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Disorders of diminished motivation (DDM) are a group of disorders involving diminished motivation and associated emotions. [1] [2] [3] [4] Many different terms have been used to refer to diminished motivation. [4] [1] [2] [3] [5] [6] [7] Often however, a spectrum is defined encompassing apathy, abulia, and akinetic mutism, with apathy the least severe and akinetic mutism the most extreme. [1] [2] [3]
DDM can be caused by psychiatric disorders like depression and schizophrenia, brain injuries, strokes, and neurodegenerative diseases. [4] [3] [1] [5] Damage to the anterior cingulate cortex and to the striatum, which includes the nucleus accumbens and caudate nucleus and is part of the mesolimbic dopamine reward pathway, have been especially associated with DDM. [3] [8] [4] Diminished motivation can also be induced by certain drugs, including antidopaminergic agents like antipsychotics, [9] [10] [4] [11] selective serotonin reuptake inhibitors (SSRIs), [12] [13] and cannabis, among others. [14] [15] [16]
DDM can be treated with dopaminergic and other activating medications, such as dopamine reuptake inhibitors, dopamine releasing agents, and dopamine receptor agonists, among others. [1] [2] [3] [11] These kinds of drugs have also been used by healthy people to improve motivation. [17] [11] A limitation of some medications used to increase motivation is development of tolerance to their effects. [18] [19]
Disorders of diminished motivation (DDM) is an umbrella term referring to a group of psychiatric and neurological disorders involving diminished capacity for motivation, will, and affect. [1] [2] [3] [4]
A multitude of terms have been used to refer to DDM of varying severities and varieties, including apathy, abulia, akinetic mutism, athymhormia, avolition, amotivation, anhedonia, psychomotor retardation, affective flattening, akrasia, and psychic akinesia (auto-activation deficit or loss of psychic self-activation), among others. [4] [1] [2] [3] [5] [6] [20] [7] Other constructs, like fatigue, lethargy, and anergia, also overlap with the concept of DDM. [6] [2] [21] [4] [7] Alogia (poverty of speech) and asociality (lack of social interest) are associated with DDM as well. [20] [7]
Often however, a spectrum of DDM is defined encompassing apathy, abulia, and akinetic mutism, with apathy being the mildest form and akinetic mutism being the most severe or extreme form. [1] [2] [3] Akinetic mutism involves alertness but absence of movement and speech due to profound lack of will. [1] [2] [3] [7] People with the condition are indifferent even to biologically relevant stimuli such as pain, hunger, and thirst. [7]
Less extreme forms of DDM, for instance apathy or anhedonia, can be a symptom of psychiatric disorders and related conditions, like depression, schizophrenia, or drug withdrawal. [4] [3] [1] [5] More extreme forms of DDM, for instance severe apathy, abulia, or akinetic mutism, can be a result of traumatic brain injury (TBI), stroke, or neurodegenerative diseases like dementia or Parkinson's disease. [4] [1] [2] [3] [5]
Reduction in motivation and affect can also be induced by certain drugs, such as dopamine receptor antagonists including D2 receptor receptor antagonists like antipsychotics (e.g., haloperidol) and metoclopramide [10] [22] [23] [24] [25] [26] and D1 receptor antagonists like ecopipam, [9] [27] [4] [11] dopamine-depleting agents like tetrabenazine and reserpine, [9] [27] [11] dopaminergic neurotoxins like 6-hydroxydopamine (6-OHDA) and methamphetamine, [9] [27] [4] [28] [29] serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) [12] [13] [30] [9] and MAO-A-inhibiting monoamine oxidase inhibitors (MAOIs), [31] and cannabis or cannabinoids (CB1 receptor agonists). [14] [15] [16] [9] [32]
Damage to a variety of brain areas have been implicated in DDM. [3] However, damage to or reduced functioning of the anterior cingulate cortex (ACC) and striatum have been especially implicated in DDM. [3] [8] [4] The striatum is part of the dopaminergic mesolimbic pathway, which connects the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc) of the ventral striatum and basal ganglia. [33] [3] [8] [4] Strokes affecting other striatal and basal ganglia structures, like the caudate nucleus of the dorsal striatum, have also been associated with DDM. [34] [3] [35]
DDM, like abulia and akinetic mutism, can be treated with dopaminergic and other activating medications. [1] [2] [3] [11] These include psychostimulants and releasers or reuptake inhibitors of dopamine and/or norepinephrine like amphetamine, methylphenidate, bupropion, modafinil, and atomoxetine; D2-like dopamine receptor agonists like pramipexole, ropinirole, rotigotine, piribedil, bromocriptine, cabergoline, and pergolide; the dopamine precursor levodopa; and MAO-B-selective monoamine oxidase inhibitors (MAOIs) like selegiline and rasagiline, among others. [1] [2] [3] [11] [4] Selegiline is also a catecholaminergic activity enhancer (CAE), and this may additionally or alternatively be involved in its pro-motivational effects. [36] [37] [31]
The dopamine D1 receptor appears to have an important role in motivation and reward. [38] Centrally acting dopamine D1-like receptor agonists like tavapadon and razpipadon and D1 receptor positive modulators like mevidalen and glovadalen are under development for medical use, including treatment of Parkinson's disease and notably of dementia-related apathy. [39] [40] [41] Centrally active catechol-O-methyltransferase inhibitors (COMTIs) like tolcapone, which are likewise dopaminergic agents, have been studied in the treatment of psychiatric disorders but not in the treatment of DDM. [42] [43] Genetic variants in catechol-O-methyltransferase (COMT) have been associated with motivation and apathy susceptibility, [42] [44] [45] [46] [47] as well as with reward, mood, and other neuropsychological variables. [48] [49] [50]
Besides in people with DDM, psychostimulants and related agents have been used non-medically to enhance motivation in healthy people, for instance in academic contexts. [17] [11] [51] [52] This has provoked discussions on the ethics of such uses. [17] [11] [52]
A limitation of certain medications used to improve motivation, like psychostimulants, is development of tolerance to their effects. [18] [19] Rapid acute tolerance to amphetamines is believed to be responsible for the dissociation between their relatively short durations of action (~4 hours for main desired effects) and their much longer elimination half-lives (~10 hours) and durations in the body (~2 days). [19] [53] [54] [55] [56] [57] [58] It appears that continually increasing or ascending concentration–time curves are beneficial for prolonging effects, which has resulted in administration multiple times per day and development of delayed- and extended-release formulations. [19] [54] [55] Medication holidays and breaks can be helpful in resetting tolerance. [18]
Another possible limitation of amphetamine specifically is dopaminergic neurotoxicity, which might occur even at therapeutic doses. [59] [60] [61] [62] [63] [64]
Besides medications, various psychological and physiological processes, including arousal, [65] mood, [66] [67] [68] [69] [70] expectancy effects (e.g., placebo), [71] [72] novelty, [73] [74] psychological stress or urgency, [75] [76] [65] rewarding and aversive stimuli, [65] availability of rewards, [77] addiction, [78] and sleep amount, [79] among others, can also context- and/or stimulus-dependently modulate or enhance brain dopamine signaling and motivation to varying degrees. Relatedly, the psychostimulant effects of amphetamine are greatly potentiated by environmental novelty in animals. [80] [81]
Attention deficit hyperactivity disorder (ADHD) often involves motivational deficits, [82] [83] and the ADHD academic Russell Barkley has referred to the condition as a "motivational deficit disorder" in various publications and presentations. [84] [85] [86] [87] However, ADHD has perhaps more accurately been conceptualized as a disorder of executive function and of directing or allocating attention and motivation rather than a global deficiency in these processes. [82] [88] [89] People with ADHD are often highly motivated towards stimuli that interest them, not uncommonly experiencing a flow-like state called hyperfocus while engaging such stimuli. [90] [82] In any case, as with management of DDM, psychostimulants and other catecholaminergic agents are used in people with ADHD to treat their symptoms, including difficulties with attention, executive control, and motivation. [91] [92] [93] Amphetamines in the treatment of ADHD appear to have among the largest effect sizes in terms of effectiveness of any interventions (medications or forms of psychotherapy) used in the management of psychiatric disorders generally. [94]
DDM (and ADHD) should not be confused with "motivational deficiency disorder" ("MoDeD"; "extreme laziness"), a fake or spoof disease created for humorous purposes in 2006 to raise awareness about disease mongering, overdiagnosis, and medicalization. [95] [96]
Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity; it is also used to treat binge eating disorder in the form of its inactive prodrug lisdexamfetamine. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.
Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.
Stimulants are a class of drugs that increase the activity of the brain. They are used for various purposes, such as enhancing alertness, attention, motivation, cognition, mood, and physical performance. Some of the most common stimulants are caffeine, nicotine, amphetamines, cocaine, methylphenidate, and modafinil.
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD ; it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect. For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine but modestly lower than amphetamines, alleviating the executive functioning deficits of sustained attention, inhibition, working memory, reaction time and emotional self-regulation.
Dextroamphetamine (INN:dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is generally regarded as the prototypical stimulant.
Atomoxetine, sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome. It may be used alone or along with psychostimulants. It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time and emotional self-regulation. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.
Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.
Dopaminergic pathways in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.
The mesocortical pathway is a dopaminergic pathway that connects the ventral tegmentum to the prefrontal cortex. It is one of the four major dopamine pathways in the brain. It is essential to the normal cognitive function of the dorsolateral prefrontal cortex, and is thought to be involved in cognitive control, motivation, and emotional response.
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.
The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.
Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.
Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.
Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.
Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours.
Attention deficit hyperactivity disorder management options are evidence-based practices with established treatment efficacy for ADHD. Approaches that have been evaluated in the management of ADHD symptoms include FDA-approved pharmacologic treatment and other pharmaceutical agents, psychological or behavioral approaches, combined pharmacological and behavioral approaches, cognitive training, neurofeedback, neurostimulation, physical exercise, nutrition and supplements, integrative medicine, parent support, and school interventions. Based on two 2024 systematic reviews of the literature, FDA-approved medications and to a lesser extent psychosocial interventions have been shown to improve core ADHD symptoms compared to control groups.
Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination with dextroamphetamine in varying ratios under brand names like Adderall and Evekeo. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. Levoamphetamine is taken by mouth.
A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.
A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known. On the other hand, many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed. Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).
A motivation-enhancing drug, also known as a pro-motivational drug, is a drug which increases motivation. Drugs enhancing motivation can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). They can also be used in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, disorders that can be caused by conditions like stroke, traumatic brain injury (TBI), and neurodegenerative diseases. Motivation-enhancing drugs are used non-medically by healthy people to increase motivation and productivity as well, for instance in educational contexts.
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: CS1 maint: DOI inactive as of September 2024 (link)Synaptic clearance mechanisms also mediate dopamine's function and vary across corticostriatal regions (127). For example, in the [ventral striatum (VS)], rapid recycling via [dopamine transporter (DAT)] predominates (127). In contrast, in the [prefrontal cortex (PFC)], DAT recycling is minimal and enzymatic degradation by catecholO-methyltransferase (COMT) is the primary mechanism for clearance, modulating evoked dopamine release measured over minutes (128–130). Reinforcement learning and apathy have both been associated with functional polymorphisms in COMT (131, 132). [...] COMT inhibitors: COMT is a catecholamine-degrading enzyme. Enzymatic degradation by COMT is the primary mechanism for synaptic dopamine clearance in the prefrontal cortex. COMT inhibitors increase cortical dopamine by inhibiting this key catabolic pathway either directly within the brain (tolcapone) or peripherally (180).
There are limited numbers of studies on the genetics of apathy. Although dopaminergic neurons have been the center of attention in studies on the motivation system for many years, a correlation between dopamine-related genes and severity of apathy is not established. The only positive genetic association came from a study of 963 healthy participants, 213 of whom had apathy, which showed an association between the single nucleotide polymorphism (SNP) in the catechol-Omethyltransferase (COMT) gene (rs4680) and a lower risk of apathy (Mitaki et al., 2013). The authors concluded that the SNP in the COMT gene leads to a reduction in COMT activity and increased dopamine in the PFC. Those with apathy also had more severe depression, so it was possible that this gene affected not only motivation but also the mood state (Mitaki et al., 2013) (Table 21.1).
Studies relating to other hypothesized genetic correlates of apathy, such as the catechol-O-methyl transferase (COMT) gene, a dopamine-related gene, have been similarly inconclusive. Although a number of authors have reported no association in AD patients [116,119], a recent casecontrol study in neurologically normal subjects found that a single-nucleotide polymorphism in the COMT gene (rs4680) was associated with a lower risk for apathy [120].
Metabolism does not appear to be altered by chronic exposure, thus dose escalation appears to arise from pharmacodynamic rather than pharmacokinetic tolerance [24]. [...] The terminal plasma half-life of methamphetamine of approximately 10 hours is similar across administration routes, but with substantial inter-individual variability. Acute effects persist for up to 8 hours following a single moderate dose of 30 mg [30]. [...] peak plasma methamphetamine concentration occurs after 4 hours [35]. Nevertheless, peak cardiovascular and subjective effects occur rapidly (within 5–15 minutes). The dissociation between peak plasma concentration and clinical effects indicates acute tolerance, which may reflect rapid molecular processes such as redistribution of vesicular monoamines and internalization of monoamine receptors and transporters [6,36]. Acute subjective effects diminish over 4 hours, while cardiovascular effects tend to remain elevated. This is important, as the marked acute tachyphylaxis to subjective effects may drive repeated use within intervals of 4 hours, while cardiovascular risks may increase [11,35].
For several decades, clinical benefits of amphetamines have been limited by the pharmacologic half-life of around 4 hours. Although higher doses can produce higher maximum concentrations, they do not affect the half-life of the dose. Therefore, to achieve longer durations of effect, stimulants had to be dosed at least twice daily. Further, these immediate-release doses were found to have their greatest effect shortly after administration, with a rapid decline in effect after reaching peak blood concentrations. The clinical correlation of this was found in comparing math problems attempted and solved between a mixed amphetamine salts preparation (MAS) 10 mg once at 8 am vs 8 am followed by 12 pm [14]. The study also demonstrated the phenomenon of acute tolerance, where even if blood concentrations were maintained over the course of the day, clinical efficacy in the form of math problems attempted and solved would diminish over the course of the day. These findings eventually led to the development of a once daily preparation (MAS XR) [15], which is a composition of 50% immediate-release beads and 50% delayed release beads intended to mimic this twice-daily dosing with only a single administration.
It has been suggested that the association between PD and ADHD may be explained, in part, by toxic effects of these drugs on DA neurons.241 [...] An important question is whether amphetamines, as they are used clinically to treat ADHD, are toxic to DA neurons. In most of the animal and human studies cited above, stimulant exposure levels are high relative to clinical doses, and dosing regimens (as stimulants) rarely mimic the manner in which these drugs are used clinically. The study by Ricaurte and colleagues248 is an exception. In that study, baboons orally self-administered a racemic (3:1 d/l) amphetamine mixture twice daily in increasing doses ranging from 2.5 to 20 mg/day for four weeks. Plasma amphetamine concentrations, measured at one-week intervals, were comparable to those observed in children taking amphetamine for ADHD. Two to four weeks after cessation of amphetamine treatment, multiple markers of striatal DA function were decreased, including DA and DAT. In another group of animals (squirrel monkeys), d/l amphetamine blood concentration was titrated to clinically comparable levels for four weeks by administering varying doses of amphetamine by orogastric gavage. These animals also had decreased markers of striatal DA function assessed two weeks after cessation of amphetamine.
Recently, however, new data from Ricaurte et al. (2005) indicate that primates may be much more susceptible than rats to AMPH-induced neurotoxicity. They examined the effect of the drug in adult baboons and squirrel monkeys, as clinically used to treat ADHD. In the first two studies, baboons were trained to orally selfadminister a mixture of AMPH salts (a 3:1 ratio of dextro [S(+)] and levo [R(-)] AMPH, which simulated a common formulation for ADHD treatment). AMPH was administered twice daily for approximately 4 weeks at escalating doses of 2.5 to 20 mg (0.67 to 1.00 mg/kg). During the second study, plasma AMPH concentrations were determined at the end of each week. In the third study, AMPH was administered by orogastric gavage to squirrel monkeys and doses were adjusted (to 0.58-0.68 mg/kg) so that for approximately the last 3 weeks plasma drug concentrations were comparable to those reported in clinical populations of children receiving chronic AMPH treatment—100 to 150 ng/ml (McGough et al., 2003). Measurements in all three investigations were taken 2 to 4 weeks after drug treatment. Results from the first two studies showed significant reductions in striatal dopamine concentration, dopamine transporter density, and vesicular monoamine transporter sites. Plasma AMPH concentration at the end of the 4 week treatment period was 168 ± 25 ng/ml. In squirrel monkeys, brain dopamine concentrations and vesicular transporter sites were also significantly reduced although dopamine transporter decreases were not statistically significant. These results raise obvious concerns about clinical drug treatment of ADHD, although extrapolation to human populations may be premature until possible species differences in mechanism of action, developmental variables, or metabolism are determined.
Amphetamine treatment similar to that used for ADHD has been demonstrated to produce brain dopaminergic neurotoxicity in primates, causing the damage of dopaminergic nerve endings in the striatum that may also occur in other disorders with long-term amphetamine treatment (57).
Repeated exposure to moderate to high levels of methamphetamine has been related to neurotoxic effects on the dopaminergic and serotonergic systems, leading to potentially irreversible loss of nerve terminals and/or neuron cell bodies (Cho and Melega, 2002). Preclinical evidence suggests that d-amphetamine, even when administered at commonly prescribed therapeutic doses, also results in toxicity to brain dopaminergic axon terminals (Ricaurte et al., 2005).
Though the paradigm used by Ricaurte et al. 53 arguably still incorporates amphetamine exposure at a level above much clinical use,14,55 it raises important unanswered questions. Is there a threshold of amphetamine exposure above which persistent changes in the dopamine system are induced? [...]
Large SMDs were found for amphetamines98, 100, 102, small to medium SMDs for methylphenidate100, 101.