically defective, have biochemical balances, and need the drugs — lies to get them to take the neurotoxins.

For many years, evidence has been increasing that taking psychiatric drugs is among the most dangerous risks in modern society. For decades, I have been explaining and documenting that psychiatric drugs overall do much more harm than good. The drug-induced dysfunction or damage causes “medication spellbinding” 4 — the inability of patients to fully perceive the harm the drugs are doing to them.5

22) Breggin, P. R. (1999a). Psychostimulants in the treatment of children diagnosed with ADHD: Part 1–Acute risks and psychological effects. Ethical Human Sciences and Services, 1(1), 13-33.

23) Breggin, P. R. (1999b). Psychostimulants in the treatment of children diagnosed with ADHD: Part II–Adverse effects on brain and behavior. Ethical Human Sciences and Services, 1(3), 213-242.

24) Breggin, P. R. (2000). Confirming the hazards of stimulant drug treatment. Ethical Human Sciences and Services, 2(3), 203-204.

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The “therapeutic” effects of stimulants are a direct expression of their toxicity.

25) Breggin, Peter R. “Psychostimulants in the treatment of children diagnosed with ADHD: Risks and mechanism of action.” International Journal of Risk & Safety in Medicine 12.1 (1999): 3-35.

Millions of children in North America are diagnosed with attention deficit/hyperactivity disorder and treated with psychostimulants such as methylphenidate, dextroamphetamine, and methamphetamine. These drugs produce a continuum of central nervous system toxicity that begins with increased energy, hyperalertness, and overfocusing on rote activities. It progresses toward obsessive/compulsive or perseverative activities, insomnia, agitation, hypomania, mania, and sometimes seizures. They also commonly result in apathy, social withdrawal, emotional depression, and docility. Psychostimulants also cause physical withdrawal, including rebound and dependence. They inhibit growth, and produce various cerebral dysfunctions, some of which can become irreversible. The “therapeutic” effects of stimulants are a direct expression of their toxicity. Animal and human research indicates that these drugs often suppress spontaneous and social behaviors while promoting obsessive/compulsive behaviors. These adverse drug effects make the psychostimulants seemingly useful for controlling the behavior of children, especially in highly structured environments that do not attend to their genuine needs.

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26) Confirming the hazards of stimulant drug treatment By Peter Breggin International Journal of Risk and Safety in Medicine, vol. 13, no. 4, pp. 199-200, 2000

Until recently, no studies have systematically examined the rate of psychotic symptoms caused by routine treatment with stimulant drugs such as methylphenidate (Ritalin) and amphetamine (Dexedrine, Adderall). Doctors who prescribe stimulant drugs often seem oblivious to the fact that they can cause psychoses, including manic-like and schizophrenic-like disorders. Without providing a scientific basis, the literature often cites rates of 1% or less for stimulant-induced psychoses (reviewed in [1,2]). Recently on television I debated a well-known expert in child psychiatry who took the position that prescribed stimulants “never” cause psychoses in children.

The rate of psychotic symptoms that first appear during stimulant treatment has recently been investigated in a 5-year retrospective study of children diagnosed with Attention Deficit Hyperactivity
Disorder (ADHD) [5]. Among 192 children diagnosed with ADHD at the Canadian clinic, 98 had been placed on stimulant drugs, mostly methylphenidate. Psychotic symptoms developed in more than 9% of the children treated with methylphenidate. According to Cherland and Fitzpatrick, “The symptoms ceased as soon as the medication was removed” [5, p. 812]. No psychotic symptoms were reported among the children with ADHD who did not receive stimulants. The psychotic symptoms caused by methylphenidate included hallucinations and paranoia. The authors conclude that, due to poor reporting, the rate of stimulant-induced psychosis and psychotic symptoms was probably much higher. In my practice of psychiatry, I am frequently consulted about children who are taking three, four, and sometimes five psychiatric drugs, including medications that are FDA-approved only for the treatment of psychotic adults. The drug treatment typically began when the children developed conflicts with adults at home or at school. In retrospect, the conflicts could easily have been resolved by interventions such as family counseling or individualized educational approaches. Usually under pressure from a school, the parents instead acquiesced to put their child on stimulants prescribed by psychiatrists, family physicians,
or pediatricians. When these children developed depression, delusions, hallucinations, paranoid fears and other drug-induced reactions while taking stimulants, their physicians mistakenly concluded that the children suffered from “clinical depression”, “schizophrenia” or “bipolar disorder” that had been “unmasked” by the medications. Instead of removing the child from the stimulants, these doctors mistakenly prescribed additional drugs, such as antidepressants, mood stabilizers, and neuroleptics. Children who were put on stimulants for “inattention” or “hyperactivity” ended up taking multiple adult psychiatric drugs that caused severe adverse effects, including psychoses and tardive dyskinesia. It is time to recognize that the supposedly increasing rates of “schizophrenia”, “depression”, and “bipolar disorder” in children in North America are often the direct result of treatment with psychiatric drugs. They should be classified as adverse drug reactions, not as primary psychiatric disorders. Doctors need to become more expert at identifying these adverse drug reactions in children and more aware of how and why to taper children from psychiatric medications [4]. When parents are willing to take a fresh approach to disciplining and caring for their children, or when the children’s school situation can be improved, it is usually possible to taper them off of all psychiatric medications. The parents are then relieved and gratified to see their children increasingly improve with the removal of each drug. What is the answer to this widespread, unwarranted use of medication in the treatment of children? As long as we respond to the signals of conflict and distress in our children by subduing them with drugs, we will not address their genuine needs. As parents, teachers, therapists, and physicians we need to retake responsibility for our children [3].We must reclaim them from the drug companies and their advocates in the medical profession. At the same time, we must address the needs of our children on an individual and societal level. On the individual level, children need more of our time and energy. Nothing can replace the personal relationships that children have with us as their parents, teachers, counselors, or doctors. On a societal level, our children need improved family life, better schools, and more caring communities.

Peter R. Breggin, M.D.
Director, International Center for the Study of Psychiatry and Psychology
4628 Chestnut Street, Bethesda, MD 29814, USA

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27) Sacrificing Depth for Speed  Dr. Sean Patrick Hatt, Integrative Psychology 2010

In spite of their seemingly ubiquitous presence, drugs used to treat ADHD are not at all similar to the caffeine in coffee or energy drinks. These are powerful pharmaceuticals that carry a long list of potentially serious risks, particularly in young people with still-developing brains.
Adverse drug reactions in stimulant formulas include impaired growth (Swanson, et al., 2007), insomnia, agitation, hypomania, mania, seizures, physical withdrawal, rebound effects, dependence (Breggin, 1999a, 1999b), and even psychosis (Breggin, 2000). Non-stimulant formulas also present safety problems, and their manufacturers were recently ordered by the United States Food and Drug Administration (FDA) to include a “black box” warning regarding the potential for increased suicidal ideation in adolescents (Carey, 2005). The black box was also subsequently ordered by the FDA for some popular stimulant formulas given an increased risk of sudden death (Pettypiece & Blum, 2006).

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Books:

28) Finally Focused: The Breakthrough Natural Treatment Plan for ADHD That Restores Attention, Minimizes Hyperactivity, and Helps Eliminate Drug Side Effects Paperback – May 9, 2017  by James Greenblatt MD (A Psychiatrist who treats ADHD children)

29) Talking Back to Ritalin: What Doctors Aren’t Telling You About Stimulants and ADHD Paperback – September 1, 2001
by Peter R. Breggin MD (A Psychiatrist who treats ADHD children)

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Anti-Oxidant treatment of ADHD

30) Verlaet, Annelies AJ, et al. “Rationale for dietary antioxidant treatment of ADHD.” Nutrients 10.4 (2018): 405.

Increasing understanding arises regarding disadvantages of stimulant medication in children with ADHD (Attention-Deficit Hyperactivity Disorder). This review presents scientific findings supporting dietary antioxidant treatment of ADHD and describes substantial alterations in the immune system, epigenetic regulation of gene expression, and oxidative stress regulation in ADHD.

As a result, chronic inflammation and oxidative stress could develop, which can lead to ADHD symptoms, for example by chronic T-cell-mediated neuroinflammation, as well as by neuronal oxidative damage and loss of normal cerebral functions.

Therefore, modulation of immune system activity and oxidant-antioxidant balance using nutritional approaches might have potential in ADHD treatment. The use of natural antioxidants against oxidative conditions is an emerging field in the management of neurodegenerative diseases. Dietary polyphenols, for example, have antioxidant capacities as well as immunoregulatory effects and, therefore, appear appropriate in ADHD therapy. This review can stimulate the development and investigation of dietary antioxidant treatment in ADHD, which is highly desired.

5.3. Pycnogenol
The herbal extract Pycnogenol®, derived from the bark of the French maritime pine (Pinus pinaster Aiton) [140], is composed of phenolic compounds, such as the monomers catechin and epicatechin,
as well as oligomeric and polymeric procyanidins [16,156]. An example of a procyanidin present in Pycnogenol® is procyanidin B1 (epicatechin-(4 !8)-catechin) [157]. This extract is standardized to contain 70  5% (w/w) procyanidins [139,158]. Studies indicate high bioavailability of the individual components of Pycnogenol®. For example, 46% of catechinmetabolites (glucuronides and sulphates)were recovered in urine [139]. Oral Pycnogenol® ingestion was detectable in plasma after a single dose of 300 mg and multiple doses of 200 mg although detection times in plasma differ per compound. Metabolite M1 (-(3,4-dihydroxy-phenyl)–valerolactone) is formed by bacterial metabolism from catechin [157,159]. This indicates that the components of Pycnogenol® can be modified during digestion and absorption as well as by the liver [139], which can both increase and decrease the actual effect in vivo. Therefore, in vitro results need to be interpreted with caution.
Pycnogenol® has multiple pharmacological effects such as  antihypertensive, anti-inflammatory and anti-diabetic effects [158]. Due to its antioxidant effect, it reduces oxidative stress and might be beneficial in ADHD [140]. Moreover, it was found to reduce histamine release from rat peritoneal mast cells [152]. Additionally, M1 is able to cross the BBB and other cell membranes, probably mediated by the GLUT-1 transporter [16,157]. This facilitated uptake also causes accumulation of M1, which is metabolized to glutathione adducts, in erythrocytes [157]. Most other external antioxidants are not effective in reducing oxidative stress in the brain, because they lack the ability to cross the BBB [62,160].

In children, Pycnogenol® administration caused positive effects on ADHD symptoms compared to placebo. Statistically significant enhanced concentration and reduced hyperactivity, as rated by the Child Attention Problems teacher rating scale, were found after 1 month of Pycnogenol® supplementation as well as improved visual-motoric coordination as rated by psychologists [16,140].

This effect could be related to a reduction of elevated catecholamine levels, as dopamine levels decreased in the urine of ADHD patients using Pycnogenol® and a trend of decreased epinephrine and norepinephrine levels was seen [5,14,16]. This could be linked to the stimulation of the enzyme endothelial nitric oxide synthase (eNOS), involved in the regulation of the release and uptake of norepinephrine and dopamine [16]. NO increase can also improve blood circulation in cerebral areas, which is impaired in ADHD [17].

However, on the contrary, inflammation is reduced by a suppression of iNOS [161]. In addition, Pycnogenol® increased the activity and expression of SOD, increased GSH levels and decreased GSSG levels, pointing towards less oxidative stress [162]. Also, an increase in
GSH reductase was found, which could explain the higher ratio of GSH/GSSG [140]. TAS levels of children with ADHD were increased to a normal level by Pycnogenol® administration [140,162],
while increased damage to DNA was lowered. It is therefore tempting to suggest that Pycnogenol® can be beneficial in ADHD because of its direct scavenging ability, chelating activity, stimulation of the DNA repair system and/or combinations thereof [140], but also due to its immune regulatory effects. However, this study had various limitations, including a short supplementation period and small placebo group [16].

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MPH is a Schedule II psychotropic controlled substance in same category as Fentanyl, Cocaine, Oxycontin

2013

31) Steiner, Dirk. “Unbagging Fidgety Philip. A pedagogical case pertaining a rethinking in dealing with syndromes of attention deficiency and/or hyperactivity in juveniles and infants.” RoSE–Research on Steiner Education 4.1 (2013).

An estimated ten to twelve million children are undergoing permanent medication with methylphenidate7 (MPH) in the United States at the present (Stolzer, 2012) 8.

Despite the questionable practice of putting children on a Schedule
II 9 categorised ‘psychotropic controlled substance’ (UN/INCB, 2003) as the remedy of choice—akin to a snort of cocaine 10, by the way—medicine very publically and quite literally won out over the critics and
those voicing misgivings—even though understandings and attempts at an explanation of the phenomenon of attention affecting syndromes have varied within scientific disciplines from the very beginning.

The so-considered ‘world-scale childhood and youth brain disorder of the new millennium’ so far, has only been manifested in a catalogue of behavioural patterns, such as ‘inattention’,‘impulsivity’, and, in some cases, ‘hyperactivity’ (ADHD Association, 2008)

Why, apparently, are such enormous numbers of our children suddenly reported to be ‘distracted’, ‘restless’, ‘hyperactive’—in brief—‘abnormal’? And where does this large-scale ‘genetically evoked brain defect’, effectively redefined as ‘ADHD’, the ‘most common disorder of childhood’ (Acosta et al., 2009; National Institutes of Health, 1998), suddenly come from? And what if attention affecting syndromes are in fact of environmental (i.e. socio-cultural) origin and are therefore a psychologic-pedagogical problem that has meanwhile been heavily—yet wrongfully—medicalised?

Now, almost three decades  [now four decades] after its first distribution, the societal danger and damage which the medication-dominated approach—as well as the existence of an ‘ADHD’ in general—is causing, are becoming more and more evident , and pedagogical concerns, as well as socio-political scruples and misgivings—official levels included—are nowadays getting ever louder .

Despite all efforts to prove the necessity and raison d’être of methylphenidate [MPH] , this becomes fairly obvious if one realises the fact that MPH [methyl phenidate] is not a ‘remedy’ that would cure anything, on the contrary, it is a psychotropic, mind-altering drug that temporarily suppresses a medical condition in order to enable those affected to function again in contemporary society And since we are talking about a problem relating to the psyche, heavy, potentially addictive, mind-altering drugs, while suppressing symptoms in the first
instance, will only worsen the mental condition itself. This leads to the conclusion that Ritalin, by itself, can actually never constitute an appropriate solution to our societal problems (cf. Leuzinger-Bohleber, Brandl, & Hüther, 2006).

Considering the explosively propagating practice of diagnosing of ‘ADHD’ and prescribing of MPH, this logical fact seems to have been widely misunderstood. Realistically, MPH constitutes a very convenient—yet radical—solution that is ruining the lives of millions of young people and thus devastating our societies. This kind of thinking and acting actually constitutes a regression

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32) Corporate Coverup? Whistleblower Doctor Alleges Shire Pharmaceuticals Neglected ADHD Drug Monitoring

THE MILLENNIAL PRESS Question Everything Corporate Coverup? Whistleblower Doctor Alleges Shire Pharmaceuticals Neglected ADHD Drug Monitoring Posted by on October 8, 2023

After paying out $56.5 million as part of the settlement with federal and state governments in 2014 for allegedly misleading the public, US and state agencies by claiming Adderall would ‘normalize’ its users and Vyvanse would provide ‘less abuse liability’, a former executive from Shire Pharmaceuticals (now Takeda Pharmaceutical Company), in charge of Data Science, has taken legal action against the company. The whistleblower, Dr. Vincent Polito

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Industry Sponsored research

Three authors are employees of Shire Pharmaceuticals, primary products, Adderall and Vyvanse , ADHD drugs. Shire struck gold in 2019 when Takeda Pharmaceutical Company purchased it for $62 billion. 

33) Shaw, M., et al. “Review of studies of ADHD: long-term outcomes with and without treatment.” European Psychiatry 26.S2 (2011): 579-579.

As awareness of ADHD has increased worldwide, interest has grown beyond the constellation of ADHD symptoms, to include long-term impact on people’s lives and society in general.
Objectives Examine the results of studies of long-term life consequences of ADHD.
Aims To identify areas of life affected long-term by ADHD and differences in outcomes with and without ADHD treatment.
Methods Following Cochrane guidelines, 12 databases were searched for studies published in English (1980–2010). Limiting criteria maximized study inclusion while maintaining high study rigor: (1) peer-reviewed, (2) primary study reports, (3) including a comparator condition, and (4) reporting long-term outcomes (mean 8 years, range 6 months-40 years from study start for prospective studies; subjects in adolescence or adulthood for retrospective or cross-sectional studies). The fully-defined electronic search yielded 4615 citations. Manual review based on titles and abstracts yielded 340 studies included in this analysis of outcomes.

Results The majority of studies (86%, 243 of 281; studies of untreated ADHD only) showed that untreated ADHD has substantial negative long-term outcomes, encompassing nine broad-ranging areas of life: non-medicinal drug use/addictive behaviour, antisocial behaviour, academic achievement, occupational achievement, public services use, self-esteem, social function, obesity, and driving outcomes.

In contrast, most studies including ADHD pharmacotherapy and/or non-pharmacotherapy (94%, 46 of 49) showed that compared with baseline or untreated ADHD, long-term outcomes improved or stabilized with treatment of ADHD.

Conclusions ADHD has notable negative long-term consequences, and this negative impact may be reduced with treatment of ADHD. Supported by Shire Development Inc.

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34) Shaw, Monica, et al. “A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment.” BMC medicine 10 (2012): 1-15.

Outcomes from 351 studies were grouped into 9 major categories: academic, antisocial behavior, driving, non-medicinal drug use/addictive behavior, obesity, occupation, services use, self-esteem, and social function outcomes. The following broad trends emerged: (1) without treatment, people with ADHD had poorer long-term outcomes in all categories compared with people without ADHD, and (2) treatment for ADHD improved long-term outcomes compared with untreated ADHD, although not usually to normal levels. Only English-language papers were searched and databases may have omitted relevant studies.
Conclusions

This systematic review provides a synthesis of studies of ADHD long-term outcomes. Current treatments may reduce the negative impact that untreated ADHD has on life functioning, but does not usually ‘normalize’ the recipients.

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++++++++++++++++ already copied over ++++++++++++++++

Methylphenidate

35) The Pharmacology of Cocaine, Amphetamines, and Other Stimulants
David A. Gorelick, MD, PhD Michael H. Baumann, PhD CHAPTER 10

All stimulants produce a similar range of psychological, behavioral, and physiologic effects, with the intensity and duration depending on potency, dose, route of administration, and duration of use (see Section 6, Chapter 46, “Management of Stimulant, Hallucinogen, Marijuana, Phencyclidine, and Club Drug Intoxication and Withdrawal”).

The initial effects—usually desired— include increased energy, alertness, and sociability; elation or euphoria; and decreased fatigue, need for sleep, and appetite (121). The intense pleasurable feeling has been described as a “total body orgasm” (122). These effects may occur after 5 to 20 mg of oral amphetamine, methamphetamine, or methylphenidate; 100 to 200 mg of oral cocaine; 40 to 100 mg of intranasal cocaine; or 15 to 25 mg of IV or smoked cocaine (122,123). Such single oral doses of stimulants improve cognitive and psychomotor performance in subjects whose performance has been impaired by fatigue, sleep deprivation, or alcohol, especially in tasks that require focused and sustained attention (vigilance) (123,124).

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MPH in mice- Brain Damage

Chronic use of MPH has long-term neurodegenerative consequences.

2012 Methylphenidate exposure induces dopamine neuron loss and activation of microglia

36) Sadasivan, Shankar, et al. “Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice.” PloS one 7.3 (2012): e33693.

Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia.

Through the use of stereological counting methods, we observed a significant reduction (∼20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing.

Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.

Enduring Changes in Neuro Glial Network

37) Cavaliere, Carlo, et al. “Methylphenidate administration determines enduring changes in neuroglial network in rats.” European Neuropsychopharmacology 22.1 (2012): 53-63.

Repeated exposure to psychostimulant drugs induces complex molecular and structural modifications in discrete brain regions of the meso-cortico-limbic system. This structural remodeling is thought to underlie neurobehavioral adaptive responses. Administration to
adolescent rats of methylphenidate (MPH), commonly used in attention deficit and hyperactivity disorder (ADHD), triggers alterations of reward-based behavior paralleled by persistent and plastic synaptic changes of neuronal and glial markers within key areas of the reward circuits. By immunohistochemistry, we observe a marked increase of glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expression and a down-regulation of glial glutamate transporter GLAST in dorso-lateral and ventro-medial striatum. Using electron microscopy, we find in the prefrontal cortex a significant reduction of the synaptic active zone length, paralleled
by an increase of dendritic spines. We demonstrate that in limbic areas the MPH-induced reactive astrocytosis affects the glial glutamatergic uptake system that in turn could determine glutamate receptor sensitization. These processes could be sustained by NO production and
synaptic rearrangement and contribute to MPH neuroglial induced rewiring.

repeated:

Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia.

Through the use of stereological counting methods, we observed a significant reduction (∼20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc.

Conclusion

Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.

MPH’s mechanism of action is to increase the availability of extracellular DA and NE in the synaptic cleft through blockade of the dopamine transporter (DAT) and norepinephrine transporter (NET) [12], [35], [36]

We found that chronic exposure to both 1 mg/kg and 10 mg/kg MPH increased the sensitivity of SNpc dopamine neurons to oxidative stress, based on a significantly increased SNpc dopamine neuron loss in mice administered MPH as compared to saline-treated control mice. Although the mechanism for this neuronal loss is unknown, a significant increase in MPH-induced activated microglia was observed; therefore, we hypothesize that an increase in free radical formation along with a concomitant neuroinflammatory response increases the sensitivity of the SNpc dopamine neurons to a later oxidative challenge. This conclusion is supported by a recent epidemiological study that showed that long-term amphetamine usage, which like MPH results in higher levels of striatal dopamine in the synaptic cleft, results in a significantly higher risk for developing Parkinson’s disease [51].

Taken together, our results suggest that chronic administration of methylphenidate in mice, at doses that approximate those at the higher therapeutic range in humans, results in a reduced expression of neurotrophic factors, increased neuroinflammation, and a small, but significant loss of SNpc dopamine neurons. These results can only be interpreted in the context on normal brain structure and function, and thus would have direct implications for the illicit/neurocognitive use of MPH. Since the underlying anatomy and biochemistry of ADHD has not been definitively characterized, our findings may or may not be generalizable to the vast majority of humans who are properly diagnosed with ADHD and are prescribed methylphenidate. Nevertheless, this work supports studies [51], [57], [58], [59] that demonstrate that drugs shown to increase the levels of dopamine in the synaptic cleft can contribute to degenerative changes in the basal ganglia.

38) Dendritic Spines:Wikipedia

A dendritic spine (or spine) is a small membranous protrusion from a neuron’s dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron’s cell body. Most spines have a bulbous head (the spine head), and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons.[1] It has also been suggested that changes in the activity of neurons have a positive effect on spine morphology.[2]

experimental findings that suggest a role for dendritic spine dynamics in mediating learning and memory,

In particular, long-term memory is mediated in part by the growth of new dendritic spines (or the enlargement of pre-existing spines) to reinforce a particular neural pathway. Because dendritic spines are plastic structures whose lifespan is influenced by input activity,[21] spine dynamics may play an important role in the maintenance of memory over a lifetime.

Neurogenesis: impact of juvenile mice MPH exposure on adult hippocampal neurogenesis. Decreased Adult neurogenesis in the hippocampus.= BRAIN DAMAGE !!!!

39) Lagace, Diane C., et al. “Juvenile administration of methylphenidate attenuates adult hippocampal neurogenesis.” Biological psychiatry 60.10 (2006): 1121-1130.

Background: The neural consequences of early-life exposure to methylphenidate (MPH; Ritalin) are of great interest given the widespread, and sometimes inappropriate, use in children. Here we examine the impact of juvenile MPH exposure on adult hippocampal neurogenesis.

Methods: Rats received MPH (2.0 mg/kg, intraperitoneal, twice daily) or saline (SAL) during preadolescence (postnatal days 20-35). Hippocampal cell proliferation (Experiment 1), neurogenesis (Experiment 2), and stress-induced changes in cell proliferation (Experiment 3) were assessed at several developmental stages including adulthood.

Results: Juvenile exposure to MPH did not alter proliferation at any developmental time point relative to control rats; however, exposure to MPH significantly decreased the long-term survival of newborn cells in adult rats, particularly in the temporal hippocampus. Although MPH-treated rats had higher levels of corticosterone after restraint stress, they did not show the expected greater decrease in hippocampal cell proliferation relative to control animals.

Conclusions: Early-life exposure to MPH inhibits the survival of adult-generated neurons in the temporal hippocampus and may reduce progenitor sensitivity to corticosterone-induced decreases in proliferation. These findings suggest that decreased adult neurogenesis is an enduring consequence of early-life exposure to MPH and are discussed for their relevance to humans.

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prolonged ADHD medication use at higher doses is significantly associated with smaller hippocampus volumes in specific subregions.

40) Fotopoulos, Nellie H., et al. “Cumulative exposure to ADHD medication is inversely related to hippocampus subregional volume in children.” NeuroImage: Clinical 31 (2021).

Structural neuroimaging studies comparing ADHD children to neurotypical children identified group differences in cortical and subcortical brain regions (Albajara Saenz, Villemonteix, & Massat, 2018). A landmark study by Shaw et al. 2007 reported a delay in peak cortical maturation of 3.5 years in children with ADHD, most apparent in prefrontal regions (Shaw et al., 2007). A mega-analysis by Hoogman et al. 2017 reported reduced volumes in the accumbens, amygdala, hippocampus, putamen, and overall brain in comparison to control children (Hoogman et al., 2017). However, there is considerable variability across neuroimaging studies in ADHD, as one meta-analysis found that only 25–50% of published reports had reproducible results (Frodl & Skokauskas, 2012). Since pharmacological agents are commonly used to treat ADHD symptoms, it is important to assess their impact on brain structure. If exposure to ADHD medication significantly alters brain structure measurements, it might provide partial explanation for the varying results across ADHD imaging studies.

Taken together, these studies do not provide evidence for abnormal brain development following exposure to ADHD medication. Rather, they highlight the confusing state of the literature where medication is reported as having either no effect on brain structure or as having a normalizing effect brain structure

studies have reported hippocampus volume reductions in adults with ADHD who had, during childhood, been treated with ADHD medication (Frodl and Skokauskas, 2012, Onnink et al., 2014). These findings were not observed in stimulant-naïve adults with ADHD. Frodl and Skokauskas (2012) have suggested that changes in smaller regions, such as the hippocampus, may go undetected as large threshold corrections for the whole brain are typically used (Frodl & Skokauskas, 2012). Moreover, in the relatively few studies that have included the hippocampus when assessing medication effects, no studies have sought to investigate subregions.

Five children with ADHD were concurrently prescribed anti-psychotics and were excluded from the final analysis (ADHD n = 101). The number of independent prescriptions for ADHD medication per child was one (n = 7), two (n = 34), three (n = 21), four (n = 18) and five (n = 21). A total of 315 prescriptions were included: Ritalin® (35.2%), Biphentin® (32.4%), Concerta® (22.6%), Vyvanse® (5.7%), Strattera® (2.5%) and Adderall® (1.6%).

Conclusions Although this study is cross-sectional, the results found within this sample of children show that prolonged ADHD medication use at higher doses is significantly associated with smaller hippocampus volumes in specific subregions.
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41) Svetlov, Stanislav I., Firas H. Kobeissy, and Mark S. Gold. “Performance enhancing, non-prescription use of Ritalin: a comparison with amphetamines and cocaine.” Journal of addictive diseases 26.4 (2007): 1-6.

Ritalin, known under chemical name methylphenidate (MPH), is a psychostimulant prescribed to treat attention-deficit/hyperactivity disorder (ADHD) and other conditions. Psychotropic effects and pharmacological pathways evoked by MPH are similar, but not identical to those produced by amphetamines and cocaine. Although not completely understood in detail, MPH psychostimulation is mediated by the increase of central dopamine (DA) and possibly norepinephrine (NE) and serotonin (ST) due to decrease of their re-uptake via binding to and inhibition of DA, NE, and ST transporters. Despite similarity in psychopharmacological effects, the rewarding/ reinforcing ability of MPH appears to be significantly lower than amphetamines and especially cocaine. MPH and similar medications have been widely used on College campuses and by students preparing for exams. Nicknamed ‘steroids for SATs,’ MPH and related medications are purchased without prescription and their use may even be encouraged by parents and tutors. However, while widely and safely used and administered for over forty years, Ritalin generated significant controversy including MPH abuse and addiction, and adverse reactions. It is now clear that treatment of ADD/ADHD with psychostimulants prevents drug abuse and addictions. Use by those without any medical or psychiatric diagnosis is increasing. In this mini-review, we discuss psychopharmacological and behavioral aspects, and outline neurochemical mechanisms that may provoke Ritalin abuse, addiction and adverse effects compared to amphetamines and cocaine.

42) Kim, Yong, et al. “Methylphenidate-induced dendritic spine formation and ΔFosB expression in nucleus accumbens.” Proceedings of the National Academy of Sciences 106.8 (2009): 2915-2920.

Methylphenidate is the psychostimulant medication most commonly prescribed to treat attention deficit hyperactivity disorder (ADHD). Recent trends in the high usage of methylphenidate for both therapeutic and nontherapeutic purposes prompted us to investigate the long-term effects of exposure to the drug on neuronal adaptation. We compared the effects of chronic methylphenidate or cocaine (15 mg/kg, 14 days for both) exposure in mice on dendritic spine morphology and ΔFosB expression in medium-sized spiny neurons (MSN) from ventral and dorsal striatum. Chronic methylphenidate increased the density of dendritic spines in MSN-D1 (MSN-expressing dopamine D1 receptors) from the core and shell of nucleus accumbens (NAcc) as well as MSN-D2 (MSN-expressing dopamine D2 receptors) from the shell of NAcc. In contrast, cocaine increased the density of spines in both populations of MSN from all regions of striatum. In general, the effect of methylphenidate on the increase of shorter spines (class 2) was less than that of cocaine. Interestingly, the methylphenidate-induced increase in the density of relatively longer spines (class 3) in the shell of NAcc was bigger than that induced by cocaine. Furthermore, methylphenidate exposure increased expression of ΔFosB only in MSN-D1 from all areas of striatum, and surprisingly, the increase was greater than that induced by cocaine. Thus, our results show differential effects of methylphenidate and cocaine on neuronal adaptation in specific types of MSN in reward-related brain regions.

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methylphenidate ADHD

MPH may induce long-lasting alterations in the adult mPFC GABAergic system when treatment was started at a young age.

43) Solleveld, Michelle M., et al. “Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients.” NeuroImage: Clinical 15 (2017): 812-818.

First stimulant exposure at a young age is thus associated with lower baseline levels of GABA+ and increased responsivity in adulthood. This effect could not be found in patients that started treatment at an adult age. Hence, while adult stimulant treatment seems to exert no major effects on GABA+ levels in the mPFC, MPH may induce long-lasting alterations in the adult mPFC GABAergic system when treatment was started at a young age.

• Early stimulant exposure results in lower baseline PFC GABA levels in adulthood.
• Exposure at young age alters the GABAergic response to stimulants in adulthood.
• First exposure to stimulants in adulthood exerts no major effects.

In conclusion, our results demonstrate that MPH effects on GABA+ levels in ADHD patients are influenced by whether a subject had first started stimulant treatment in childhood or in adulthood. Our data thus suggest that long-lasting alterations may have occurred in GABAergic neurotransmission in the mPFC, selectively in subjects who had been first exposed to stimulant treatment early during childhood, but not in those who started medication only from later in their lives onward. Future studies are therefore warranted to assess the underlying mechanisms as well as the consequences of these lower GABA+ levels on cognitive and behavioral problems in ADHD.

44) Brookshire, Bethany R., and Sara R. Jones. “Chronic methylphenidate administration in mice produces depressive‐like behaviors and altered responses to fluoxetine.” Synapse 66.9 (2012): 844-847.

Methylphenidate (MPH) is a psychostimulant used in the treatment of attention-deficit/hyperactivity disorder in children and adults. Increasing abuse rates of this drug have raised questions regarding the effects of chronic, high-dose MPH administration. Although the effects of chronic MPH exposure have been well-documented in regard to reward-related behaviors in adolescent and adult animals, there are few studies of the effects of MPH on depressive-like behaviors and antidepressant responses, particularly in adult models. We examined the effects of chronic (14 days) high-dose (20 mg/kg i.p.) MPH exposure on locomotor activity and forced swim test behavior in C57Bl/6J mice. We show that MPH treatment ameliorates the locomotor suppression seen in response to fluoxetine. In addition, chronic MPH treatment produces depressive-like effects in the forced swim test, with decreased latency to first immobility and a trend toward increased immobility. These effects are reversed with acute fluoxetine administration, in contrast to saline-treated animals, which show no response to fluoxetine. The induction of depressive-like behaviors after chronic MPH treatment in adult mice is in agreement with previous studies in adolescent rats, and the marked alterations in fluoxetine responses implicate alterations in the serotonin system and possibly the dopamine system produced by MPH.

45) Carlezon Jr, William A., Stephen D. Mague, and Susan L. Andersen. “Enduring behavioral effects of early exposure to methylphenidate in rats.” Biological psychiatry 54.12 (2003): 1330-1337.

Background: Methylphenidate (MPH) is a stimulant prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulant drugs can cause enduring behavioral adaptations, including altered drug sensitivity, in laboratory animals. We examined how early developmental exposure to stimulants affects behavior in several rodent models.

Methods: Rats received MPH or cocaine during preadolescence (P20-35). Behavioral studies began during adulthood (P60). We compared how early exposure to MPH and cocaine affects sensitivity to the rewarding and aversive properties of cocaine using place conditioning. We also examined the effects of early exposure to MPH on depressive-like signs using the forced swim test, and habituation of spontaneous locomotion, within activity chambers.

Results: In place-conditioning tests, early exposure to MPH or cocaine each made moderate doses of cocaine aversive and high doses less rewarding. Early MPH exposure also caused depressive-like effects in the forced swim test, and it attenuated habituation to the activity chambers.

Conclusions: Early exposure to MPH causes behavioral changes in rats that endure into adulthood. Some changes (reduced sensitivity to cocaine reward) may be beneficial, whereas others (increases in depressive-like signs, reduced habituation) may be detrimental. The effects of MPH on cocaine-related behaviors may be a general consequence of early stimulant exposure.

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ADHD and MTHFR

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46) Nancy Mullan, MD MTHFR+ and ADHD

Free ebook on MTHFR https://www.nancymullanmd.com/ebook-form

All of the symptoms of ADHD are associated with MTHFR mutations, including the impaired immunity that predisposes ADHD sufferers to have an increased incidence of ear infections. ADHD is on the autism spectrum, and 98% of individuals with Autism Spectrum Disorder have at least one MTHFR mutation

Diet is the foundation of heath no matter what you are trying to treat. Double handfuls of nutritional supplements will not overcome a problem with diet. The solution also involves getting genetic testing, subsequent additional testing to determine body biochemistry, and nutritional supplements to address the problems uncovered. 
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47) Dr RoseAnn MTHFR and ADHD

The MTHFR genetic mutation is important in clinical conditions because it has been linked to various health issues, including ADHD, OCD, anxiety, and depression (Wan et. al., 2018).

Studies have suggested a possible connection between MTHFR genetic mutations and an increased risk for ADHD. The MTHFR gene plays a critical role in folate metabolism, which is essential for the production of neurotransmitters such as serotonin, dopamine, and norepinephrine. These neurotransmitters play important roles in regulating mood, attention, and behavior, and disruptions in their function have been implicated in the development of ADHD.

The mechanisms behind this association are not yet fully understood, but research suggests that MTHFR genetic mutations may lead to reduced folate metabolism, which in turn can impact neurotransmitter production and function. Reduced levels of neurotransmitters such as dopamine and norepinephrine have been implicated in ADHD, suggesting a possible link between MTHFR genetic mutations and the disorder.

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48) MTHFR: The Link Between ADD/ADHD, Folate, and Genetics June 28, 2016

Adolescents 13-18, Anxiety, Autism, Children 5-12, Vitamins and Supplements by Cori Burke, ND
Dr. Cori Burke is a Naturopathic Physician and graduate of the National University of Natural Medicine.
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MTHFR

49) Why ADHD & Learning Disabilities Can ‘Run in the Family’ & What You Can Do: Understanding the MTHFR Gene
info@lorrainedriscoll.com January 14, 2020

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Amphetamines

50) Selemon, Lynn D., et al. “Amphetamine sensitization alters dendritic morphology in prefrontal cortical pyramidal neurons in the non-human primate.” Neuropsychopharmacology 32.4 (2007): 919-931.

Amphetamine (AMPH) sensitization in the nonhuman primate induces persistent aberrant behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, psychomotor depression, and profound cognitive impairment. The present study examined whether AMPH sensitization induces similarly long-lasting morphologic alterations in prefrontal cortical pyramidal neurons. Three to 3½ years postsensitization, sensitized, and AMPH-naïve control monkeys were killed. Blocks of prefrontal cortex were Golgi-impregnated for elucidation of pyramidal dendritic morphology in layers II/superficial III (II/IIIs), deep III, and V/VI. In AMPH-sensitized animals as compared to AMPH-naïve controls, pyramidal dendrites in layer II/IIIs exhibited reduced overall dendritic branching and reduced peak spine density (22%) on the apical trunk. Across all layers, the distance from soma to peak spine density along the apical trunk was decreased (126.38±7.65 μm in AMPH-sensitized compared to 162.98±7.26 μm in AMPH-naïve controls), and basilar dendritic length was reduced (32%). These findings indicate that chronic dopamine dysregulation, consequent to AMPH sensitization, results in enduring, atrophic changes in prefrontal pyramidal dendrites that resemble the pathologic alterations described in patients with schizophrenia and may contribute to the persistence of schizophrenia-like behavioral changes and cognitive dysfunction associated with sensitization. These findings may also provide key insights into the etiologic origin of the pronounced behavioral disturbances and cognitive dysfunction associated with schizophrenia.

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Hippocampus

51) Arroyo-García, Luis Enrique, et al. “Amphetamine sensitization alters hippocampal neuronal morphology and memory and learning behaviors.” Molecular Psychiatry 26.9 (2021): 4784-4794.

Another LINK to Entire Paper

An increase in the dopaminergic tone caused by AMPH sensitization generates oxidative stress, neuronal death, and morphological changes in the hippocampus that affect cognitive behaviors like short- and long-term memories.

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52) Tendilla-Beltrán, Hiram, Luis Enrique Arroyo-García, and Gonzalo Flores. “Amphetamine and the Biology of Neuronal Morphology.” Handbook of Substance Misuse and Addictions: From Biology to Public Health. Cham: Springer International Publishing, 2022. 1-24.

Amphetamines are widely used psychostimulants for both therapeutic and recreational purposes. These drugs enhance monoaminergic neurotransmission. Amphetamines increase dopamine, noradrenaline, and serotonin availability in the synaptic cleft, mainly by the reverse action of the monoamine transporters (MATs), which in physiological conditions are the main mechanism for monoamine recapture. Moreover, monoamines are closely related to the reward system, which is an ensemble of corticolimbic structures that hierarchizes sensory information according to motivation or pleasure. It has been widely studied the increased motor behavioral effects after repeated and intermittent amphetamine exposure, described as behavioral sensitization, which is part of the complex addictive behavior. Interestingly, amphetamines have neuroplasticity effects, since chronic exposure to these drugs hypertrophies the dendritic arbor and increases the number of dendritic spines in neurons of the corticolimbic system. Also, amphetamines induce oxidative stress. These neuronal impairments can be related to the memory and learning disturbances and ultimately to the behavioral sensitization induced by amphetamine exposure.

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Damage to dopaminergic neurons in striatum monkeys

53) Ricaurte, George A., et al. “Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates.” Journal of Pharmacology and Experimental Therapeutics 315.1 (2005): 91-98.

Pharmacotherapy with amphetamine is effective in the management of attention-deficit/hyperactivity disorder (ADHD), now recognized in adults as well as in children and adolescents. Here we demonstrate that amphetamine treatment, similar to that used clinically for adult ADHD, damages dopaminergic nerve endings in the striatum of adult nonhuman primates. Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity in nonhuman primates are on the order of those reported in young patients receiving amphetamine for the management of ADHD. These findings may have implications for the pathophysiology and treatment of ADHD. Further preclinical and clinical studies are needed to evaluate the dopaminergic neurotoxic potential of therapeutic doses of amphetamine in children as well as adults.

54) Gerlach, Manfred, Edna Grünblatt, and Klaus W. Lange. “Is the treatment with psychostimulants in children and adolescents with attention deficit hyperactivity disorder harmful for the dopaminergic system?.” ADHD Attention Deficit and Hyperactivity Disorders 5 (2013): 71-81.

Reduces BDNF

A major concern regarding psychostimulant medication (amphetamine and methylphenidate) in the treatment of children and adolescents with attention deficit/hyperactivity disorder (ADHD) are the potential adverse effects to the developing brain, particularly in regard to dopaminergic brain function. The present review focuses on the pharmacology of these psychostimulants, their mode of action in the human brain and their potential neurotoxic effects to the developing brain in animals, particularly concerning DA brain function. The potential clinical significance of these findings for the treatment of ADHD in children and adolescents is discussed. Studies on sensitization to psychostimulants’ rewarding effects, which is a process expected to increase the risk of substance abuse in humans, are not included. The available findings in non-human primates support the notion that the administration of amphetamine and methylphenidate with procedures simulating clinical treatment conditions does not lead to long-term adverse effects in regard to development, neurobiology or behaviour as related to the central dopaminergic system.

55) Angelucci, Francesco, et al. “Chronic amphetamine treatment reduces NGF and BDNF in the rat brain.” European Neuropsychopharmacology 17.12 (2007): 756-762.

see (63)

Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia.

56) Advokat, Claire. “Literature review: Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD.” Journal of Attention Disorders 11.1 (2007): 8-16.

Objective: A review of amphetamine treatment for attention-deficit/hyperactivity disorder (ADHD) was conducted, to
obtain information on the long-term neurological consequences of this therapy. Method: Several databases were accessed for research articles on the effects of amphetamine in the brain of laboratory animals and ADHD diagnosed individuals. Results: In early studies, high doses of amphetamine, comparable to amounts used by addicts, were shown to damage dopaminergic pathways. More recent studies, using therapeutic regimens, appear contradictory. One paradigm shows significant decreases in striatal dopamine and transporter density after oral administration of “therapeutic” doses in primates. Another shows morphological evidence of “trophic” dendritic growth in the brains of adult and juvenile rats given systemic injections mimicking “therapeutic” treatment. Imaging studies of ADHD-diagnosed individuals show an increase in striatal dopamine transporter availability that may be reduced by methylphenidate treatment. Conclusion: Clarification of the neurological consequences of chronic AMPH treatment for ADHD is needed.

57) Bourgeois, Florence T., Jeong Min Kim, and Kenneth D. Mandl. “Premarket safety and efficacy studies for ADHD medications in children.” PLoS One 9.7 (2014): e102249.

Conclusions: Clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events or long-term safety and efficacy.

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2022

58) Mechler, Konstantin, et al. “Evidence-based pharmacological treatment options for ADHD in children and adolescents.” Pharmacology & Therapeutics 230 (2022): 107940.

statistically significant reduction in height and weight gain

Findings from longitudinal studies indicate that treatment with psychostimulants is associated with a statistically significant reduction in height and weight gain (Cortese et al., 2018; Faraone, Biederman, Morley, & Spencer, 2008; Greenhill et al., 2020; Swanson et al., 2017).

Lisdexamfetamine dimesylate is a prodrug that is metabolized to dextroamphetamine and is available as Vyvanse.

While short-term efficacy and safety of both stimulants and non-stimulants have been soundly demonstrated in various clinical trials (Banaschewski et al., 2006; Cortese et al., 2018; Faraone & Buitelaar, 2009; Padilha, Virtuoso, Tonin, Borba, & Pontarolo, 2018; Reed et al., 2016; Savill et al., 2015), a comparable extent of systematic assessments for longer-term outcomes is not yet available.

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59) Teixeira-Gomes, Armanda, et al. “The neurotoxicity of amphetamines during the adolescent period.” International Journal of Developmental Neuroscience 41 (2015): 44-62.

Amphetamine-type psychostimulants (ATS), such as amphetamine (AMPH), 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) are psychoactive substances widely abused, due to their powerful central nervous system (CNS) stimulation ability. Young people particularly use ATS as recreational drugs. Moreover, AMPH is used clinically, particularly for attention deficit hyperactivity disorder, and has the ability to cause structural and functional brain alterations. ATS are known to interact with monoamine transporter sites and easily diffuse across cellular membranes, attaining high levels in several tissues, particularly the brain. Strong evidence suggests that ATS induce neurotoxic effects, raising concerns about the consequences of drug abuse. Considering that many teenagers and young adults commonly use ATS, our main aim was to review the neurotoxic effects of amphetamines, namely AMPH, MDMA, and METH, in the adolescence period of experimental animals. Reports agree that adolescent animals are less susceptible than adult animals to the neurotoxic effects of amphetamines. The susceptibility to the neurotoxic effects of ATS seems roughly located in the early adolescent period of animals. Many authors report that the age of exposure to ATS is crucial for the neurotoxic outcome, showing that the stage of brain maturity has a strong importance. Moreover, recent studies have been undertaken in young adults and/or consumers during adolescence that clearly indicate brain or behavioural damage, arguing for long-term neurotoxic effects in humans. There is an urgent need for more studies during the adolescence period, in order to unveil the mechanisms and the brain dysfunctions promoted by ATS.

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60) Krasnova, Irina N., and Jean Lud Cadet. “Methamphetamine toxicity and messengers of death.” Brain research reviews 60.2 (2009): 379-407.

Methamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, loss of gray matter accompanied by hypertrophy of the white matter and microgliosis in different brain areas. In the present review, we summarize data on the animal models of METH neurotoxicity which include degeneration of monoaminergic terminals and neuronal apoptosis. In addition, we discuss molecular and cellular bases of METH-induced neuropathologies. The accumulated evidence indicates that multiple events, including oxidative stress, excitotoxicity, hyperthermia, neuroinflammatory responses, mitochondrial dysfunction, endoplasmic reticulum stress converge to mediate METH-induced terminal degeneration and neuronal apoptosis. When taken together, these findings suggest that pharmacological strategies geared towards the prevention and treatment of the deleterious effects of this drug will need to attack the various pathways that form the substrates of METH toxicity.

Concluding Remarks

In summary, the brains of human METH addicts, who abuse large doses of the drug, are characterized by a variety of neuropathological changes. These include degeneration of monoaminergic terminals, dysregulation of energy metabolism, evidence of oxidative stress, as well as microgliosis and reactive astrogliosis. The deleterious effects of the drug have been consistently replicated in animal models. These studies have helped to identify some of the pathways that form the mechanistic substrates for METH-induced damage to monoaminergic terminals. Similarly, recent investigations have clarified the bases for neuronal apoptosis caused by METH exposure in various regions of the mammalian brain. This knowledge is just beginning to impact on the thinking regarding how to best approach the development of potentially effective therapeutic strategies that will address the neurological and psychiatric deterioration observed in some METH addicts. The use of therapeutic agents that address solely the addictive properties of METH might not be sufficient to attenuate the varied neuropathological end-points caused by the use of the drug. One possibility might be the need to combine therapeutic anti-addictive drugs with neuroprotective agents within the same clinical setting where these patients are being treated. The combination of anti-addictive agents with the anti-manic drug, lithium, that has been shown to have neuroprotective properties (Chuang, 2004), might be a fruitful approach to the treatment of METH abusers. In any case, more studies are needed in order to further clarify strategies that might serve to promote recovery of monoaminergic systems in models of METH toxicity.

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61) Steinkellner, Thomas, et al. “The ugly side of amphetamines: short-and long-term toxicity of 3, 4-methylenedioxymethamphetamine (MDMA,‘Ecstasy’), methamphetamine and D-amphetamine.” (2011): 103-115.

Amphetamines exert their acute effects both in the central nervous system (CNS) and in peripheral tissues. The acute clinical outcome is dependent upon the dose administered and typically includes positively prescribed

subjective effects such as an increased state of arousal, euphoria, increased energy and talkativeness, but also negative emotions including anxiety, paranoia or auditory and visual hallucinations (Baylen and Rosenberg 2006; Cruickshank and Dyer, 2009).

The peripheral effects of amphetamines are primarily mediated by its interaction with the noradrenaline transporter (NAT) and are associated with an increase in extracellular noradrenaline (NA) concentrations. These effects include increases in heart rate, blood pressure, respiration rate, body temperature, psychomotor activation and reduced appetite (Boenisch and Bruess, 2006; Cruickshank and Dyer, 2009). It is the sympathomimetic stimulating effect of amphetamines which renders them attractive as doping agents (Docherty, 2008).

Amphetamines also increase locomotor activity, an effect which can be enhanced by the repeated administration of the drug. This hyperactivity is referred to as ‘behavioural sensitisation’ and is neurochemically correlated with an increase in striatal DA release. It can persist for several months following the last drug administration, thereby mimicking the sensitised states of human psychostimulant abusers (Paulson and Robinson, 1995; Pierce and Kalivas, 1997).

Taken together, these observations are consistent with a cellular model where amphetamine action in mesocorticolimbic dopaminergic neurons is the fundamental mechanism contributing to their reinforcing and addictive properties (Nestler, 2005; Kalivas, 2007).

Chronic METH abuse leads to the degeneration of monoaminergic terminals (Davidson et al., 2001; Krasnova and Cadet, 2009) and reduced DAT and DA levels in the striatum of mice, rats and monkeys (Anderson and Itzhak, 2006; Graham et al., 2008; Melega et al., 2008). Similar effects have been reported in people subjected to positron emission tomography (PET) (Volkow et al., 2001).

Amphetamines and psychotic episodes

One of the prime findings in amphetamine abuse is the induction of psychotic episodes that are almost indistinguishable from the positive symptoms seen in schizophrenic patients (Ujike and Sato, 2004; Hermens et al., 2009). This supports the conjecture that there might be a link between amphetamine abuse and the psychopathic traits observed in schizophrenia.

psychostimulants such as d-AMPH or METH can increase the susceptibility of users to psychotic symptoms either during acute amphetamine abuse or during withdrawal (Ujike and Sato, 2004; Hermens et al., 2009).

It has been recently shown that impulsive antisocial behaviours (a possible ‘negative symptom’ that can occur in schizophrenia) correlates with an increase in amphetamine-induced DA release in the NAc measured by [18F]fallypride PET and functional magnetic resonance imaging. These observations provide evidence for an association between substance abuse and psychopathic traits (Buckholtz et al., 2010). To obtain an animal model for the psychotic symptoms of schizophrenia, animals are subjected to amphetamine-induced sensitisation and observed during withdrawal periods after the sensitisation regimen (Paulson and Robinson, 1995; Peleg-Raibstein et al., 2009). Sensitised animals show an increase in subsequent amphetamine-induced DA release in the striatum and an increase in locomotor activity (Paulson and Robinson, 1995; Iwata et al., 1997). Thus, sensitisation is not only a model for addiction but also for psychosis (Gainetdinov et al., 2001).

Conclusions and future perspectives

Amphetamines are the second most commonly abused drugs in Europe after cannabis (EMCDDA, 2009) and the devastating effects of METH addiction are obvious in many parts of the world (Karila et al., 2010). All three drugs (METH, d-AMPH and MDMA) have been reported to induce psychotic episodes or ‘seizures’ in humans (Ujike and Sato, 2004; Karlsen et al., 2008). Furthermore, the loss of nigrostriatal dopaminergic neurons observed following repeated METH administration in animals has been associated with the pathogenesis of PD (Sonsalla et al., 1996; Harvey et al., 2000; Granado et al., 2010). These unintended (‘side’) effects should be carefully assessed when considering the long-term effects of amphetamine abuse on mental health and well-being.

Conversely, both d-AMPH and METH are used in the treatment of ADHD, narcolepsy and obesity. Likewise, MDMA abuse has been implicated in both the origin and treatment of PD (Morton, 2005; Sotnikova et al., 2005). Moreover, MDMA has even been suggested as a therapeutic aid in post-traumatic stress disorder (Morton, 2005). Long-term amphetamine administration has been shown to induce ample neurodegenerative side effects in animal models, thus rendering this the main cause for concern in humans following chronic amphetamine abuse.

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62) Edinoff, Amber N., et al. “Methamphetamine use: a narrative review of adverse effects and related toxicities.” Health Psychology Research 10.3 (2022).

Methamphetamine use increased four-fold from 2015 to 2016. Due to this increase in methamphetamine use and its associated medical complications, the mortality rate associated with methamphetamine use has doubled over the past ten years. Cardiopulmonary symptoms include chest pain, palpitations, and shortness of breath. Methamphetamine-related myocardial infarction can also occur. Central nervous system symptoms include agitation, anxiety, delusions, hallucinations, and seizures. Methamphetamine-induced psychosis may unmask underlying psychiatric disorders. It can also cause cerebral vasculitis, which elicits cortical blindness and ischemic strokes. Methamphetamine-induced neurotoxicity in serotonergic systems is more diffuse, involving the striatum, hippocampus, septum, amygdala, and hypothalamus leading to mood changes, psychosis, and memory impairment.

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63)  see (55) duplicate Angelucci, Francesco, et al. “Chronic amphetamine treatment reduces NGF and BDNF in the rat brain.” European Neuropsychopharmacology 17 (2007): 756-762.

Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia.
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Berberine

64) Mohseni, Fahimeh, et al. “Berberine hydrochloride improves cognitive deficiency through hippocampal up-regulation of neurotrophins following inhalant self-administration of methamphetamine.” Iranian Journal of Basic Medical Sciences 26.1 (2023): 23.

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ALA and Lithium Reversed Amphetamine increased locomotor activity and reversed the decrease in BDNF.

65) Macêdo DS, et al. Effects of alpha-lipoic acid in an animal model of mania induced by d-amphetamine. Bipolar Disord 2012: 14: 707–718.

Objectives: Oxidative stress and neurotrophic factors are involved in the pathophysiology of bipolar disorder (BD). Alpha-lipoic acid (ALA) is a naturally occurring compound with strong antioxidant properties. The present study investigated ALA effects in an amphetamine-induced model of mania.

Methods: In the reversal protocol, adult mice were first given d-amphetamine (AMPH) 2 mg/kg, intraperitoneally (i.p.) or saline for 14 days. Between days 8 and 14, the animals received ALA 50 or 100 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention paradigm, mice were pretreated with ALA, Li, or saline prior to AMPH. Locomotor activity was assessed in the open-field task. Superoxide dismutase (SOD) activity, reduced glutathione (GSH), and thiobarbituric acid-reactive substance (TBARS) levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). Brain-derived neurotrophic factor (BDNF) levels were measured in the HC.

Results: ALA and Li prevented and reversed the AMPH-induced increase in locomotor activity. Prevention model: ALA and Li co-administration with AMPH prevented the decrease in SOD activity induced by AMPH in the HC and ST, respectively; ALA and Li prevented GSH alteration in the HC and TBARS formation in all brain areas studied. Reversal model: ALA reversed the decrease in SOD activity in the ST. TBARS formation was reversed by ALA and Li in all brain areas. Furthermore, ALA reversed AMPH-induced decreases in BDNF and GSH in the HC.

Conclusions: Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA’s possible antimanic effect.

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Low-Dose Nutritional Lithium for ADHD James Greenblatt, MD

66) Why Low-Dose Nutritional Lithium Should Be an Option for ADHD James Greenblatt, MD

I continue to prescribe low-dose nutritional lithium to my patients. I use the treatment to stabilize mood. To help with addictions. To slow or stop memory loss in seniors. And I use it to effectively ease or erase irritability, anger, and aggression in children with ADHD.

67) Lithium, The Magic Mineral That Charges Cell Phones and Preserves Memory By James Greenblatt, MD, and Kayla Grossmann, RN Townsend Letter, October 2015

A 4-year-old boy, Peter, had severe ADHD. Even at this young age, he was shunned by other children, and his parents were asked to remove him from preschool. It was easy to observe his aggressive behaviors in my office. A trace mineral analysis from a hair sample revealed no detectable lithium. I prescribed 250 mcg of lithium in liquid form. Peter’s annoying aggressiveness diminished. He became able to make friends, and eventually he began to participate cooperatively with other children in a new preschool.

Shawn at age 8 was often in trouble for bullying. Although he had been diagnosed with ADHD, stimulants had not been helpful. His trace mineral analysis showed no detectable lithium. On 2 mg of lithium orotate, he showed significant improvement, and he lost interest in bullying other children.

68) Nutritional Lithium and Memory Preservation By James Greenblatt, MD07/01/2019

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69) Greenblatt, James, Jennifer Dimino, and Winnie T. Lee. “OPCs for the Treatment of ADHD: A Functional Medicine Approach By James Greenblatt, MD 04/05/2020 May 8th, 2023 No Comments 13 min read.”

OPCs (Pycnogenol) for the Treatment of ADHD: A Functional Medicine Approach

Science has demonstrated that OPCs directly benefit brain networks, neuron-to-neuron signaling, biochemical changes and metabolic processes that have been identified as underlying factors for many of the symptoms of ADHD. While it is speculative just how exactly OPCs improve cognitive function among individuals with ADHD, the available literature supports OPCs as a safe, naturally occurring, and therapeutic adjunct treatment that can improve cognitive performance and minimize the hallmark ADHD symptoms of hyperactivity and inability to focus. Their use as medicine over thou- sands of years is testament to their efficacy and safety, and modern research has corroborated that they are in- deed effective and safe.

In over three decades of using OPCs to treat patients with ADHD, we have never observed any negative side effects associated with OPC supplementation. Instead, we have observed patients whose thinking becomes progressively clearer once they start taking OPCs. Count- less patients have also reported an improved ability to concentrate and maintain focus, a steady improvement in their ability to read, write, and listen, and parents of patients have shared anecdotal stories about improvements in behaviors at home and performance in school.

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Pycnogenol (OPC) proanthocyanidin extract, maritime pine bark.

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Dr Breggin ADHD drugs / Kids

70) Peter Breggin, MD – ADHD Kids – A Lifelong Road to Tragedy.
Simple Truths about Psychiatry Vol. 8

i’m peter bregen i’m a psychiatrist and this is one in my series of simple truths about psychiatry i’ve already talked to you about stimulant drugs for children and now i want to talk to you about adhd or attention deficit disorder but first remember that stimulant drugs don’t cure anything they don’t fix anything they don’t improve anything they cause biochemical imbalances in the brain that make children docile that take away their
spontaneity and make them obsessively focus on things that they don’t care about there’s no evidence that stimulant drugs improve anything past the first few weeks when they subdue behavior, there’s no improvement in academic performance, social life, how people feel about themselves, sports. these drugs should not be given to children that’s the vast weight of scientific evidence that you can find in my books like psychiatric drug withdrawal and brain disabling treatments in psychiatry but now let’s go on to what is adhd.

i want you to imagine you know maybe in your late twenties or thirties that you went back to school was it fun do you remember going back to school and thinking wow it was great not too many of us think like that in fact let’s suppose somebody said you could have a six-figure salary for 20 years and retire and all you would have to do is everything you did in school you would just sit all day long in hard chairs with a desk in front of
you you’d have one person teaching you all day long you’d have to raise your hand to go to the bathroom you wouldn’t be able to socialize would
you do that for 20 years even for a good retirement you see adhd is about what we’re trying to make our children do that they’re not comfortable willing or able to do.
if you look in the diagnostic manual for what are the criteria for adhd they’re about kids who are uncomfortable in class the criteria include things like fidgeting in chairs, squirming in chair, cutting off the teacher to answer questions before she’s finished asking them,
not standing in line, being too active.

what happened is that the drug companies actually created the diagnosis adhd to sell it to teachers and say we have a medication that will get rid of all your difficulties in your classroom they held workshops they work to the department of education to do it now is adhd a disease well it can’t be a disease because think about it what might make a child say fidget in class or be hyperactive in class or interrupt the teacher.  why it could be almost anything. it could be that the child’s behind in class and uneasy and anxious because they can’t keep up it might be that the child’s the
opposite of that that the child’s way ahead of class that the child’s thinking about things far beyond what’s going on in the classroom and is bored it could be that the teacher is boring.  well maybe the teacher’s been depressed for years. maybe the teacher doesn’t know how to have moral authority, get the kids to quiet down, and listen to her or maybe the child’s going through a divorce at home and is just anxious and fidgety and nervous and needy or maybe the child’s malnourished maybe the child has an underlying problem like head injury from sports.

because that can give you all the same kinds of activities.
in other words this list of behaviors doesn’t mean anything in my experience it means the parents aren’t disciplining the child properly and within minutes in my office the child’s quieted down because i’m giving intense attention really caring about the child i’m interested in what the child has to say and the parents learn how to engage a child right in front of their eyes or the child doesn’t have any problem at all but school is boring i’ve even seen children turn around overnight with a change of teacher.

so adhd is not a disease, it’s not a disorder, but once you start giving a child drugs for adhd you create all kinds of diseases and disorders children get depressed on the drugs, they get psychotic on the drugs. they lose weight, get skinny, weakened and fatigued on the drugs they lose interest in socializing on the drugs which is one of the main effects that the teachers often see as positive because the kid’s not trying to socialize in class anymore let me say in a word there’s no disorder there’s no disease. the drugs just flattened behavior the great news is is that if your child has adhd like symptoms your child is almost certainly either perfectly normal and bored in school or needs his parents to learn to discipline him better while also providing unconditional love.

read my book talking back to ritalin or the ritalin factbook you’ll find everything i’m saying is documented with dozens of references and you’ll find better approaches to helping your child be the normal kid he really is thank you

71) Dr Breggin ADHD drugs PART ONE: watch you tube video

1) ADHD drugs suppress over all human growth, suppressing growth hormone cycles, brain is not growing normally

2) ADHD drugs are highly addictive: schedule II DEA
same as morphine, cocaine, fentanyl.

3) Changes the brain: animal studies show peristent, permanent brain damage

4) Drug Label says do not give to child who is agitated or depressed.

5) Adverese effects of ADHD drugs: many children become depressed,  start having Insomnia, anxiety, OCD disorder.

6) average pediatriciian does not recognize these adverse effects.

apathy anxiety depression insomnia are drug adverse effects.They will give a second drug !!! Kid gets depressed….doctor gives antidepressant….inducing increased suicidality, suicidal behavior. Kid is now on 3-4-5 drugs. Then they will add anti psychotic drugs.

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72) Part 2 Dr Breggin on ADHD Drugs

Features of ADHD: hyperactivity, inattention, impulsivity. There is no common disease process. ADHD is a list of behaviors that make trouble to teachers. Drugs include:

Amphetamines
amphetamine
dextroamphetamine
lisdexamfetamine

Brand names :
Adderall XR (generic available)
Dexedrine (generic available)
Dyanavel XR
Evekeo
ProCentra (generic available)
Vyvanse

Methamphetamine (Desoxyn)
Methylphenidate works by blocking the reuptake of norepinephrine and dopamine in your brain.Transdermal patch under the brand name Daytrana.

Aptensio XR (generic available)
Metadate ER (generic available)
Concerta (generic available)
Daytrana
Ritalin (generic available)
Ritalin LA (generic available)
Methylin (generic available)
QuilliChew
Quillivant

On drug, brain is suppressed by psychiatric drug

Studies on Chimps with ADHD meds:

Chimps stop being spontaneous and stop trying to esccape.
Thats what we do to our children. Make them good caged children.
They become zombie like. The spirit is dimished.
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methylphenidate plays havoc with the developing young brain.

73) Smart Drugs, the Good, Bad and Ugly by David Tomen February 2, 2017 NootropicsExpert

MPH [Methylphenidate] is a stimulant that blocks the transporters that reuptake dopamine and norepinephrine into the presynaptic neuron following their release. This action prolongs the availability of these neurotransmitters in synapses to exert effects on postsynaptic neurons.[v]

The Dark Side of Methylphenidate – Methylphenidate Plays Havoc with the Developing Young Brain.

The problem with cognitive enhancers like methylphenidate is directly related to their effects on regulation of dopamine and norepinephrine in your brain.

At optimal doses, dopamine binds to D1 receptors. And norepinephrine binds to α2 receptors. This action leads to an increase in prefrontal cortex signal-to-noise ratio. Which enhances the flow of information and strengthens communication between neurons.[viii] Helping executive function and working memory.

When dopamine and norepinephrine go beyond optimal levels, you have a problem. They activate dopamine D2 receptors and noradrenergic α1 and β receptors. This weakens the signal-to-noise ratio by activating neurons that are not supposed to be involved in the current task.

This activation of neurons that are not supposed to be involved results in hyperactivity, distractibility and poor impulse control.

But to further complicate things. Levels of dopamine and norepinephrine in a normal, healthy brain are not constant. They vary slightly even within the same person based on seasons, time of day, or the activity you are involved in.

And to be honest, there’s no way to measure optimal levels of these neurotransmitters. So dosing methylphenidate (or any other stimulant) is mostly guess work.

Methylphenidate and the Developing Brain

Methylphenidate is particularly popular in high schools and college campuses right around exam time. MPH helps you stay awake. And even helps with cognition and memory.[ix]

But there is growing evidence that methylphenidate plays havoc with the developing young brain.  Your prefrontal cortex is the region in your brain at the center for judgement control, behavior inhibition and control, emotion, logical thinking, working memory and decision making.  And continues to develop through to your late 20’s and early 30’s.[x] Studies show that using MPH early in life can alter circadian rhythms, increase anxiety that persists into adulthood, and even cause problems with object-recognition memory.[xi]{xi}

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MPD were able to change the locomotor diurnal rhythm patterns, which suggests that these MPD doses exerts long-term effects.

 

—————- return to above article before reference ——————

A change or reduction in this behavioral flexibility caused by methylphenidate can lead to problems at work. Resulting in lower wages, unemployment or even disciplinary action.

recent research shows that methylphenidate is bad news for the developing brain. Anyone aged 5 – 35 years ago should take pause before dosing with this drug. Because it negatively affects the developing brain. The results of using methylphenidate could stay with you for life. Long after you stop using it.

[xxxvii] Silverstone P.H., Asghar S.J., O’Donnell T., Ulrich M., Hanstock C.C. “Lithium and valproate protect against dextro-amphetamine induced brain choline concentration changes in bipolar disorder patients.” World Journal of Biological Psychiatry. 2004 Jan; 5(1):38-44. (source)

[xxxviii] Klongpanichapak S., Govitrapong P., Sharma S.K., Ebadi M. “Attenuation of cocaine and methamphetamine neurotoxicity by coenzyme Q10.” Neurochemical Research. 2006 Mar;31(3):303-11. (source)

[xxxix] Wu P.H., Shen Y.C., Wang Y.H., Chi C.W., Yen J.C. “Baicalein attenuates methamphetamine-induced loss of dopamine transporter in mouse striatum.” Toxicology. 2006 Sep 21;226(2-3):238-45 (source)

[xl] Klongpanichapak S., Phansuwan-Pujito P., Ebadi M., Govitrapong P. “Melatonin protects SK-N-SH neuroblastoma cells from amphetamine-induced neurotoxicity.” Journal of Pineal Research. 2007 Aug; 43(1):65-73. (source)

[xli] Achat-Mendes C., Anderson K.L., Itzhak Y. “Impairment in consolidation of learned place preference following dopaminergic neurotoxicity in mice is ameliorated by N-acetylcysteine but not D1 and D2 dopamine receptor agonists.” Neuropsychopharmacology. 2007 Mar; 32(3):531-41. (source)

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74)  Lee, Min J., et al. “Does repetitive Ritalin injection produce long-term effects on SD female adolescent rats?.” Neuropharmacology 57.3 (2009): 201-207.

Methylphenidate (MPD), or Ritalin, is a psychostimulant that is prescribed for an extended period of time to children and adolescents with attention deficit hyperactivity disorder. Adolescence is a time of critical brain maturation and development, and the drug exposure during this time could lead to lasting changes in the brain that endure into the adulthood. Circadian rhythms are 24 h rhythms of physiological processes that are synchronized by the master-clock, the suprachiasmatic nucleus, to keep the body stable in a changing environment. The aim of present study is to observe the effect of repeated MPD exposure on the locomotor diurnal rhythm activity patterns of female adolescent Sprague-Dawley (SD) rats using the open field assay. 31 female adolescent SD rats were divided into four groups: control, 0.6 mg/kg, 2.5 mg/kg, and 10 mg/kg MPD group. On experimental day 1, all groups were given an injection of saline. On experimental days 2-7, animals were injected once a day with either saline, 0.6 mg/kg, 2.5 mg/kg, or 10 mg/kg MPD, and experimental days 8-10 were the washout period. A re-challenge injection was given to each animal on experimental day 11 with the similar dose as the experimental days 2-7. The locomotor movements were counted by the computerized animal activity monitoring system. The data were analyzed statistically to find out whether the diurnal rhythm activity patterns were altered. The obtained data showed that repeated administrations of 2.5 mg/kg and 10 mg/kg MPD were able to change the locomotor diurnal rhythm patterns, which suggests that these MPD doses exerts long-term effects.

75) BOOK Chapter 16
Williams, York. “An Exploration of ADHD and Comorbidity With Substance Abuse and Brain Development.” New Developments in Diagnosing, Assessing, and Treating ADHD (2020): 245.

Recent human and animal studies suggest MPH [Methylphenidate] alters the dopaminergic system with long-term effects beyond termination of treatment

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Note: The GABAergic system is the main inhibitory neurotransmitter system in brain circuits.

76) See (43) Solleveld, Michelle M., et al. “Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients.” NeuroImage: Clinical 15 (2017): 812-818.

• Early stimulant exposure results in lower baseline PFC GABA levels in adulthood.
• Exposure at young age alters the GABAergic response to stimulants in adulthood.
• First exposure to stimulants in adulthood exerts no major effects.

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significantly lower GABA levels in the medial prefrontal cortex,

77) Study (Solleveld, Michelle 2017)   : Children Given Ritalin Suffer Longterm Brain Damage July 3, 2017 Sean Adl-Tabatabai

The researchers used Magnetic Resonance Spectroscopy scans to examine GABA levels in the medial prefrontal cortex of 44 male ADHD patients. They found evidence that methylphenidate use by children produced long-lasting alterations in GABA neurotransmission in this region of the brain.

Patients who were treated for the first time with stimulants as children showed significantly lower GABA levels in the medial prefrontal cortex, compared to those who started treatment as adults. A dose of methylphenidate also produced a significant increase in GABA levels in patients treated in childhood, but not in patients treated in adulthood.

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78) Grund, Thorsten, et al. “Influence of methylphenidate on brain development–an update of recent animal experiments.” Behavioral and Brain Functions 2.1 (2006): 1-14.

recent human and animal studies suggest that MPH alters the dopaminergic system with long-term effects beyond the termination of treatment.

Animal studies imply that the effects of MPH may depend on the neural responder system: Whereas structural and functional parameters are improved by MPH in animals with psychomotor impairments, they remain unaltered or get worse in healthy controls. While recent behavioural studies do not fully support such a differential effect of MPH in ADHD, the animal studies certainly prompt for further investigation of this issue. Furthermore, the abuse of MPH, when (rarely) intravenously applied, may even impair the maturation of dopaminergic fibres in subcortical brain areas. This argues for careful clinical assessment and diagnostics of ADHD symptomatology not only in conjunction with the prescription of MPH. Hence, one should be assured that MPH is only given to children with clear ADHD symptomatology leading to psychosocial impairment. The animal data suggest that under these conditions MPH is supportive for brain development and the related behaviour in children with ADHD

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79) NIDA Study Shows That Methylphenidate (Ritalin) Causes Neuronal Changes in Brain Reward Areas

Similarities and Differences Compared to Cocaine were Found.

The researchers exposed mice to two weeks of daily injections of cocaine or methylphenidate, after which reward areas of the brain were examined for changes in dendritic spine formation—related to the formation of synapses and the communication between nerve cells; and the expression of a protein (delta Fos B) which has been implicated in the long term actions of addictive drugs. Both drugs increased dendritic spine formation, and the expression of delta Fos B; however the precise pattern of their effects was distinct. It differed in the types of spines affected, the cells that were affected, and the brain regions. In some cases there was overlap between the two drugs, and in some cases, methylphenidate produced greater effects than cocaine—for example, on protein expression in certain regions.

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+++++++++ GOOD IMAGES ++++++++++

MPH – Microglial Activation

80) Carias, Emily, et al. “Chronic oral methylphenidate treatment increases microglial activation in rats.” Journal of Neural Transmission 125 (2018): 1867-1875.

In vitro autoradiography using [3H] PK 11195 was performed to measure microglial activation

These findings indicate that chronic MP results in widespread microglial activation immediately after treatment and following the cessation of treatment in some brain regions.

Human Subjects In Vivo Pet Study

80A) Yokokura, Masamichi, et al. “In vivo imaging of dopamine D1 receptor and activated microglia in attention-deficit/hyperactivity disorder: a positron emission tomography study.” Molecular psychiatry 26.9 (2021): 4958-4967.

Alterations in the cortical dopamine system and microglial activation have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), one of neurodevelopmental disorders that can be conventionally treated with a dopamine enhancer (methylphenidate) albeit unsatisfactorily. Here, we investigated the contributions of the dopamine D1 receptor (D1R) and activated microglia and their interactions to the clinical severities in ADHD individuals using positron emission tomography (PET). Twenty-four psychotropic-naïve ADHD individuals and 24 age- and sex-matched typically developing (TD) subjects underwent PET measurements with [11C]SCH23390 for the D1R and [11C](R)PK11195 for activated microglia as well as assessments of clinical symptoms and cognitive functions. The ADHD individuals showed decreased D1R in the anterior cingulate cortex (ACC) and increased activated microglia in the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) compared with the TD subjects. The decreased D1R in the ACC was associated with severe hyperactivity in the participants with ADHD. Microglial activation in the DLPFC were associated with deficits in processing speed and attentional ability, and that in the OFC was correlated with lower processing speed in the ADHD individuals. Furthermore, positive correlations between the D1R and activated microglia in both the DLPFC and the OFC were found to be significantly specific to the ADHD group and not to the TD group. The current findings suggest that microglial activation and the D1R reduction as well as their aberrant interactions underpin the neurophysiological mechanism of ADHD and indicate these biomolecular changes as a novel therapeutic target.

 

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81) Quintero, Javier, José R. Gutiérrez-Casares, and Cecilio Álamo. “Molecular characterisation of the mechanism of action of stimulant drugs lisdexamfetamine and methylphenidate on ADHD neurobiology: A review.” Neurology and Therapy 11.4 (2022): 1489-1517.

ADHD pathophysiology is largely unknown.

82) Schmitz, Felipe, et al. “Methylphenidate causes behavioral impairments and neuron and astrocyte loss in the hippocampus of juvenile rats.” Molecular neurobiology 54 (2017): 4201-4216.

Results showed that chronic methylphenidate administration
caused loss of astrocytes and neurons in the hippocampus
o f  juvenile  rats. BDNF and pTrkB immunocontents and NGF levels were decreased, while TNF-α and IL-6 levels, Iba-1 and caspase 3 cleaved immunocontents (microglia marker and active apoptosis
marker, respectively) were increased.

Both exploratory activity and object recognition memory were impaired by methylphenidate. These findings provide additional evidence that early-life exposure to methylphenidate can have complex effects, as well as provide new basis for understanding of the biochemical and behavioral consequences associated with chronic use of methylphenidate during central nervous system development ADHD is a complex neuropsychiatric disease characterized mainly by high levels of inattention, hyperactivity, and impulsivity [1–3]. However, recent studies have reported a large increase in the incidence of MPH misuse among young adults and students who do not meet the criteria for ADHD, in search of cognitive enhancement [4, 5], in preschool children with 2–4 years of age [6, 7].

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Methylphenidate exposure induces dopamine neuron loss and activation of microglia in Basal Ganglia (Mice)

83) See  36) Sadasivan, Shankar, et al. “Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice.” PloS one 7.3 (2012): e33693.

Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia.

Through the use of stereological counting methods, we observed a significant reduction (∼20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc.

Conclusion: Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.

We found that chronic exposure to both 1 mg/kg and 10 mg/kg MPH increased the sensitivity of SNpc dopamine neurons to oxidative stress, based on a significantly increased SNpc dopamine neuron loss in mice administered MPH as compared to saline-treated control mice. Although the mechanism for this neuronal loss is unknown, a significant increase in MPH-induced activated microglia was observed; therefore, we hypothesize that an increase in free radical formation along with a concomitant neuroinflammatory response increases the sensitivity of the SNpc dopamine neurons to a later oxidative challenge. This conclusion is supported by a recent epidemiological study that showed that long-term amphetamine usage, which like MPH results in higher levels of striatal dopamine in the synaptic cleft, results in a significantly higher risk for developing Parkinson’s disease [51].

Taken together, our results suggest that chronic administration of methylphenidate in mice, at doses that approximate those at the higher therapeutic range in humans, results in a reduced expression of neurotrophic factors, increased neuroinflammation, and a small, but significant loss of SNpc dopamine neurons. These results can only be interpreted in the context on normal brain structure and function, and thus would have direct implications for the illicit/neurocognitive use of MPH. Since the underlying anatomy and biochemistry of ADHD has not been definitively characterized, our findings may or may not be generalizable to the vast majority of humans who are properly diagnosed with ADHD and are prescribed methylphenidate. Nevertheless, this work supports studies [51], [57], [58], [59] that demonstrate that drugs shown to increase the levels of dopamine in the synaptic cleft can contribute to degenerative changes in the basal ganglia.

84) Wang, Gene-Jack, et al. “Long-term stimulant treatment affects brain dopamine transporter level in patients with attention deficit hyperactive disorder.” PloS one 8.5 (2013): e63023.

Discussion  This study shows that long-term treatment with MPH up-regulated DAT availability in the ventral striatum, providing the first evidence of DAT neuroplasticity after long-term treatment with a clinically relevant dose of MPH in the human brain. DAT is responsible for recycling DA from the extracellular space into the pre-synaptic terminal [14]. The DAT levels in the membrane are regulated by the concentration of extracellular DA; DAT levels decrease when extracellular DA is low and increase when extracellular DA is high [15]. Repeated administration of a variety of stimulant drugs (e.g., cocaine, amphetamine) has been shown to change DAT expression in  preclinical models. These studies show different results for stimulant drugs that are DAT blockers, such as cocaine, from those of stimulant drugs that are DA releasers, such as methamphetamine and amphetamine. Cocaine, which like MPH blocks DAT, temporarily increases the expression of DAT after chronic administration [16]. Indeed humans, postmortem and imaging studies have shown increased DAT (20–50%) in the striatum of chronic cocaine abusers when compared with controls [17], [18]. These increases are positively correlated with the severity of cocaine use and can recover with detoxification. This is consistent with an adaptation response to compensate for chronic increases in extracellular DA secondary to repeated cocaine intoxication.

Similarly, subchronic MPH treatment results in an attenuation of DA release in rodents, which was ascribed to either an upregulation of DAT or enhanced autoreceptor sensitivity [19]. In ADHD adults we also recently showed that long-term treatment with clinical doses of MPH resulted in an attenuation of MPH induced DA increases in the striatum [20]. Similar to treatment with other DAT blockers the increased expression of DAT in the striatum after long term MPH treatment in this study might reflect an accelerated clearance of synaptic DA in response to chronic DA enhancement from long-term exposure to MPH [14]. In this study the clinical measures at follow-up were obtained while subjects were under the influence of the medication (MPH), which explains the significant improvement in all of the clinical symptoms. However it would have been desirable to test them also when they were not under the effects of MPH (i.e. in the morning prior to medication intake) to assess if the upregulation of DAT after chronic MPH was associated with impaired performance.

Few studies have investigated the behavioral consequences of long-term exposure to MPH and the extent to which chronic exposure results in tolerance is still a matter of debate. Indeed, studies on the chronic effects of MPH have reported conflicting results with some documenting sensitization to the locomotor effects of MPH [21], others tolerance [22], and others no changes [23]. The reasons for these discrepancies are likely to reflect differences in doses, conditions of drug administration and age of the animals. The findings on the effects of chronic MPH (using doses that are therapeutically relevant), on the rewarding effects of drugs of abuse are also not consistent. Whereas one study reported that MPH pretreatment in preadolescence or in adulthood decreased the rewarding effects of cocaine (as assessed by conditioned place preference) later in life [24], two others [25], [26] reported that chronic MPH treatment in adolescence or in adulthood enhanced cocaine’s reinforcing effects (as assessed by cocaine self-administration and the latency for acquisition of self-administration). These behavioral changes are likely to reflect in part changes in brain DA activity since DA is involved both in locomotor activity as well as the rewarding effects of cocaine. In this study, even though the ADHD subjects did not show more hyperactivity as compared to the controls prior to MPH treatment, the SWAN scores for the hyperactivity/impulsivity dimension in the ADHD subjects were significantly reduced after long-term MPH treatment.

We hypothesize that the increased DAT availability is a compensation for the pharmacologic occupancy of DAT (estimated to be greater than 50%) [27] and the increased elevations in synaptic DA. The results of this prospective treatment study and theory of DAT plasticity suggest that some of the discrepancies in the literature regarding the levels of DAT in ADHD may reflect treatment histories. Note also that in some instances the results are confounded by measuring DAT while the pharmacological effects of MPH are still present [28], which would result in lower measures of DAT availability secondary to DAT occupancy by MPH. Thus we postulate that decreased synaptic levels of DA might drive the changes in DAT levels reported in ADHD (which vary to maintain equilibrium of synaptic DA levels in brain).

Here we report an upregulation of DAT secondary to long-term treatment with stimulant medication, which could result in further decreases in dopaminergic signaling when the individual with ADHD is not medicated (i.e. over weekend holidays). To the extent that reduced DA release in ADHD is associated with inattention [29], this could result in more severe inattention and the need for higher doses of medication. Though there is limited literature on loss of efficacy of stimulant medication with long-term treatment this is an area that merits further investigation. Studies are necessary to test if DAT down-regulate after MPH discontinuation and the time necessary for their recovery.

=====================

85) Hsu, Sanford Pc, et al. “Long-term challenge of methylphenidate changes the neuronal population and membrane property of dopaminergic neuron in rats.” Neurochemistry international 122 (2019): 187-195.

The number of dopaminergic neurons in the substantia nigra (SN), the serotonergic neurons in the dorsal raphe nucleus, and the cholinergic neurons in the tegmental nucleus significantly decreased as compared with Normal group, whereas the noradrenergic neurons in the locus coeruleus substantially increased.

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2023 – Chronic MPH is perfectly safe in monkeys, no long term  significant neurochemical or neural metabolic changes in the central nervous system 6 months after cessation. Using PET Brain imaging. Industry sponsored.

86) Zhang, X., et al. “Discontinuation of methylphenidate after long-term exposure in nonhuman primates.” Neurotoxicology and Teratology 97 (2023): 107173.

The blockage of the dopamine transporter (DAT) and the norepinephrine transporter (NET) by MPH may help with ADHD symptoms by boosting monoamine levels in the synapse.

This study demonstrates that 6 months after cessation of long-term, chronic MPH treatment, there are no significant neurochemical or neural
metabolic changes in the central nervous system (CNS) of non-human primates (NHPs) and suggests that microPET imaging is helpful in assessing the status of biomarkers of neurochemical processes linked to chronic CNS drug exposure.

============ Industry Sponsored =============

87) Ludolph, A. G., et al. “Methylphenidate exerts no neurotoxic, but neuroprotective effects in vitro.” Journal of neural transmission 113 (2006): 1927-1934.

Methylphenidate (MPH) is the most common used drug in child and adolescent psychiatry. Despite of this fact, however, little is known about its exact pharmacological mechanisms. Here we investigated the toxic effects of MPH in vitro in human embryonic kidney (HEK-293) cells stably expressing the human dopamine transporter (HEK-hDAT cells) and in cultured rat embryonic (E14.5) mesencephalic cultures. MPH alone (up to 1 mM) affected neither the growth of HEK-hDAT cells nor the survival of dopaminergic (DA) neurons in primary cultures after treatment up to 72 h. No differences in neuronal arborisation or in the density of synapses were detected. 1-methyl-4-phenylpyridinium (MPP(+)) showed no toxic effect in HEK-293 cells, but had significant toxic effects in HEK-hDAT cells and DA neurons. MPH (1 microM – 1 mM) dose-dependently reduced this cytotoxicity in HEK-hDAT cells and primary mesencephalic DA neurons. The presented results show that application of MPH alone does not have any toxic effect on DA cells in vitro. The neurotoxic effects of MPP(+) could be significantly reduced by co-application of MPH, an effect that is most likely explained by MPH blocking the DAT.

A. G. Ludolph reports having received lecture fees from UCB/Celltech, Medice and Janssen, and research funding from UCB/Celltech and Medice. She is involved in clinical trials with Böhringer Ingelheim, Eli Lilly, Janssen-Cilag.

88) Volz, T. J. “Neuropharmacological mechanisms underlying the neuroprotective effects of methylphenidate.” Current Neuropharmacology 6.4 (2008): 379-385.

This work was supported by Grants DA00869, DA04222, DA13367, DA11389, DA019447, and DA00378 from the National Institute on Drug Abuse as well as a Focused Funding Gift from Johnson & Johnson.

Johnson & Johnson to Pay More Than $2.2 Billion to Resolve Criminal and Civil Investigations. Monday, November 4, 2013

===============

Memory in Mice Imroved by Low dose MPH, impaired by high dose

89) Salman, Tabinda, et al. “Enhancement and impairment of cognitive behaviour in Morris water maze test by methylphenidate to rats.” Pakistan journal of pharmaceutical sciences 32.3 (2019).

Abstract: Methylphenidate (MPD), a psycho-stimulant is a prescription medicine for the treatment of Attention deficit hyperactivity disorder (ADHD). The drug is also being increasingly used by general population for enhancing cognition. Only few preclinical studies have been carried out on the effects of MPD on cognition and these studies show either an
enhancement or impairment of memory following the administration of MPD. The present study was designed to evaluate the effects of different doses of methylphenidate on acquisition and retention of memory in Morris water-maze test. Twenty four male Albino Wistar rats (weighing 180-220gm) were randomly assigned to four groups: (1) Control
(2) 0.5mg/kg (3) 2.5mg/kg (4) 5 mg/kg methylphenidate. Animals received drug or water orally before training phase. Memory acquisition was monitored 2hrs post drug administration while memory retention was determined next day. It was found that the clinically relevant doses of methylphenidate (0.5mg/kg and 2.5mg/kg) improved memory acquisition and its retention but higher dose (5mg/kg) impaired both. We suggest that MPD-induced increase of catecholamine
neurotransmission may have a role in the improvement of water maze performance while agonist activity of the drug for 5HT-1A receptor in the impaired performance at high doses. Food intake and body weight changes were not affected by MPD administration due to short-term administration of the drug. Results may help in improving pharmaco-therapeutic use of MPD for ADHD.

long-lasting alterations – Ex-Vivo Neurochemistry, In vivo Electrophysiology

90) Di Miceli, Mathieu, Asma Derf, and Benjamin Gronier. “Consequences of Acute or Chronic Methylphenidate Exposure Using Ex Vivo Neurochemistry and In Vivo Electrophysiology in the Prefrontal Cortex and Striatum of Rats.” International Journal of Molecular Sciences 23.15 (2022): 8588.

long-lasting alterations of striatal and prefrontal neurotransmission were observed, even after extensive washout periods.

2012 Industry Sponsored

PET SCan Work- no long term effects in monkeys ———-

91) Soto, Paul L., et al. “Long-term exposure to oral methylphenidate or dl-amphetamine mixture in peri-adolescent rhesus monkeys: effects on physiology, behavior, and dopamine system development.” Neuropsychopharmacology 37.12 (2012): 2566-2579.

This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [11C]MPH and [11C]raclopride dynamic PET scans were performed to image dopamine transporter and D2-like receptors, respectively. Binding potential (BPND), an index of tracer-specific binding, and amphetamine-induced changes in BPND of [11C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D2 receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys.

Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.

Dr Ator’s work has been funded by the NIH and she has received funding from Helsinn Healthcare to conduct an abuse liability evaluation of an unrelated compound. She has received compensation for consulting on abuse liability evaluation from Bristol Myers Squibb and F Hoffmann LaRoche. Dr Riddle’s, Dr Wilcox’s, and Dr Zhou’s work has been funded by the NIH. Dr Soto’s work has been funded by the NIH; he has received compensation, unrelated to his scientific work, for database/software consulting from Shands Hospital at the University of Florida. Dr Weed has been an employee of Bristol Myers Squibb since the end of the PET scans that occurred following the 18 months of treatment in this study. Bristol Myers-Squibb provided no financial support for these studies and had no scientific involvement. Dr Wong’s work has been funded by the NIH, Avid, Biotie, GE, Intracellular, Johnson & Johnson, Eli Lilly, H Lundbeck, Merck, Orexigen, Otsuka, F Hoffmann LaRoche, and Sanofi-Aventis. He has received compensation for consulting from Amgen.

============= ADHD Drugs More Risk Than Reward Kimberly Urban =========

92) Urban, Kimberly R., and Wen-Jun Gao. “Psychostimulants as cognitive enhancers in adolescents: more risk than reward?.” Frontiers in Public Health 5 (2017): 260.

MPH exerts its therapeutic effect by blocking the function of the DA transporter (DAT) and norepinephrine transporter [NET, thereby increasing the bioavailability of the neurotransmitters and correcting the deficit thought to cause ADHD (16–18)]. The first stimulant approved for ADHD treatment AMPH (Adderall©) blocks reuptake but also increases vesicular release of DA; the effect on DA release is the main action at low doses (19). There is a large body of research supporting the conclusion that psychostimulant treatment reduces symptoms of ADHD, particularly hyperactivity (20). However, how other psychostimulants may affect cognitive performance is less clear, due to varying dosages, varying ages of subjects, and the fact that many tests of executive function contain non-executive domains on which improvement is noted after psychostimulant treatment. For example, MPH is effective at improving performance on a simple reaction time, task-switching paradigm, focused attention, word-matching, and go/no-go tasks in children with diagnosis of ADHD, but not spatial working memory (SWM), pattern recognition, or divided attention tasks (21–30). Regardless, stimulant medications seem to improve cognitive function in an inverted-U curve manner, with lower doses improving and higher doses impairing various aspects of cognition (17).

studies corroborated the theory that low-dose psychostimulant treatment (doses that correspond to those given to ADHD patients) appears to enhance prefrontal cortical-dependent functions and cognitive performance in healthy individuals in a similar manner to ADHD patients (42–45). This led to consideration of MPH as a nootropic, or cognitive-enhancing, drug

Today, MPH is increasingly abused by adolescents and adults seeking an advantage in scholastic performance and work productivity. It is used to aid memory when studying for exams and to improve focus and wakefulness (46, 47). MPH and other similar substances are also highly abused by members of the military to improve attention in high-stress situations and combat the effects of sleep deprivation (48). Prevalence reports range from 2 to 20% of respondents admitting to cognitive enhancement (47,

adolescent MPH exposure was found to reduce social play, impair pattern learning and reversal learning, increase locomotor hyperactivity, and response to cocaine, sometimes lasting into adulthood (57–60). Early exposure to MPH has also been shown to result in increased anxiety lasting into adulthood and alter circadian rhythms (61–65).

These results suggest that there is an age-dependent effect of MPH in the PFC, and that the juvenile brain may be hypersensitive to the effects of psychostimulants, and even a low dose may push the healthy developing brain into a hyperdopaminergic and hyperadrenergic state.

Thus, psychostimulants given at low doses similar to those used to treat ADHD may indeed provide an effective and largely safe cognitive enhancement, as the PFC of adults has finished maturing (11, 12, 99).

However, in the adolescent brain, levels of DA and NE are naturally higher, as the PFC development is ongoing and synaptic pruning has not been completed; thus, adding psychostimulants likely pushes the levels of DA and NE beyond the optimal range and into excessive levels (12). This is consistent with impairments in pattern learning and object-memory, reduced pyramidal neuron activity, and reduced NR2B-containing NMDA receptor levels seen in our studies

Until the research is completed to give us a more thorough understanding of the drugs’ actions in the developing PFC, off-label use of psychostimulants and nootropics may present more risk than reward for adolescents.

Kimberly Urban You Tube Interview 2015

2015   Episode 38 – Dr. Kimberly Urban and the Impact of Nootropics on Neuroplasticity

Dr. Kimberly Urban:

Since I had done my thesis research on methylphenidate (Ritalin), I was able to bring my research into the review. Based on my findings, on the Ritalin research over 6 years for Doctoral Thesis.

Host: Tell us about your Ritalin Research, and high points of 6 years of study:

Dr. Urban: When I came into the lab, I have always been interested in the prefrontal cortex (PFC). I think of the PFC as the CEO of the brain. The big box area of the bring that brings together sensory information that is coming in, integrates it, decides what to do about it, and plans for actions to the motor cortex, and generate a response. The PFC is what you would use to determine what to respond to, what not to respond to. What signal is important to pay attention to, or not. I was always interested in how this brain region (PFC) figures this out. And what can happens when the PFC goes wrong. As I came into the lab and started reading papers, my early perception was , oh man, we have been using Ritalin for 30-40 years. How can we possibly not know anything about it? We must have answered all the questions already ! However, when I started to look more into the research, it was shocking to me that all the Ritalin studies were done on adult rodent (mouse) models. Yet the drug is primarily given to children.

The adult brain is extremely different from the young brain, especially in the prefrontal cortex which does not finish developing until age late 20’s to early 30’s. [The developing brain] is a vastly different environment chemically and cellularly than an adult brain.

So I was wondering that all this research on adult rats (mice) showed the drug was safe, what dosage ranges were good, and had figured out dosage ranges in rats that were equivalent to therapeutic dosages given to humans. So I wondered if all this adult rat research was actually relevant to the young (developing) brain. And, going in , I really had no idea.

As I started looking at the young rats, and I was very very careful which doses I gave. One mg per kg in the rat produces a blood level very similar to what you find in humans, ADHD patients that have been successfully treated. So, we call that a therapeutically relevant dose. And, I was very careful to use that kind of dose, because if you give enough of any kind of drug, you are going to get an effect. I wanted to make sure I was giveing realistic amounts of this drug.

And, I found that these young rats. The results I was getting were vastly different from everything everybody else had published. The drug is supposed to correct an underactivity in the prefrontal cortex (PFC). Basically, that area of the brain is kind of sedated in people with ADHD, and that is because of low levels of dopamine and norepinehrine, two neurotransmitters important for regulating attention and motivation and everything. What researchers found looking at adult rats, when you give the drug to a normal rat, the drug excites that region of the brain, the PFC. That is what you expect the drug to do. It is a stimulant.

Differing effects of MPH based on Age: Adults rats PFC excited. Young Rats PFC depressed.

However, when I gave the drug to the young rats, it actually depressed cellular function in that region of the brain (PFC). The drug depressed the neurons responsiveness to stimuli coming in, and it also depressed the communication between cells (neuron cells). This was very very different from all the previous research. That is how the project got started. I wanted to understand what was going on here, and what it might mean.

And what I found was that, when you look at all the interrelationships between these different neurotransmitter systems, none of them exist in a vaccuum, they are all interrelated, they all work together. All the previous research had been talking about dopamine or norepinephrine, but, you can’t look at the brain and assume that anything that affects dopamine or norepinephrine is only going to affect those. Those neurotransmitters interleave with others.

Dopamine is very related to Glutamate which is an excitatory transmitter. It is the final step in a process that tells the neurons to respond, in other words, it activates the neuron. Glutamate is involves in plasticity, referring to the brains ability to adapt and change to incoming stimuli and you know, shift attention, and either increase or decrease responsiveness, and strengthen or weaken synapses. Its basically flexibility. Glutamate is really involved in this flexibility because of the different receptors that exist for it. And one of those receptors is called the NMDA receptor, allowing for the long course of changes that are needed for plasticity, and, methylphenidate given to the young rats at this low dose really depressed that subunit. So what you got was that is looked like the prefrontal cortex (PFC) was changing such that NR2B was disappearing in these NMDA subunits, and you would get a much more rigid brain area.

Question from Host:
what has the been the response to these findings?
It flies in the face of exactly what Ritalin has been used for, for the last several decades.

It is important to keep in mind that what I am looking at is a normal brain envirnment. An ADHD brain is going to be very different.

We know from decades of research both on human children and rodent models that the drug works in ADHD to decrease inattentiveness and hyperactivity, and you know, that makes sense.

I am not looking at ADHD brains. I am looking at normal brains.

We have an envirmonment where it is easy to have a child prescribed the drug. It is become the drug du jour. If a child is not paying attention in school or not getting good grades it [methylphenidate drug ] is the first course of action rather than one of the last.

Parents want their children to have the best lives possible. We want to do the best we can for them. So, if you can put a diagnosis [ADHD] on something, and eliminate the problem by giving a pill [methylphenidate], that’s easy, a quick fix. For some children that is definitely the case that the drug works wonders, and it has saved many peoples lives. But the problem comes where you try to have it as a one-size-fits all cure and its not. There is a lot more that can cause problems in school and inattentiveness than just ADHD. You know, anything from a child being bullied by somebody, and their attention is on the bully in the classroom, to a child learning faster than the rest of the class and they are bored or maybe they are struggling to keep up and they get frustrated and give up. All of these situations are not kids with ADHD, but many times, they end up being prescribed the drug anyways..

I found mostly positive responses to my research because Im very careful to be clear that I am not saying it [methylphenidate] is a bad drug for ADHD. It is a good drug for ADHD, but it is not a good drug for normal children.

When you get into the Adult brain, and all the development is finished, it [methylphenidate MPH] is not as dangerous. In my research, I did look at adult rats, my research matched with everything alse out there. It[MPH] slightly excites that region of the brain [PFC], but it doesnt push it too far. So in adults, it probably does work as a cognitive enhancer. I do not have pesonal experience with it, but there is enough research that it does seem to work in healthy adults at very low doses.

I’m very specific with what I am saying with my research that it [MPH] is dangerous for normal children, or that it is probably dangerous for normal children.

My research is just at the beginning looking at the activities of individual brain cells. There is a lot more that needs to be done, but we had to start somewhere. To find such striking results is very encouraging.

————- ————–

Urban, Kimberly R., and Wen-Jun Gao. “Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain.” Frontiers in systems neuroscience 8 (2014): 38.

Cognitive enhancement is perhaps one of the most intriguing and controversial topics in neuroscience today. Currently, the main classes of drugs used as potential cognitive enhancers include psychostimulants (methylphenidate (MPH), amphetamine), but wakefulness-promoting agents (modafinil) and glutamate activators (ampakine) are also frequently used. Pharmacologically, substances that enhance the components of the memory/learning circuits—dopamine, glutamate (neuronal excitation), and/or norepinephrine—stand to improve brain function in healthy individuals beyond their baseline functioning. In particular, non-medical use of prescription stimulants such as MPH and illicit use of psychostimulants for cognitive enhancement have seen a recent rise among teens and young adults in schools and college campuses. However, this enhancement likely comes with a neuronal, as well as ethical, cost. Altering glutamate function via the use of psychostimulants may impair behavioral flexibility, leading to the development and/or potentiation of addictive behaviors. Furthermore, dopamine and norepinephrine do not display linear effects; instead, their modulation of cognitive and neuronal function maps on an inverted-U curve. Healthy individuals run the risk of pushing themselves beyond optimal levels into hyperdopaminergic and hypernoradrenergic states, thus vitiating the very behaviors they are striving to improve. Finally, recent studies have begun to highlight potential damaging effects of stimulant exposure in healthy juveniles. This review explains how the main classes of cognitive enhancing drugs affect the learning and memory circuits, and highlights the potential risks and concerns in healthy individuals, particularly juveniles and adolescents. We emphasize the performance enhancement at the potential cost of brain plasticity that is associated with the neural ramifications of nootropic drugs in the healthy developing brain.

https://www.foxnews.com/health/ritalin-may-pose-brain-risks-for-young-people-without-adhd-study-shows

Now, research is showing that methylphenidate may have some hidden side effects for those taking the drug without a prescription – or for those misdiagnosed with ADHD.“We realized this is a drug prescribed to children and there aren’t good diagnostic measures in terms of determining who has ADHD and who doesn’t and it’s probably overprescribed,” study author Dr. Kimberly Urban, a member of the psychology department at the University of Delaware, told FoxNews.com. “And we wanted to find what it could do to a normal brain.”

In collaboration with Wen-Jun Gao, an associate professor in the department of neurobiology and anatomy at Drexel University in Philadelphia, Urban analyzed the effects of methylphenidate on the brains of young, healthy rats. In a study published in Frontiers in Systems Neuroscience, the researchers focused on studying the effects of the drug on the brain’s prefrontal cortex, a region important for cognitive function. There are two basic cell types in the prefrontal cortex: pyramidal cells, or excitatory cells, and interneurons, or inhibitory cells.

Some rats received just one dose of the drug, while others were treated with it for up to three weeks.

“We looked at the pyramidal cells and saw their activity was decreased, so you are slowing down the prefrontal cortex; there is less activity overall,” Urban said. “And we saw reduced communication between [the two types of] neurons and saw an alteration in plasticity [in the prefrontal cortex], which is the brain’s ability to change and adapt to new incoming information.”

The effects were similar in rats treated with varying dosages, though those treated for longer periods of time showed slightly stronger effects.

As a result of these observations, the researchers theorized that, in a normal, non-ADHD brain, methylphenidate may decrease working memory and the ability for a person to shift attention from one thing to another.

“If you get up and think, ‘Oh I need to go to the kitchen to get something,’ [working memory is] the thing that enables you to remember what you went to the kitchen for,” Urban explained.

However, Urban noted that the drug has very different, positive effects for people with ADHD. People with ADHD tend to have an under-active prefrontal cortex; drugs like Ritalin act as a stimulant to increase activity in that region, allowing people to improve their attention span. But in people without ADHD, those same medications may “overload” the brain, causing it to begin to shut down.

“It’s really important when you talk about these drugs and the research we do to specify it’s not bad for ADHD, it is correcting an existing deficit,” Urban said. “But for a normal brain…it can have very different effects.”

These findings pose a risk both to those who use “smart” drugs recreationally, to enhance performance, and for those misdiagnosed with ADHD. The researchers noted that there is no test that can definitively diagnose ADHD; the diagnosis is usually made with a combination of assessments that test for attention difficulties.

“From our point of view, ADHD diagnosis is problematic; many people are probably diagnosed wrong, some people may just be smart, hyperactive, but find teacher or class boring, so they say, ‘Oh you have ADHD,’” Gao told FoxNews.com. “ [In] this case if [a doctor] gives them the drug it may actually damage their brain eventually, so that is a problem.”

Over the long term, the researchers suspect that young people who abuse methylphenidate could be vulnerable to developing hyper-focused or rigid behavior, difficulties with multitasking or problems with short-term memory – particularly because a person’s prefrontal cortex does not finish fully developing until their late 20s or early 30s.

In short, any brief enhancements in attention gained by taking the drug may come at a high cost to the brain later in life.

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Neuro-Inflammation and Vaccines

Akinrinade, Ibukun Dorcas, et al. “Interplay of glia activation and oxidative stress formation in fluoride and aluminium exposure.” Pathophysiology 22.1 (2015): 39-48.

Giannotta, G., and N. Giannotta. “Vaccines and Neuroinflammation.” Int J Pub Health Safe 3.163 (2018): 2.

Background: Post-vaccination adverse reactions (AEs) are a reason of strong debate among scientists. Unfortunately, we often make the mistake of discussing just the epidemiology but not the molecular biology. The action mechanism of the vaccines is still not fully known despite the fact that aluminum adjuvants have been used for about 100 years.
Hypothesis: We hypothesized a link between vaccinations and neuroinflammation. The peripheral proinflammatory
cytokines (IL-1β, IL-6, and TNF-α), expressed after the injection of the vaccines can reach the brain and can cause neuroinflammation after microglia activation. Elevated pro-inflammatory cytokines, particularly TNF-α, have been described in studies regarding the cytokines profile in autistic children. IL-1β represents a cytokine that controls the local pro-inflammatory cascade and thereby affects the balance between protective
immunity and destructive inflammation. A subgroup of children with ASD (Autism Spectrum Disorder) has developed
neuroinflammation. Several postmortem studies have confirmed the activation of microglia and neuroinflammation.
A recent study has shown the presence of aluminum in the brain of individuals with autism and this aluminum was
also found in microglia cells. Aluminum from vaccines is redistributed to numerous organs, including brain, where
it accumulates. Each vaccine adds to this tissue different level of aluminum. Aluminum, like mercury, activates microglia leading to chronic brain inflammation and neurotoxicity. Conclusion: The molecular mechanisms presented here demonstrate how peripheral cytokines, expressed after vaccination, can cause neuroinflammation in some subjects, after microglia activation, depending on the immunogenetic background and the innate immune memory

Dunn, Geoffrey A., Joel T. Nigg, and Elinor L. Sullivan. “Neuroinflammation as a risk factor for attention deficit hyperactivity disorder.” Pharmacology Biochemistry and Behavior 182 (2019): 22-34.

Vázquez-González, Daniela, et al. “A Potential Role for Neuroinflammation in ADHD.” Neuroinflammation, Gut-Brain Axis and Immunity in Neuropsychiatric Disorders. Singapore: Springer Nature Singapore, 2023. 327-356.

Hoekstra, Pieter J. “Attention-deficit/hyperactivity disorder: is there a connection with the immune system?.” European Child & Adolescent Psychiatry 28.5 (2019): 601-602.

Rossignol, Daniel A., and Richard E. Frye. “A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures.” Molecular psychiatry 17.4 (2012): 389-401.

Lovell, Brian, Mark Moss, and Mark Wetherell. “The psychosocial, endocrine and immune consequences of caring for a child with autism or ADHD.” Psychoneuroendocrinology 37.4 (2012): 534-542.

CDC schedule as of 2017, 13 vaccines, 51-54 shots or oral doses, for 16 diseases


List of ADHD Drugs

Amphetamines
amphetamine
dextroamphetamine
lisdexamfetamine
Brand names :
Adderall XR (generic available)
Dexedrine (generic available)
Dyanavel XR
Evekeo
ProCentra (generic available)
Vyvanse
Methamphetamine (Desoxyn)
Methylphenidate works by blocking the reuptake of norepinephrine and dopamine in your brain.Transdermal patch under the brand name Daytrana.
Aptensio XR (generic available)
Metadate ER (generic available)
Concerta (generic available)
Daytrana
Ritalin (generic available)
Ritalin LA (generic available)
Methylin (generic available)
QuilliChew
Quillivant

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The Manipulation of Data and Attitudes about ADHD

Leo, Jonathan, and Jeffrey Lacasse. “The Manipulation of Data and Attitudes about ADHD: A Study of Consumer Advertisments.” Rethinking ADHD: from brain to culture (2009): 287-312.

Between 1994 and 1999, the production of Ritalin increased eight hundred percent, with ninety percent of it being consumed in the United States

ADHD has been the subject of considerable controversy over the years. It has no biological diagnostic markers; it has been theorized to be over-diagnosed in Western countries; and it can be treated by both psychosocial and pharmacological interventions. In addition, the most popular treatments for ADHD are Schedule II pharmaceuticals – psychostimulant drugs, such as methylphenidate or amphetamine, which carry both addictive properties and the risk of iatrogenic harm, and are largely prescribed to a vulnerable population

Leo, Jonathan, and Jeffrey R. Lacasse. “The New York Times and the ADHD epidemic.” Society 52 (2015): 3-8.

Drug companies were given the means, the motive,and the message to disease monger ADHD and blow it up out of all proportion.They succeeded beyond all  expectations in achieving a triumph of clever advertising over common sense.
Allen Frances, Chair, DSMIIV, February 12, 2014

These Are The Ridiculous Ads Big Pharma Used To Convince Everyone They Have ADHD Richard Feloni Dec 16, 2013, 3:29 PM EST

== Methylphenidate Enhanced and Impairment of Memory  ====

Salman, Tabinda, et al. “Enhancement and impairment of cognitive behaviour in Morris water maze test by methylphenidate to rats.” Pakistan journal of pharmaceutical sciences 32.3 (2019).

Abstract: Methylphenidate (MPD), a psycho-stimulant is a prescription medicine for the treatment of Attention deficit hyperactivity disorder (ADHD). The drug is also being increasingly used by general population for enhancing cognition. Only few preclinical studies have been carried out on the effects of MPD on cognition and these studies show either an enhancement or impairment of memory following the administration of MPD.

The present study was designed to evaluate the effects of different doses of methylphenidate on acquisition and retention of memory in Morris water-maze test. Twenty four male Albino Wistar rats (weighing 180-220gm) were randomly assigned to four groups: (1) Control (2) 0.5mg/kg (3) 2.5mg/kg (4) 5 mg/kg methylphenidate. Animals received drug or water orally before training phase. Memory acquisition was monitored 2hrs post drug administration while memory retention was determined next day. It was found that the clinically relevant doses of methylphenidate (0.5mg/kg and 2.5mg/kg) improved memory acquisition and its retention but higher dose (5mg/kg) impaired both. We suggest that MPD-induced increase of catecholamine neurotransmission may have a role in the improvement of water maze performance while agonist activity of the drug for 5HT-1A receptor in the impaired performance at high doses. Food intake and body weight changes were not affected by MPD administration due to short-term administration of the drug. Results may help in improving pharmaco-therapeutic use of MPD for ADHD.

Methylphenidate (MPD) is the most prescribed and commonly used psychostimulant in the treatment of attention deficit hyperactivity disorder (Greydanus et al., 2007). It increases extra cellular concentration of dopamine and nor-epinephrine by blocking the uptake of these two neurotransmitters (Kuczenski and Segal, 2002). ADHD is a developmental disorder characterized by severe and persistent impulsiveness, inattention and hyperactivity (Newcorn and Halperin, 2000). Center for Disease Control reported that prescribed use of MPD to treat symptoms associated with ADHD has dramatically increased in the recent years (Pastor and Reuben, 2008). There is a growing trend to use MPD as ‘cognitive enhancer’ for studying or recreational purposes which later results intolerance (Steiner and Van Waes, 2012). Intranasal abuse produces effects rapidly that are quite comparable with the effects of cocaine (Dupont et al., 2008). Psychostimulant abuse largely produces psychiatric symptoms as reported in clinical data (Morton
and Stockton, 2000).

Studies on the effect of MPD on memory function have reported mixed results depending upon dosage and route of administration (Scherer et al., 2010; Gerasimov et al., 2000). Acute doses of methylphenidate have been reported to improve attention, learning memory while reducing impulsivity in a variety of tasks (Britton, 2012). Moreover, studies have used doses significantly higher (2-15mg/kg i.v. or 10-50mg/kg i.p.) to check their effect on long course of administration (Gerasimov et al., 2000). Different route of drug administration may provide different behavioural and neurochemical effects. In majority of animal studies, MPD treatment have been achieved through sub-cutaneous or intra-peritoneal injections across a broad range of doses (0.5-80.0mg/kg) that surpass the recommended low therapeutically oral doses (0.3-1.0mg/kg) in humans (Yang et al., 2006). On the other hand, repeated methylphenidate administration has been observed to function as a reinforcer and enhance its abuse potential in laboratory settings (Hiranita et al., 2009; Rush and Baker, 2001).

The biochemical action of MPD

The biochemical action of MPD is well characterized (Somkumar et al., 2016). The dopamine transporter (DAT) and norepinephrine transporter (NET) are blocked by MPD, resulting in elevated concentration of dopamine and norepinephrine at synapses (Hannestad et al., 2010). In contrast, the mechanisms by which therapeutic dose of MPD acutely improves cognitive functions and overdose of it induces psychosis are still not clear (Cheng et al., 2014).

Only few studies have been preferred on the effects of clinically relevant doses of oral methylphenidate on cognition (Haleem et al., 2015). These studies are not consistent and have reported mixed results i.e. both enhancement and suppression of working memory is reported to occur following various doses of MPD (Urban et al., 2013). So the aim of study is to monitor the effect of clinically relevant doses (0.5mg/kg and 2.5mg/kg) as well as higher dose of MPD (5mg/kg) for single dose administration to examine its effect on cognitive functions. Water Maze test was used to monitor MPD effects on memory acquisition and its retention on a single day trial of MPD.

MPH (MPD) Binds to DAT with similar affinity to Cocaine

Methylphenidate is high affinity reuptake inhibitor of dopamine (DA) and nor-epinephrine (NE) (Han and Gu, 2006). It binds to DA transporter and inhibits its uptake with potency similar to cocaine (Chen et al, 2005). MPD has also been shown to bind with NE transporter and found to be an effective in vitro inhibitor of NE uptake and might increase extra cellular NE (Vanicek et al, 2014). The promising memory effects of MPD on learning and memory are possibly due to its ability to increase DA and/or NA transmission (Goodman et al., 2006; Juarez & Han, 2016).

RESULTS

Fig. 1 shows the effect of methylphenidate on acquisition learning in Morris water maze test. One-way ANOVA showed that the effects (F=66.057; df=3,20; p<0.01) were significant. Post-hoc test showed that low doses (0.5mg/kg, 2.5mg/kg) methylphenidate improved learning acquisition but higher dose (5mg/kg) impaired it. Increase in learning acquisition was greater at dose of 2.5mg/kg than 0.5mg/kg.

Fig. 2 illustrates the effect of methylphenidate on memory retention in Morris water maze test (20 hours after drug administration). One-way ANOVA showed that the effects (F=39.135; df= 3,20; p<0.01) were significant. Post-hoc analysis showed that low doses (0.5mg/kg, 2.5 mg/kg) methylphenidate increased memory retention. Conversely, high dose (5mg/kg) of methylphenidate increased the time to reach the platform. Thus, low doses of methylphenidate enhanced memory while high dose impaired it. Unlike memory acquisition, the effects of 0.5 mg/kg and 2.5mg/kg of methylphenidate on memory
retention were comparable.

CONCLUSION  The present study shows that low dose of MPD which are also clinically relevant for improving memory and may be useful for ADHD patients. Higher doses, on the other hand, are expected to produce adverse effects on memory and should be avoided.

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++++++++++++++++ already Copied OVer +++++++++++++++

The Adderall Epidemic

Etiology of ADHD

Núñez-Jaramillo, Luis, Andrea Herrera-Solís, and Wendy Verónica Herrera-Morales. “ADHD: Reviewing the causes and evaluating solutions.” Journal of personalized medicine 11.3 (2021): 166.

ADHD is an NDD with a complex etiology. While it is clear that its main cause is alterations in neurodevelopmental processes such as synaptogenesis, myelination, and neurogenesis [5], the causes of these neurodevelopmental alterations are diverse. In some cases they might be associated with environmental factors such as premature birth [6], perinatal problems [9], nutrition during pregnancy [10], or exposure to heavy metals [17–19,26,27,29]. Additionally, there is strong evidence of genetic influence on ADHD [43,44], and an interaction between environmental and genetic factors cannot be discarded.

======    Academic Acheivement ? ===============

de Faria, Joyce Costa Melgaço, et al. ““Real‐world” effectiveness of methylphenidate in improving the academic achievement of Attention‐Deficit Hyperactivity Disorder diagnosed students—A systematic review.” Journal of Clinical Pharmacy and Therapeutics 47.1 (2022): 6-23.

Results and Discussion: Nine studies (from ten reports) were included in the review: four cohorts, two before-and-after designs and three cross-sectional studies. They involved 12,269 children and adolescents aged 6–18 years. The doses of methylphenidate ranged from 10 to 72 mg/day, and the duration of the treatment from 2.6 months to 4.25 years. Five of these studies concluded that methylphenidate improves academic performance. However, three of the four lowest-bias risk studies concluded that the drug is ineffective. Five studies assessed the long-term use of methylphenidate, and four of them concluded that it does not result in better outcomes in the school setting. Most included studies had considerable limitations and significant heterogeneity regarding methodological design and academic performance measurement criteria.

What is new and Conclusion: Although some studies indicate that the short-term use of methylphenidate may improve outcomes in the school environment, the available evidence does not support the establishment of adequate conclusions about the real benefits of methylphenidate in the academic improvement of ADHD students.

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Book
Seitler, Burton Norman. “ADHD: What We’ve Been Told Ain’t Necessarily So.” Deconstructing ADHD: Mental Disorder or Social Construct? 3 (2022): 119.

Watson Arcona Antonuccio 2015

There is no evidence stimulant medications used for ADHD increase intellectual functioning or scholarly contributions”

Compelling new evidence indicates ADHD drug treatment is associated with deterioration in academic and secial-emotional functioning p.10

Raine research studies : Australian children on stimulant medication for eight years, summary of findings:
1) Long term cardiovascular damage (increase in diastolic blood pressure)
2) School failure – despite the long-held (and what turns out to be false) belief that children concentrate better and have higher acheivement when on stimulants.
3) Children receiving stimulants have a 10 times greater chance of being identified by a teacher as performing below grade level.

Inattention and hyperactivity slightly worsened over the long term (contrary to what the general public believes and what some professionals have opined.)

===== No increment in academic learning =============

https://pubmed.ncbi.nlm.nih.gov/35604744/

Pelham, William E., et al. “The effect of stimulant medication on the learning of academic curricula in children with ADHD: A randomized crossover study.” Journal of consulting and clinical psychology 90.5 (2022): 367-380.

Results: Medication had large, salutary, statistically significant effects on children’s academic seatwork productivity and classroom behavior on every single day of the instructional period. However, there was no detectable effect of medication on learning the material taught during instruction: Children learned the same amount of subject-area and vocabulary content whether they were taking OROS-MPH or placebo during the instructional period.

Acute effects of OROS-MPH on daily academic seatwork productivity and classroom behavior did not translate into improved learning of new academic material taught via small-group, evidence-based instruction. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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Click to access JCU_ADHD%20_Boon%20%2011_12_19.pdf

Boon, Helen J. “What do ADHD neuroimaging studies reveal for teachers, teacher educators and inclusive education?.” Child & Youth Care Forum. Vol. 49. Springer US, 2020.

To synthesise neuroimaging studies, which examined differences in brain organisation and function in those with ADHD compared to matched unaffected controls. The overarching goal was to enhance teachers’ understanding of ADHD by providing synthesised research findings around the neurological basis of ADHD.
Method

The PRISMA method was used to search the Medline, PsycINFO, Web of Science and Scopus databases to complete a systematic review of peer-reviewed research that compared individuals with ADHD with matched controls published between 2010 and December 2015.
Results

The identification and analyses of 174 MRI and fMRI relevant studies across a sample of over 24,000 showed that there are significant differences in neural anatomy and processing in ADHD compared to unaffected matched controls.
Conclusions

Compelling evidence shows ADHD is a neurodevelopmental disability, not a socially determined set of behaviours. Results point to an urgent need for teacher professional learning and systematic up-to-date preservice teacher education along with inclusive education policy reform.

Antunes, Marta, and Inês Aguiar. “Trichotillomania, obsessive-compulsive symptoms, and methylphenidate− Is there a link?.” NASCER E CRESCER-BIRTH AND GROWTH MEDICAL JOURNAL 32.1 (2023): 38-40.

Cregin, Dennis, et al. “The Adderall Epidemic: A Proposed Cyclic Relationship between ADHD Medication Use, Academic Performance, and Mental Distress.” Impulse (19343361) 18.1 (2021).

A total of 879 individuals completed an anonymous Google Form survey that was administered at colleges/universities in the U.S. using social media platforms. The survey included questions regarding frequency of ADHD medication use, symptoms experienced, perception of safety, GPA, and general demographic information. Our results indicate that the use of ADHD medication is significantly correlated with a self-reported low GPA as well as an increase in reported mental health side effects (including depression,anxiety, and panic attacks) and physical side effects (including sleep disturbances, fatigue, headaches, and weight loss). Conversely, belief in the efficacy of ADHD medications in aiding academic performance was negatively correlated with a self-reported high GPA. It thus appears that the use of non-prescription ADHD medications is not associated with increased academic performance. Furthermore, mental and physical symptoms related to illicit ADHD medication use are likely to contribute to the observed poor academic performance. It is therefore recommended that college student populations are educated on these findings to decrease illicit use of ADHD medications as study aids.

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Wilcox, Victor T., et al. “Methylphenidate Elicits Long Term Sex Difference Effects.” Pharmacol Ther 3.1 (2022): 1027.

Tissue analyses have identified interesting patterns of astrocyte
atrophy and loss of blood-brain barrier immunological privilege
and inflammation with higher doses of MPD. Interestingly low-dose
MPD can increase cellular junction integrity supporting MPD being
of potential benefit in cognition and treatment of ADHD at lower
dosage, while higher dosages lead to inflammatory and degenerative
effects undermining beneficial effects of the drug

the six daily MPD exposure
in rats can be considered long term consumption of the drug,

Considering the controversial nature of treating
millions of children with MPD, the appreciated differences between
male and females suggest further study of sex differences with use are
warranted as they may impact clinical decisions for human patients.
The variations in locomotor activity expression between sexes and
between the five different locomotor behavior expressions suggest that
the each of these regulate by different neuronal circuits and that MPD
affects each neuronal circuit differently and argue that distinct neuronal
circuits are involved and warrant identification and individual study
to determine the effects of MPD on each circuit. The present study
focused on WKY rats to study sex effects in a non-ADHD rat model.
But further study is warranted to identify sex differences in MPD in
ADHD models such as SHR rats and possibly other genetic strains,
both with early and late initiation of MPD, particularly to determine
sex impacts on chronic behavioral changes and subsequent tendency
towards SUD. [substance abuse disorder]

==================================================

Salman, Tabinda, et al. “Repeated administration of methylphenidate produces reinforcement and downregulates 5-HT-1A receptor expression in the nucleus accumbens.” Life sciences 218 (2019): 139-146.

Evidence suggests that therapeutic or non therapeutic use of MPD results in drug overuse and addiction [8].

Methods: Learning acquisition and memory retention in Morris water-maze test were used to assess cognitive effects of MPD. Reinforcing effects were evaluated in conditioned place-preference (CPP) paradigm. The expression of 5-hydroxytryptamine (5-HT; serotonin)-1A receptor in the nucleus accumbens and prefrontal cortex of repeated MPD treated animals was determined by qRT-PCR.

Findings: Lower doses (0.5 and 2.5 mg/kg) of MPD enhanced learning acquisition and memory retention but higher doses (5 mg/kg) impaired these. The drug administered repeatedly at a dose of 2.5 mg/kg was reinforcing in CPP test, but sensitization like effects of this dose were only transient. These animals tested in water-maze test exhibited improved memory retention but no effect occurred on learning acquisition. The expression of 5-HT-1A receptor was markedly attenuated in the nucleus accumbens; attenuation in the prefrontal cortex was not significant.

Significance: The findings suggest that clinically relevant doses of MPD can produce drug addiction, but effects of the drug on memory retention are retained. A downregulation of 5-HT-1A receptor in the nucleus accumbens seems important in the reinforcing effects of MPD.

===================
Salman, Tabinda, et al. “Differential effects of memory enhancing and impairing doses of methylphenidate on serotonin metabolism and 5-HT1A, GABA, glutamate receptor expression in the rat prefrontal cortex.” Biochimie 191 (2021): 51-61.

Methylphenidate (MPD), a psychostimulant, is a prescription medicine for treating attention deficit hyperactivity disorder (ADHD). Previously we have shown that moderate doses of MPD enhanced learning and memory while higher doses impaired it. To understand neurochemical mechanisms and receptors involved in memory enhancing and impairing effects of MPD, the present study concerns the effects of these doses of MPD on serotonin, 5-HT1A, GABA, and NMDA receptor mRNA expression in the prefrontal cortex (PFC). We found that low doses (2.5 mg/kg) of MPD improved performance in the water-maze test but higher doses (5 mg/kg) impaired memory retention. Animals showing improved performance had high 5-HT metabolism in the PFC while these levels were not affected in the group treated with higher MPD doses and exhibiting impaired memory. There was downregulation of 5-HT1A receptors in the PFC of rats treated with higher dose MPD, which didn’t occur in low dose of MPD treated animals. Further, a decrease in GABAAreceptor mRNA expression occurred in low doses of MPD treated animals and GluN2A expression was reduced in higher doses of MPD treated animals. The findings suggest that memory enhancing doses of MPD increase 5-HT and reduce GABAA receptor mRNA expression in the PFC to release excitatory glutamate neurons from the inhibitory influence of GABA. Conversely, higher dose of MPD downregulates 5-HT1A receptor mRNA expression to enhance inhibitory GABA influence on glutamate neurons and impair cognitive performance. The findings show an important role of 5-HT1A heteroreceptors in the PFC for improving therapeutic use of MPD and developing novel cognitive enhancers.
=========================

Arnsten, Amy FT, and Anne G. Dudley. “Methylphenidate improves prefrontal cortical cognitive function through α2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder.” Behavioral and brain functions 1.1 (2005): 1-9.

Conclusion

The administration of low, oral doses of MPH to rats has effects on PFC cognitive function similar to those seen in humans and patients with ADHD. The rat can thus be used as a model for examination of neural mechanisms underlying the therapeutic effects of MPH on executive functions in humans. The efficacy of idazoxan and SCH23390 in reversing the beneficial effects of MPH indicate that both noradrenergic α2 adrenoceptor and dopamine D1 receptor stimulation contribute to cognitive-enhancing effects of MPH.

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Berridge, Craig W., et al. “Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function.” Biological psychiatry 60.10 (2006): 1111-1120.

The current observations suggest that the therapeutic actions of low-dose psychostimulants involve the preferential activation of catecholamine neurotransmission within the PFC.

Low-Dose MPH Exerts Unique Behavioral and Neurochemical Actions

At moderate and high doses, psychostimulants impair cognition
and exert pronounced reinforcing and locomotor-activating
actions (McGaughy and Sarter 1995; Rebec and Bashore 1984;
Segal 1975). In contrast, at low doses used in the treatment of
ADHD, these drugs are devoid of locomotor-activating effects,
and instead reduce movement and impulsivity and increase
cognitive function, including sustained attention and working
memory (Solanto 1998). Importantly, these actions occur in both
ADHD and normal human subjects (Elliott et al 1997; Mehta et al
2001; Rapoport et al 1980; Rapoport and Inoff-Germain 2002;
Solanto 1998; Vaidya et al 1998; Wilens et al 2004).

================== !!!!!!!!!!!!!!!!!!!!!!! GOOD !!!!!!!!!!!!!!!!!!!!

2012

Urban, Kimberly R., Barry D. Waterhouse, and Wen-Jun Gao. “Distinct age-dependent effects of methylphenidate on developing and adult prefrontal neurons.” Biological psychiatry 72.10 (2012): 880-888.

Attention deficit/hyperactivity disorder (ADHD) is a commonly diagnosed behavioral disorder. The major symptoms of childhood ADHD include hyperactivity, inattentiveness, impulsivity, and risk-taking; if untreated these behaviors may persist for life (1-4). The etiology of ADHD is unknown, but a delayed maturation of prefrontal cortex (PFC) in ADHD patients has been proposed (5). Functional MRI studies have revealed decreased blood flow in PFC of affected individuals, and the symptoms resemble those seen in patients with PFC injury (6, 7).

The clinical community largely subscribes to a dopamine (DA)/norepinephrine (NE) hypofunction hypothesis of ADHD; therefore, the pharmaceuticals prescribed to treat ADHD focus on raising levels of DA and NE to restore brain functions associated with attention (6-8). Methylphenidate (Ritalin®, MPH) is the most commonly prescribed medication (9). It has been determined that MPH acts primarily on the dopaminergic and noradrenergic systems through blockade of DA and NE transporters, thereby increasing the concentrations of these neurotransmitters in the brain to correct the attention deficits and hyperactivity (10-14). However, beyond this well-documented biochemical action, the basis for its clinical efficacy is not well characterized, particularly at the level of individual neurons.

Because of the paucity of juvenile rodent studies, and the limited range of doses that have been explored, it is necessary to examine the effects of clinically-relevant doses of MPH in a juvenile rat system. In this study, we examined age- and dose-dependent effects of MPH administration on neuronal excitability and synaptic transmission in the layer 5 pyramidal neurons of rat PFC.

Discussion

There are several novel findings here. First, we observed distinct age-dependent actions of MPH on prefrontal neurons. In particular, juvenile PFC neurons are supersensitive to even very low doses of MPH. Both single-dose and chronic treatment regimens of MPH at doses that enhance attentional processes and pyramidal neuron activity in adult rats () resulted in a significant decrease of neuronal excitability and synaptic transmission in PFC layer 5 pyramidal neurons in juvenile rats. Second, higher doses of MPH induced long-lasting depressant effects on juvenile rat PFC neurons.

Low doses of MPH improve working memory and sustained attention (16) in the absence of enhanced arousal or locomotor activation (1, 12). Collectively, these results indicate that the behavioral and cognitive actions of low-dose MPH are applicable to both normal rats and ADHD patients and are qualitatively distinct from the behavioral effects observed in response to higher doses.

However, it is apparent that developmental age and MPH dose play a critical role in determining the effects of drug administration on prefrontal neurons. Treatment with MPH resulted in significant reduction in both excitability and synaptic transmission in the juvenile rat. This reduction in excitability may seem counterintuitive, as the drug has previously been found to increase cortical excitability at low doses and increase locomotion at higher doses in adult rats.(24, 50) The reason for these discrepancies is unknown but our data indicate that juvenile rat prefrontal neurons are supersensitive to MPH and that the observed effects are age-dependent. Indeed, in a study of the long-term effects of MPH treatment in adolescent animals, Brandon et al (34) administered MPH (2 mg/kg, IP) during PD35–42 and found an enhanced rewarding effect on subsequent cocaine self-administration. In contrast, the same dose (2 mg/kg, IP) in slightly younger rats (PD20–35) was found to attenuate the rewarding effect (35, 51). Our results were opposite to those seen in adult rats, in which prefrontal neurons are excited by low-dose stimulant treatment (10, 52) or by systemic administration of 2 mg/kg MPH (53). Taken together these results argue for an age-dependent action of MPH on prefrontal neurons.

ADHD is thought to result from prefrontal hypoactivity, a condition corrected by the administration of stimulants (6, 54). However, it is not clear whether the behaviorally effective range of doses identified in adult rodents can be directly translated to juveniles. Therefore, even a dose of MPH thought to be within the clinically-relevant range, 1 mg/kg, may in fact cause excessively high levels of DA and NE in the juvenile PFC. If so, the results seen here may in fact be explained through the actions of DA and NE on cAMP-HCN signaling. It has been reported that physiological levels of NE in the PFC activate α2A-adrenoceptors, which inhibit cAMP signaling (55). Excessive levels of NE, however, activate not only the high affinity α2A receptors, but also lower affinity α1 and β1 receptors (55). This increased cAMP signaling could result in decreased neuronal activity and synaptic transmission via over-activation of the cAMP-HCN channels. Activation of HCN channels results in an influx of cations which hyperpolarize neurons and render them unresponsive to incoming synaptic stimuli. This results in a decrease in excitability and, therefore, a decrease in signal transmission by the unresponsive neuron. Consistent with this assumption, treatment with 1 mg/kg MPH resulted in increased amplitude of Ih current concomitant with the decreased excitability in juvenile rat PFC neurons. Thus the significant decrease in excitability observed in juvenile pyramidal neurons is likely due to MPH creating excessive levels of NE and DA, which in turn increase cAMP-HCN signaling across the PFC, decreasing neuronal responsiveness and transmission (56, 57). However, further studies are needed to elucidate the mechanisms of the opposing MPH actions in adult rats in which the HCN channel properties appear to be different (58, 59). It is known that a developmental decrease in time kinetics of I(h) in hippocampus leads to increased adult pyramidal neuron firing rate, and changes in HCN channel isoforms lead to reduced involvement of the channel in I(h) (58, 59). Furthermore, the expression of DA receptors changes over development, with D2 (inhibitory) higher during juvenile period, and D1 (excitatory) levels higher in adulthood (60-62).

The optimal dose-response range for juvenile rats is lower than that for adults. Therefore, clinical dose ranges for use in humans may need to be adjusted for age as well as weight (currently only body weight is taken into account). Furthermore, these effects are reversible at the 1 mg/kg dose but not at higher doses, indicating potential lasting effects from long-term treatment or drug abuse and stressing the need for tighter regulation of ADHD diagnoses and more careful observation of patients currently undergoing treatment. This research emphasizes the importance of further examination of MPH effects in the juvenile developing brain, and suggests a reexamination of the definition of “therapeutic range” when designing treatment regimens for patients or behavioral paradigms for experimental subjects.

In addition, our data suggest a discrepancy between PFC functional outcomes in adults vs. juvenile rats following administration of equivalent doses of MPH and thus reveal a potential for permanent, or at least long-lasting, PFC changes in MPH-treated children. MPH is generally thought to be safe and free of lasting significant side effects when it is administered at the recommended, clinically-approved doses (5-15 mg, 3 times daily oral in humans) (63). However, recent studies have shown that the drug may cause changes to brain circuitry and function that persist long after drug clearance (49, 64, 65). For example, MPH induces deficits in object recognition and spatial working memory for up to 42 days post-drug administration in both adult and peri-adolescent rats (64, 65). These results and other similar studies suggest that MPH may indeed cause lasting, even permanent, changes in neuronal function (41, 43, 49). Our findings that passive membrane properties of PFC neurons did not recover to control levels following high MPH doses agree with this body of evidence.

Conclusions

These results suggest that the juvenile prefrontal cortex is supersensitive to methylphenidate, and the accepted therapeutic range for adults is an overshoot. Juvenile treatment with MPH may result in long-lasting, potentially permanent, changes to excitatory neuron function in the prefrontal cortex of juvenile rats.

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!!!!!!!!!!!!!! GOOD   2013     !!!!!!!!!!!!!!!

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Urban, Kimberly R., and Wen-Jun Gao. “Methylphenidate and the juvenile brain: enhancement of attention at the expense of cortical plasticity?.” Medical hypotheses 81.6 (2013): 988-994.

Above imge: Comparison of action potentials in prefrontal cortex neurons in juvenile mice (upper frame) and adult mice (lower frame) injected with single dose saline upper graph, and single dose methylphenidate lower chart.

A) Juvenile Mice: Upper Frame Left side, Blue Ellipse and Arrow: juvenile mice injected with chronic saline (upper graph controls) compared to chronic methyphenidate (MPH) (lower graph). Notice decreased frequency of action potential spikes after MPH in juvenile mice, indicating depression of brain activity in PFC from single dose MPH.

A) Juvenile Mice Upper Frame Green Ellipse/Arrow shows action potential spikes after chronic saline (Green Ellipse and Arrow) or After chronic MPH (Red Ellipse and Arrow). Notice chronic MPH use decreases frequency of spikes, which then stop short, indicating severe depression of prefrontal cortex neurons in juvenile mice.

B) Adult Mice Lower Frame: Green Arrow and Elipse shows chronic Saline given to Adult mice (serving as controls), while Red Ellipse and Arrows shows Chronic MPH administration to the adult mice. Notice chronic MPH dosage increases frequency of action potential spikes in adult mice compared to saline controls indicating increased stimulation of PFC neurons, the opposite of the depressive effect in juvenile mice.

Last updated on by Jeffrey Dach MD

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