Methylphenidate is a
psychostimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
drugA drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
approved for
treatmentThis is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
of
attention-deficit hyperactivity disorderAttention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
,
postural orthostatic tachycardia syndromePostural orthostatic tachycardia syndrome is a condition of dysautonomia, more specifically orthostatic intolerance, in which a change from the supine position to an upright position causes an abnormally large increase in heart rate, called tachycardia...
and
narcolepsyNarcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...
. It may also be prescribed for
off-label useOff-label use is the practice of prescribing pharmaceuticals for an unapproved indication or in an unapproved age group, unapproved dose or unapproved form of administration...
in treatment-resistant cases of lethargy,
depressionDepression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, neural insult and
obesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. Methylphenidate belongs to the
piperidinePiperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
class of compounds and increases the levels of
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and
norepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
in the brain through
reuptake inhibitionA reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
of the
monoamine transporterMonoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
s. Methylphenidate possesses structural similarities to
amphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
and its pharmacological effects are more similar to those of
cocaineCocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, though MPH is less potent and longer in duration of action.
Medical uses
MPH is the most commonly prescribed psychostimulant and works by increasing the activity of the
central nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention. The short-term benefits and cost effectiveness of methylphenidate are well established, although long-term effects are unknown. The long term effects of methylphenidate on the developing brain are unknown. Methylphenidate is not approved for children under six years of age.
Attention deficit hyperactivity disorder
Methylphenidate is approved by the
U.S. Food and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) for the treatment of
attention-deficit hyperactivity disorderAttention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
The addition of behavioural modification therapy (e.g. cognitive behavioral therapy (CBT)) has additional benefits on treatment outcome. There is a lack of evidence of the effectiveness in the long term of beneficial effects of methylphenidate with regard to learning and academic performance. One study found that pharmacological treatment of ADHD in childhood reduces the risk that children will resort to substance abuse in adolescence by 85%, while untreated ADHD was a significant risk factor in developing substance abuse. A meta analysis of the literature concluded that methylphenidate quickly and effectively reduces the signs and symptoms of ADHD in children under the age of 18 in the short term but found that this conclusion may be biased due to the high number of low quality clinical trials in the literature. There have been no placebo controlled trials investigating the long term effectiveness of methylphenidate beyond 4 weeks thus the long term effectiveness of methylphenidate has not been scientifically demonstrated. Serious concerns of
publication biasPublication bias is the tendency of researchers, editors, and pharmaceutical companies to handle the reporting of experimental results that are positive differently from results that are negative or inconclusive, leading to bias in the overall published literature...
regarding the use of methylphenidate for ADHD have also been noted. A diagnosis of ADHD must be confirmed and the benefits and risks and proper use of stimulants as well as alternative treatments should be discussed with the parent before stimulants are prescribed. The dosage used can vary quite significantly from individual child to individual child with some children responding to quite low doses whereas other children require the higher dose range. The dose, therefore, should be titrated to an optimal level that achieves therapeutic benefit and minimal side-effects. This can range from anywhere between 5–30 mg twice daily or up to 60 mg a day. Therapy with methylphenidate should not be indefinite. Weaning off periods to assess symptoms are recommended.
Narcolepsy
NarcolepsyNarcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...
, a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden need for sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance. Methylphenidate improves measures of
somnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
on standardized tests, such as the
Multiple Sleep Latency TestThe Multiple Sleep Latency Test is a sleep disorder diagnostic tool. It is used to measure the time elapsed from the start of a daytime nap period to the first signs of sleep, called sleep latency...
, but performance does not improve to levels comparable to healthy controls.
Adjunctive
Use of stimulants such as methylphenidate in cases of treatment resistant depression is controversial. In individuals with cancer, methylphenidate is commonly used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function. Methylphenidate may be used in addition to an antidepressant for treatment-refractory major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. However, benefits tend to be only partial with stimulants being, in general, less effective than traditional antidepressants and there is some suggestive evidence of a risk of
habituationHabituation can be defined as a process or as a procedure. As a process it is defined as a decrease in an elicited behavior resulting from the repeated presentation of an eliciting stimulus...
. Stimulants may however, have fewer side-effects than tricyclic antidepressants in the elderly and medically ill. A review of the literature found that methylphenidate was ineffective for refractory cases of major depression.
Substance dependence
Methylphenidate has shown some benefits as a replacement therapy for individuals dependent on
methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
. Cocaine and methamphetamine interfere with the protein
DATThe dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
, over time causing DAT upregulation and lower
cytoplasmThe cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic dopamine levels in their absence. Methylphenidate and
amphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
have been investigated as a chemical replacement for the treatment of cocaine dependence in the same way that
methadoneMethadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
is used as a replacement for
heroin. Its effectiveness in treatment of cocaine or other psychostimulant dependence has not been proven and further research is needed.
Early research began in 2007–2008 in some countries on the effectiveness of methylphenidate as a substitute agent in refractory cases of cocaine dependence, owing to methylphenidate's longer half life, and reduced vasoconstrictive effects. This replacement therapy is used in other classes of drugs such as opiates for maintenance and gradual withdrawal such as methadone, suboxone, etc.
Pervasive developmental disorderPervasive developmental disorders is a diagnostic category refers to a group of disorders characterized by delays or impairments in communication, social behaviors, and cognitive development.Pervasive developmental disorders include Autism, Asperger's syndrome, Rett's syndrome, Childhood...
s
Given the high
comorbidityIn medicine, comorbidity is either the presence of one or more disorders in addition to a primary disease or disorder, or the effect of such additional disorders or diseases.- In medicine :...
between ADHD and
autismAutism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, a few studies have examined the efficacy and effectiveness of methylphenidate in the treatment of autism. However, most of these studies examined the effects of methylphenidate on attention and hyperactivity symptoms among children with
autism spectrum disordersThe term "autism spectrum" is often used to describe disorders that are currently classified as pervasive developmental disorders. Pervasive developmental disorders include autism, Asperger syndrome, Childhood disintegrative disorder, Rett syndrome and Pervasive Developmental Disorder Not Otherwise...
. Aman and Langworthy (2000) attempted to examine the effects of methylphenidate on social-communication and self-regulation behaviors among children with
disordersThe term "autism spectrum" is often used to describe disorders that are currently classified as pervasive developmental disorders. Pervasive developmental disorders include autism, Asperger syndrome, Childhood disintegrative disorder, Rett syndrome and Pervasive Developmental Disorder Not Otherwise...
.
The sample included 33 children with pervasive developmental disorder (29 boys) with a mean age of 6.93 years (range 5–13). This was a 4-week randomized, double-blind, cross-over placebo study, with treatment changing each week between 4 conditions: placebo, low dose, medium dose, and high dose. In this design, neither the experimenters nor the families know which of the 4 treatments the child is receiving at any given time. In addition, the treatment condition changes randomly each week, without anyone knowing the nature of the old or new condition. This allows the experimenters to assume that consistent changes in behaviors that occur during a particular treatment is truly due to the effect of that treatment and not to the expectation of the treatment (placebo effect).
The results indicate that children showed significantly more joint attention behaviors when receiving methylphenidate than when receiving the placebo (although the most effective dosage varied by individual). Furthermore, at a group level, the low dose of methylphenidate resulted in significantly improved joint attention behaviors when compared to the placebo, but no differences were noted between the low, medium, and high doses. Low and medium doses of methylphenidate also resulted in improved self-regulation behavior when compared to placebo.
The study presents compelling preliminary evidence suggesting that methylphenidate is effective in improving some social behaviors among children with autism spectrum disorders.
Investigational
Animal studies using rats with ADHD-like behaviours were used to assess the safety of methylphenidate on the developing brain and found that psychomotor impairments, structural and functional parameters of the dopaminergic system were improved with treatment. This animal data suggests that methylphenidate supports brain development and hyperactivity in children diagnosed with ADHD. However, in normal control animals methylphenidate caused long lasting changes to the dopaminergic system suggesting that if a child is misdiagnosed with ADHD they may be at risk of long lasting adverse effects to brain development. Animal tests found that rats given methylphenidate grew up to be more stressed and emotional. It is unclear due to lack of followup study whether this occurs in ADHD like animals and whether it occurs in humans. However, long lasting benefits of stimulant drugs have not been found in humans.
Pregnancy
The
U.S. Food and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) gives methylphenidate a
pregnancy categoryThe pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites that are present in breast...
of C, and women are advised to only use the drug if the benefits outweigh the potential risks. Not enough animal and human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2007, empirical literature included 63 cases of prenatal exposure to methylphenidate across three empirical studies. One of these studies (N = 11) demonstrated no significant increases in malformations. A second (N = 13) demonstrated one major malformation in newborns with early exposure to methylphenidate, which was in the expected range of malformations. However, this was a cardiac malformation, which was not within the statistically expected range. Finally, in a retrospective analysis of patients' medical charts (N = 38), researchers examined the relationship between abuse of intravenous methylphenidate and pentazocine in pregnant women. Twenty-one percent of these children were born prematurely, and several had stunted growth and withdrawal symptoms (31% and 28%, respectively). Intravenous methylphenidate abuse was confounded with the concurrent use of other substances (e.g., cigarettes,
alcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
) during pregnancy.
Adverse effects
Some adverse effects may emerge during chronic use of methylphenidate so a constant watch for adverse effects is recommended. Some adverse effects of stimulant therapy may emerge during long-term therapy, but there is very little research of the long-term effects of stimulants. The most common side effects of methylphenidate are nervousness, drowsiness and
insomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
. Other adverse reactions include:
- Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
- Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
- Alopecia
Alopecia means loss of hair from the head or body. Alopecia can mean baldness, a term generally reserved for pattern alopecia or androgenic alopecia. Compulsive pulling of hair can also produce hair loss. Hairstyling routines such as tight ponytails or braids may induce Traction alopecia. Both...
- Angina
Angina pectoris, commonly known as angina, is chest pain due to ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries . Coronary artery disease, the main cause of angina, is due to atherosclerosis of the cardiac arteries...
- Appetite loss
Anorexia is the decreased sensation of appetite...
- Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
- Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
and pulseIn medicine, one's pulse represents the tactile arterial palpation of the heartbeat by trained fingertips. The pulse may be palpated in any place that allows an artery to be compressed against a bone, such as at the neck , at the wrist , behind the knee , on the inside of the elbow , and near the...
changes (both up and down)
- Cardiac arrhythmia
- Diaphoresis
Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions.Diaphoretic is the state of perspiring profusely, or something that has the power to cause increased perspiration....
(sweating)
- Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
- Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
- Dysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
or EuphoriaEuphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
- Formication
Formication is the medical term for a sensation that resembles that of insects crawling on the skin. It is one specific form of a set of sensations known as paresthesia, which also include the more common prickling, tingling sensation of "pins and needles"...
- Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s
- Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
(including skin rash, urticariaUrticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
, feverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, arthralgiaArthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
, exfoliative dermatitis, erythema multiformeErythema multiforme is a skin condition of unknown cause, possibly mediated by deposition of immune complex in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure...
, necrotizing vasculitis, and thrombocytopenic purpuraThrombocytopenic purpura are purpura associated with a reduction in circulating blood platelets which can result from a variety of causes.- Types :...
)
- Lethargy
- Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
increased or decreased
- Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
- Palpitation
A palpitation is an abnormality of heartbeat that causes a conscious awareness of its beating, whether it is too slow, too fast, irregular, or at its normal frequency. The word may also refer to this sensation itself...
s
- Pupil dilation
- Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
- Short-term weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
- Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
- Stunted growth
Stunted growth is a reduced growth rate in human development. It is a primary manifestation of malnutrition in early childhood, including malnutrition during fetal development brought on by the malnourished mother. In developing countries, stunted growth is a common problem affecting a large...
- Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
- Xerostomia
Xerostomia is the medical term for the subjective complaint of dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties, cottonmouth, drooth, or doughmouth. Several diseases, treatments, and medications can cause xerostomia. It can also be exacerbated by smoking or...
(dry mouth)
Risks to health
Researchers have also looked into the role of methylphenidate in affecting
stature, with some studies finding slight decreases in height acceleration.
Other studies indicate height may normalize by adolescence. In a 2005 study, only "minimal effects on growth in height and weight were observed" after 2 years of treatment. "No clinically significant effects on vital signs or laboratory test parameters were observed."
A 2003 study tested the effects of dexmethylphenidate (Focalin), levomethylphenidate, and (racemic) dextro-, levomethylphenidate (Ritalin) on mice to search for any carcinogenic effects. The researchers found that all three preparations were non-genotoxic and non-clastogenic; d-MPH, d, l-MPH, and l-MPH did not cause mutations or chromosomal aberrations. They concluded that none of the compounds present a carcinogenic risk to humans. Current scientific evidence supports that long-term methylphenidate treatment does not increase the risk of developing cancer in humans.
It was documented in 2000, by Zito et al. "that at least 1.5% of children between the ages of two and four are medicated with stimulants, anti-depressants and anti-psychotic drugs, despite the paucity of controlled scientific trials confirming safety and long-term effects with preschool children."
On March 22, 2006, the FDA Pediatric Advisory Committee decided that medications using methylphenidate ingredients do not need
black box warningsIn the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
about their risks, noting that "for normal children, these drugs do not appear to pose an obvious cardiovascular risk." Previously, 19 possible cases had been reported of
cardiac arrestCardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
linked to children taking methylphenidate and the Drug Safety and Risk Management Advisory Committee to the FDA recommend a
"black-box" warningIn the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
in 2006 for stimulant drugs used to treat attention deficit/hyperactivity disorder.
Doses prescribed of stimulants above the recommended dose level is associated with higher levels of
psychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, substance misuse and psychiatric admissions.
Long-term effects
The effects of long-term methylphenidate treatment on the developing brains of children with ADHD is the subject of study and debate. Although the safety profile of short-term methylphenidate therapy in clinical trials has been well established, repeated use of psychostimulants such as methylphenidate is less clear. There are no well defined withdrawal schedules for discontinuing long-term use of stimulants. There is limited data that suggests there are benefits to long-term treatment in correctly diagnosed children with ADHD, with overall modest risks. Short-term clinical trials lasting a few weeks show an incidence of psychosis of about 0.1%. A small study of just under 100 children that assessed long-term outcome of stimulant use found that 6% of children became psychotic after months or years of stimulant therapy. Typically, psychosis would abate soon after stopping stimulant therapy. As the study size was small, larger studies have been recommended. The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown. Concerns have been raised that long-term therapy might cause drug dependence,
paranoiaParanoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
,
schizophreniaSchizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and behavioral sensitisation, similar to other stimulants. Psychotic symptoms from methylphenidate can include
hearing voicesHearing Voices or Hearing voices may be:* Auditory hallucination* Hearing Voices , 2001 audio-recording collection by D. Mahler* Hearing Voices Movement, a different way of viewing people who hear voices...
, visual hallucinations, urges to harm oneself, severe
anxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
,
euphoriaEuphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
,
grandiosityGrandiosity is chiefly associated with narcissistic personality disorder, but also commonly features in manic or hypomanic episodes of bipolar disorder....
, paranoid delusions,
confusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, increased
aggressionIn psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...
and
irritabilityIrritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
. Methylphenidate psychosis is unpredictable in whom it will occur. Family history of mental illness does not predict the incidence of stimulant toxicosis in children with ADHD. High rates of childhood stimulant use is found in patients with a diagnosis of
schizophreniaSchizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and
bipolar disorderBipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
independent of ADHD. Individuals with a diagnosis of bipolar or schizophrenia who were prescribed stimulants during childhood typically have a significantly earlier onset of the psychotic disorder and suffer a more severe clinical course of psychotic disorder. Knowledge of the effects of chronic use of methylphenidate is poorly understood with regard to persisting behavioral and neuroadaptational effects.
Tolerance and behavioural sensitisation may occur with long-term use of methylphenidate. There is also cross tolerance with other stimulants such as amphetamines and
cocaineCocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
. Stimulant
withdrawalWithdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
or rebound reactions can occur and should be minimised in intensity, e.g. via a gradual tapering off of medication over a period of weeks or months. A very small study of abrupt withdrawal of stimulants did suggest that withdrawal reactions are not typical. Nonetheless, withdrawal reactions may still occur in susceptible individuals. The
withdrawalWithdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
or rebound symptoms of methylphenidate can include
psychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
,
depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
,
irritabilityIrritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
and a temporary worsening of the original ADHD symptoms. Methylphenidate, due to its very short elimination half life, may be more prone to rebound effects than d-amphetamine. Up to a third of children with ADHD experience a
rebound effectThe rebound effect, or rebound phenomenon, is the tendency of some medications, when discontinued suddenly, to cause a return of the symptoms it relieved, and that, to a degree stronger than they were before treatment first began...
when methylphenidate dose wears off.
Interactions
Intake of adrenergic agonist drugs or
pemolinePemoline was first synthesized in 1913 but it's activity was not discovered until the 1930s. Under the names it was used as a medication used to treat attention-deficit hyperactivity disorder and narcolepsy. Under the Convention on Psychotropic Substances, it is a Schedule IV drug...
with methylphenidate increases the risk of liver toxicity. Antidepressants taken in conjunction with methylphenidate may cause
hypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
,
hypothermiaHypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
and convulsions. When methylphenidate is coingested with ethanol, a metabolite called
ethylphenidateEthylphenidate is a potent psychostimulant that acts as both a dopamine reuptake inhibitor and norepinephrine reuptake inhibitor, meaning it effectively boosts the levels of the norepinephrine and dopamine neurotransmitters in the brain, by binding to, and partially blocking the transporter...
is formed via hepatic transesterification, not unlike the hepatic formation of
cocaethyleneCocaethylene is the ethyl ester of benzoylecgonine. It is structurally similar to cocaine, which is the methyl ester of benzoylecgonine. Cocaethylene is formed in vivo when cocaine and ethyl alcohol have been ingested simultaneously....
from cocaine and alcohol. Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%. Ethylphenidate is more selective to the
dopamine transporterThe dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
(DAT) than methylphenidate, having approximately the same efficacy as the parent compound, but has significantly less activity on the
norepinephrine transporterThe norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
(NET).
Contraindications
Methylphenidate should not be prescribed concomitantly with
tricyclic antidepressantTricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s, such as
desipramineDesipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
, or
monoamine oxidase inhibitorMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s, such as
phenelzinePhenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
or
tranylcypromineTranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
, as methylphenidate may dangerously increase plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects). Methylphenidate should not be prescribed to patients who suffer from severe arrhythmia, hypertension or
liver damageThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. It should not be prescribed to patients who demonstrate drug-seeking behaviour, pronounced agitation or nervousness. Care should be taken while prescribing methylphenidate to children with a family history of
Paroxysmal Supraventricular Tachycardia (PSVT)Supraventricular tachycardia is a general term that refers to any rapid heart rhythm originating above the ventricular tissue. Supraventricular tachycardias can be contrasted to the potentially more dangerous ventricular tachycardias - rapid rhythms that originate within the ventricular...
.
Special precautions
Special precaution is recommended in individuals with epilepsy with additional caution in individuals with uncontrolled epilepsy due to the potential for methylphenidate to lower the seizure threshold.
Abuse potential
Methylphenidate has high potential for
abuseA substance-related disorder is an umbrella term used to describe several different conditions associated with several different substances .A substance related disorder is a condition in which an individual uses or abuses a...
due to its pharmacological similarity to
cocaineCocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
and amphetamines. Methylphenidate, like other stimulants, increases
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
levels in the brain, but at therapeutic doses this increase is slow, and thus
euphoriaEuphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
does not typically occur except in rare instances. The abuse potential is increased when methylphenidate is crushed and insufflated (snorted), or when it is injected, producing effects almost identical to cocaine. Cocaine-like effects can also occur with very large doses taken orally. The dose, however, that produces euphoric effects varies between individuals. Methylphenidate is actually more potent than cocaine in its effect on dopamine transporters. Methylphenidate should not be viewed as a weak stimulant as has previously been hypothesised.
The primary source of methylphenidate for abuse is diversion from legitimate prescriptions, rather than illicit synthesis. Those who use it to stay awake do so by taking it orally, while intranasal and intravenous are the preferred means for inducing euphoria. IV users tend to be adults whose use may cause panlobular pulmonary emphysema.
Abuse of prescription stimulants is higher amongst college students than non-college attending young adults. College students use methylphenidate either as a study aid or to stay awake longer. Increased alcohol consumption due to stimulant misuse has additional negative effects on health. Methylphenidate's pharmacological effect on the central nervous system is almost identical to that of cocaine. Studies have shown that the two drugs are nearly indistinguishable when administered intravenously to cocaine addicts.
However, cocaine has a slightly higher affinity for the dopamine receptor in comparison to methylphenidate, which is thought to be the mechanism of the euphoria associated with the relatively short-lived cocaine high. Reports of users experimenting with mixing methylphenidate with caffeine and benzocaine to produce a powder for
insufflationInsufflation is the practice of inhaling a substance. Insufflation has limited medical use, but is a common route of administration with many respiratory drugs used to treat conditions in the lungs and paranasal sinus .The technique is common for many recreational drugs and is also used for some...
(snorting) for an even more cocaine-like effect began to appear in the middle 1970s; this is apparently an incrementation upon a mixture known as Toot containing
phenylpropanolaminePhenylpropanolamine , also known as the stereoisomers norephedrine and norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine chemical classes which is used as a stimulant, decongestant, and anorectic agent. It is commonly used in prescription and over-the-counter cough...
, caffeine, and benzocaine in the search for legal highs. As moderate doses of cocaine have caffeine-like effects and benzocaine produces a slight stimulant effect of its own perhaps 5% the strength of cocaine with a ceiling in that range, the mixture is reported to have at least some of the sought-after effects.
Patients who have been prescribed Ritalin have been known to sell their tablets to others who wish to take the drug recreationally. In the USA it is one of the top ten stolen prescription drugs and is known as "kiddie coke", "Vitamin R" and "The R Ball". Recreational users may crush the tablets and either snort the powder, or dissolve the powder in water, filter it through cotton wool into a syringe to remove the inactive ingredients and other particles and inject the drug intravenously. Both of these methods increase
bioavailabilityIn pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
and produce a much more rapid onset of effects than when taken orally (within c.5–10 minutes through insufflation and within just 10–15 seconds through intravenous injection); however the overall duration of action tends to be decreased by any non-oral use of drug preparations made for oral use.
Methylphenidate is sometimes used by students to enhance their mental abilities, improving their concentration and helping them to study. Professor
John HarrisJohn Harris, FRSA, FMedSci , is a British bioethicist and philosopher. He is the Lord Alliance Professor of Bioethics and Director of the Institute for Science, Ethics and Innovation at the University of Manchester. He was educated at the University of Kent and Balliol College, Oxford...
, an expert in bioethics, has said that it would be unethical to stop healthy people taking the drug. He also argues that it would be "not rational" and against human enhancement to not use the drug to improve people's cognitive abilities. Professor Anjan Chatterjee however has warned that there is a high potential for abuse and may cause serious adverse effects on the heart, meaning that only people with an illness should take the drug. In the
British Medical JournalBMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
he wrote that it was premature to endorse the use of Ritalin in this way as the effects of the drug on healthy people have not been studied. Professor Barbara Sahakian has argued that the use of Ritalin in this way may give students an unfair advantage in examinations and that as a result universities may have to consider making students give urine samples to be tested for the drug.
Overdose
In 2004, over 8000 methylphenidate ingestions were reported in US poison center data. The most common reasons for intentional exposure were drug abuse and suicide attempts. An overdose manifests in agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia. Benzodiazepines may be used as treatment if agitation, dystonia, or convulsions are present.
Detection in biological fluids
The concentration of methylphenidate or ritalinic acid, its major metabolite, may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.
Pharmacology
Methylphenidate is a chain substituted
amphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
derivative that primarily acts as a
norepinephrine-dopamine reuptake inhibitorA norepinephrine-dopamine reuptake inhibitor is a drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter and the dopamine transporter , respectively...
Similar to
amphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
s and
cocaineCocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, a key target of methylphenidate is the dopamine transporter (DAT).
Moreover, it is thought to act as a
releasing agentA releasing agent , or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and...
by increasing the release of dopamine and norepinephrine, though to a much lesser extent than amphetamines. Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from amphetamines, as methylphenidate is thought to increase general firing rate, whereas amphetamines reverse the flow of the monoamine transporters.
Although methylphenidate is an amphetamine derivative, subtle differences exist in its pharmacology; amphetamine works as a dopamine transport substrate whereas methylphenidate works as a dopamine transport blocker. Methylphenidate is most active at modulating levels of
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and to a lesser extent noradrenaline.
Methylphenidate has both
DATThe dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
and
NETThe norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextro- and levorotary enantiomers displayed receptor affinity for the
serotonergicSerotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
5HT
1A and 5HT
2B subtypes, though direct binding to the
serotonin transporterThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
was not observed.
The enantiomers and the relative psychoactive effects and CNS stimulation of dextro- and levo-methylphenidate is analogous to what is found in amphetamine, where dextro-amphetamine is considered to have a greater psychoactive and CNS stimulatory effect than levo-amphetamine.
Pharmacodynamics
Methylphenidate exerts its therapeutic effects via blocking the reuptake of dopamine into nerve terminals (as well as stimulating the release of dopamine from dopamine nerve terminals) resulting in increased
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
levels in the
synapseIn the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
. The onset of
central nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
effects occurs rapidly after intake of methylphenidate and persist for about 4 hours.
The mechanism of action is comparable with that of cocaine with usual doses of both drugs occupying 50% of dopamine transporters. However, effects such as
euphoriaEuphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
that resembles that of cocaine are rare at doses prescribed clinically.
The means by which methylphenidate affects people diagnosed with ADHD are not well understood. Some researchers have theorized that ADHD is caused by a
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
imbalance in the
brainThe brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
s of those affected. Methylphenidate is a norepinephrine and
dopamine reuptake inhibitorA dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
, which means that it increases the level of the dopamine
neurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the
synapseIn the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s. This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse. It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus. An alternate explanation that has been explored is that the methylphenidate affects the action of
serotoninSerotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
in the brain. However, benefits with other stimulants that have a different mechanism of action indicates that support for a deficit in specific neurotransmitters is unsupported and unproven by the evidence and remains a speculative
hypothesisA hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...
.
Many have asked why a stimulant would be used to treat hyperactivity, as it seems paradoxical. However,
MRIMagnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
scans have revealed that people with ADHD show differences from non-ADHD individuals in brain regions important for attention regulation and control of impulsive behavior. Methylphenidate's cognitive enhancement effects have been investigated using fMRI scans even in non-ADHD brains, which revealed modulation of brain activity in ways that enhance mental focus. Methylphenidate increased activity in the
prefrontal cortexThe prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
and attention-related areas of the parietal cortex during challenging mental tasks; these are the same areas that the above study demonstrated to be shrunken in ADHD brains. Methylphenidate also increased deactivation of
default networkThe default network is a network of brain regions that are active when the individual is not focused on the outside world and the brain is at wakeful rest. Also called the default mode network , default state network, or task-negative network , it is characterized by coherent neuronal oscillations...
regions during the task. Thus, by modifying the activity of certain brain regions known to play important roles in the
executive functionsThe executive system is a theorized cognitive system in psychology that controls and manages other cognitive processes. It is responsible for processes that are sometimes referred to as the executive function, executive functions, supervisory attentional system, or cognitive control...
, methylphenidate stimulates mental focus and self-control.
One study finds that methylphenidate reduces the increases in brain glucose metabolism during performance of a cognitive task by about 50%. This suggests that, similar to increasing dopamine and norepinephrine in the striatum and prefrontal cortex, methylphenidate may focus activation of certain regions and make the brain more efficient. This is consistent with the observation that stimulant drugs can enhance attention and performance in some individuals. If brain resources are not optimally distributed (for example, in individuals with ADHD or sleep deprivation), improved performance could be achieved by reducing task-induced regional activation. Stimulant delivery when brain resources are already optimally distributed may then adversely affect performance.
A paper published in Biological Psychiatry reports that methylphenidate fine-tunes the functioning of neurons in the
prefrontal cortexThe prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
– a brain region involved in attention, decision-making and impulse control – while having few effects outside it. The team studied PFC neurons in rats under a variety of methylphenidate doses, including one that improved the animals' performance in a working memory task of the type that ADHD patients have trouble completing. Using microelectrodes, the scientists observed both the random, spontaneous firings of PFC neurons and their response to stimulation of the
hippocampusThe hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
. When they listened to individual PFC neurons, the scientists found that while cognition-enhancing doses of methylphenidate had little effect on spontaneous activity, the neurons' sensitivity to signals coming from the hippocampus increased dramatically. Under higher, stimulatory doses, on the other hand, PFC neurons stopped responding to incoming information.
Mechanism of action
According to research of U.S. Department of Energy's Brookhaven National Laboratory methylphenidate works in the treatment of attention deficit hyperactivity disorder by increasing levels of
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in the brain.
DopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, a
neurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
, plays a role in feelings of pleasure and is naturally released in rewarding experiences. Neuroimaging studies of medication-free depressed patients have found that depressed subjects have a functional deficiency of synaptic dopamine. Dopamine decreases "background firing" rates and increases the signal to noise ratio in target neurons by increasing dopamine levels in the brain. As a result, the drug may improve attention and decrease distractibility in activities that normally do not hold the attention of children with attention deficit hyperactivity disorder. However, sympathomimetic amines do have a
dependence liabilityAmphetamine dependence refers to a state of dependence on a drug in the amphetamine class.Tolerance is developed rapidly in amphetamine abuse, thereby the amount of the drug that is needed to satisfy the addiction needs to be increased at regular intervals....
and a potential for tolerance adaptation because of their
dopaminergicDopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
effects when taken in doses outside of their therapeutic range or for an extended period of time.
Chemistry
Four isomers of methylphenidate are known to exist. One pair of threo isomers and one pair of erythro are distinguished, from which only d-threo-methylphenidate exhibits the pharmacologically usually desired effects. When the drug was first introduced it was sold as a 3:1 mixture of erythro:threo
diastereomerDiastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...
s. The erythro diastereomers are also pressor amines. "TMP" is referring only to the threo product that does not contain any erythro diastereomers. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotary methylphenidate is called d-TMP. A review on the synthesis of enantiomerically pure ("R,2R)-(+)-threo-methylphenidate hydrochloride has been published.
History
Methylphenidate was first synthesized in 1944, and was identified as a stimulant in 1954.
Methylphenidate was synthesized by Ciba (now
NovartisNovartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
) chemist Leandro Panizzon. His wife, Marguerite, had low blood pressure and would take the drug as a stimulant before playing tennis. He named the substance Ritaline, after his wife's nickname, Rita.
Originally it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo. Subsequent studies of the racemates showed that the central stimulant activity is associated with the threo racemate and were focused on the separation and interconversion of the erythro isomer into the more active threo isomer.
Beginning in the 1960s, it was used to treat children with
ADHD or ADDAttention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
, known at the time as hyperactivity or minimal brain dysfunction (MBD). Production and prescription of methylphenidate rose significantly in the 1990s, especially in the
United StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.
Most brand-name Ritalin is produced in the
United StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
, and methylphenidate is produced in the United States,
MexicoThe United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
,
SpainSpain , officially the Kingdom of Spain languages]] under the European Charter for Regional or Minority Languages. In each of these, Spain's official name is as follows:;;;;;;), is a country and member state of the European Union located in southwestern Europe on the Iberian Peninsula...
and
PakistanPakistan , officially the Islamic Republic of Pakistan is a sovereign state in South Asia. It has a coastline along the Arabian Sea and the Gulf of Oman in the south and is bordered by Afghanistan and Iran in the west, India in the east and China in the far northeast. In the north, Tajikistan...
. Other generic forms, including "Methylin", "Metadate" and "Attenta" are produced by numerous pharmaceutical companies throughout the world. Ritalin is also sold in
CanadaCanada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
,
AustraliaAustralia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
, the
United KingdomThe United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
,
SpainSpain , officially the Kingdom of Spain languages]] under the European Charter for Regional or Minority Languages. In each of these, Spain's official name is as follows:;;;;;;), is a country and member state of the European Union located in southwestern Europe on the Iberian Peninsula...
,
GermanyGermany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
,
IsraelThe State of Israel is a parliamentary republic located in the Middle East, along the eastern shore of the Mediterranean Sea...
and other European countries (although in much lower volumes than in the United States). In Belgium the product is sold under the name "Rilatine" and in Brazil, Portugal and Argentina as "Ritalina". In Thailand, it is found under the name "Hynidate"
Ritalina is not produced in Argentina but in Spain by Novartis Labs.
Sustained-release preparations of methylphenidate are now also available. These include various preparations (e.g. "Ritalin LA", "Equasym XL") that provide two standard doses – half the total dose being released immediately and the other half released four hours later – providing approximately eight hours of continuously sustained effect. In 2000
JanssenJanssen Pharmaceutica is pharmaceutical company, established in Belgium in 1953 by Paul Janssen. Its headquarters are located in Beerse, in the Campine region of the province of Antwerp, Belgium. It was created not as a subsidiary of a chemical factory but solely with the aim of conducting...
received
U.S. Food and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approval to market "Concerta", a controlled-release methylphenidate tablet providing a continuous effect for up to about 12 hours. Although, Concerta has a different time-release profile than Ritalin, with less than half of the dose being immediately released, and the remaining released in a controlled dose over the next 8–12 hours. Metadate CD, another variant of MPH time-release, acts similarly in relation to the profile of Concerta.
Legal status
- Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances
The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamines, barbiturates, benzodiazepines, and psychedelics signed at Vienna on February 21, 1971...
.
- In the United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, methylphenidate is classified as a Schedule IIThe Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...
controlled substanceA controlled substance is generally a drug or chemical whose manufacture, possession, or use are regulated by a government. This may include illegal drugs and prescription medications ....
, the designation used for substances that have a recognized medical value but present a high likelihood for abuse because of their addictive potential.
- In the United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, methylphenidate is a controlled 'Class B' substance, and possession without prescription is illegal, with a sentence up to 14 years and/or an unlimited fine.
- In New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...
, it is a 'class B2 controlled substance'. Unlawful possession is punishable by six-month prison sentence and distribution of it is punishable by a 14-year sentence.
Available forms
The dosage forms of methylphenidate are patches, liquid, tablets, and capsules. A formulation by the
NovartisNovartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
trademark name Ritalin, is an instant-release racemic mixture, although a variety of formulations and generic brand names exist. Generic brand names include Ritalina, Rilatine, Attenta, Methylin, Penid, and Rubifen; and the
sustained releaseTime release technology, also known as sustained-release , sustained-action , extended-release , time-release or timed-release, controlled-release , modified release , or continuous-release , is a mechanism used in pill tablets or capsules to...
tablets Concerta, Metadate CD, Methylin ER, Ritalin LA, and Ritalin-SR. Focalin is a preparation containing only
dextro-methylphenidateDexmethylphenidate, otherwise known as d-threo-methylphenidate , is the dextrorotatory enantiomer of methylphenidate. It is a norepinephrine-dopamine reuptake inhibitor and releasing agent and thus a psychostimulant, which affects the CNS...
, rather than the usual racemic
dextroDextro is the pseudonym given to the Scottish Falkirk born DIY musician, Ewan Mackenzie. Under the Dextro moniker he has released a number of works, most notably the albums Winded , Consequence Music and the 12" single Do You Need Help...
- and levo-methylphenidate mixture of other formulations. A newer way of taking methylphenidate is by using a
transdermal patchA transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of...
(under the brand name
DaytranaDaytrana is a medicinal patch marketed by Shire Pharmaceuticals and developed under contract by Noven Pharmaceuticals that was approved in June 2007. In the literature, Daytrana is most commonly referred to as Methylphenidate Transdermal System .Daytrana is approved by the U.S...
), similar to those used for
nicotine replacement therapyNicotine replacement therapy is the remedial administration of nicotine to the body by means other than tobacco, usually as part of smoking cessation. Common forms of nicotine replacement therapy are nicotine patches and nicotine gum...
.
Brand names include Concerta, MediKinet, Equasym XL, Metadate, Methylin, and MPH
Concerta tablets are marked with the letters "ALZA" and followed by: "18", "27", "36", or "54", relating to the mg dosage strength. Approximately 22% of the Concerta dose is immediate release, and the remaining 78% of the dose is evenly released over 10–12 hours post ingestion.
Ritalin LA capsules are marked with the letters "NVR" (abbrev.: Novartis) and followed by: "R20", "R30", or "R40", depending on the (mg) dosage strength. The capsules contain two types of beads; 50% of the beads are immediate release, and the other 50% of the beads are enteric-coated, designed to give a second delayed release approximately 5 hours post ingestion.
Metadate CD capsules contain two types of beads; 30% of the beads are immediate release, and the other 70% of the beads are evenly sustained release over approximately 8 hours.
Controversy
Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. One such criticism is prescribing psychostimulants medication to children to reduce ADHD symptoms. Calls have been made that methylphenidate be severely restricted in its use. The pharmacological effects of methylphenidate resemble closely those of
cocaineCocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
and amphetamines, which is the desired effect in the treatment of ADHD, and how methylphenidate works.
The abuse pattern of methylphenidate is very similar to heroin and amphetamines. A 2002 study showed that rats treated with methylphenidate are more receptive to the reinforcing effects of cocaine. The contention that methylphenidate acts as a
gateway drugThe gateway drug theory is the hypothesis that the use of less deleterious drugs may lead to a future risk of using more dangerous hard drugs and/or crime...
has been discredited by multiple sources, according to which abuse is statistically very low and "stimulant therapy in childhood does not increase the risk for subsequent drug and alcohol abuse disorders later in life".
Another controversial idea surrounding ADHD is that a group of ADHD children have, in general, healthy brains with no gross neurological deficits. This concept, however, is seen as outdated by a few scientists in current medical research, who claim they can identify an ADHD child's brain using CT brain scans, and how methylphenidate interacts with it. The problem herein is that no control was used in the cited research that would differentiate an ADHD child's brain from one that had been treated with stimulants beforehand.
Treatment of ADHD by way of Methylphenidate has led to legal actions including
malpracticeIn law, malpractice is a type of negligence in, which the professional under a duty to act, fails to follow generally accepted professional standards, and that breach of duty is the proximate cause of injury to a plaintiff who suffers harm...
suits regarding
informed consentInformed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...
, inadequate information on
side effectsIn medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
, misdiagnosis, and coercive use of medications by school systems. In the U.S. and the United Kingdom, it is approved for use in children and adolescents. The FDA recently approved the use of methylphenidate for use in treating adult ADHD. Methylphenidate has been approved for adult use in the treatment of
narcolepsyNarcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...
.
Anti-Ritalin political campaign
In 2002,
Neil BushNeil Mallon Bush is the fourth of six children of former President George Herbert Walker Bush and Barbara Bush . His five siblings are George Walker Bush, the former President of the United States; Jeb Bush, the former governor of Florida; Robin Bush, who died of leukemia in 1953 at the age of...
told the
New York PostThe New York Post is the 13th-oldest newspaper published in the United States and is generally acknowledged as the oldest to have been published continuously as a daily, although – as is the case with most other papers – its publication has been periodically interrupted by labor actions...
that he "endured his own Ritalin hell seven years ago when educators in a Houston private school diagnosed his son, Pierce, (then) 16, with Attention Deficit Disorder (ADD) and pushed medication."
In a September 26, 2002, episode of
CNNCable News Network is a U.S. cable news channel founded in 1980 by Ted Turner. Upon its launch, CNN was the first channel to provide 24-hour television news coverage, and the first all-news television channel in the United States...
Interview, Bush told
Connie ChungConnie Chung, full name: Constance Yu-Hwa Chung Povich is an American journalist who has been an anchor and reporter for the U.S. television news networks NBC, CBS, ABC, CNN, and MSNBC. Some of her more famous interview subjects include Claus von Bülow and U.S...
:
Neil Bush spent years researching the issue and found that "the educators were wrong" about his son. "There is a systemic problem in this country, where schools are often forcing parents to turn to Ritalin," he said. "It's obvious to me that we have a crisis." Also that year, Bush testified before a hearing of the
United States CongressThe United States Congress is the bicameral legislature of the federal government of the United States, consisting of the Senate and the House of Representatives. The Congress meets in the United States Capitol in Washington, D.C....
to speak out against over-medicating children for learning disorders.
He has suggested that many parents believe the ADD and ADHD diagnoses and subsequent medicating of their children because it explains why they aren't doing well in school, saying "it's the system that is failing to engage children in the classroom. My heart goes out to any parents who are being led to believe their kids have a disorder or are disabled."
Neil BushNeil Mallon Bush is the fourth of six children of former President George Herbert Walker Bush and Barbara Bush . His five siblings are George Walker Bush, the former President of the United States; Jeb Bush, the former governor of Florida; Robin Bush, who died of leukemia in 1953 at the age of...
(along with filmmaker
Michael MooreMichael Francis Moore is an American filmmaker, author, social critic and activist. He is the director and producer of Fahrenheit 9/11, which is the highest-grossing documentary of all time. His films Bowling for Columbine and Sicko also place in the top ten highest-grossing documentaries...
) is credited in the cast of a 2005 documentary called The Drugging of Our Children directed by
Gary NullGary Michael Null is an American talk radio host and author on alternative and complementary medicine and nutrition. On his talk radio show and in his books and self-produced movies, Null has criticized the medical community, promoted a range of alternative cancer treatments and dietary...
. In the film's trailer Bush says: "Just because it is easy to drug a kid and get them to be compliant doesn't make it right to do it".
External links