Neuropsychological Effects of Chronic Methamphetamine Use on Neurotransmitters and Cognition: A Review

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J Neuropsychiatry Clin Neurosci 15:3, Summer 2003 317

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Neuropsychological

Effects of ChronicMethamphetamine Useon Neurotransmitters andCognition: A ReviewThomas E. Nordahl, M.D., Ph.D.Ruth Salo, Ph.D.Martin Leamon, M.D.

Received January 4, 2002; revised April 2, 2002; accepted April 5, 2002.From the Department of Psychiatry, University of California DavisMedical Center, Sacramento, California. Address correspondence toDr. Thomas E. Nordahl, Department of Psychiatry, University of Cali-fornia Davis Medical Center, 2230 Stockton Boulevard, Sacramento,CA 95817; [email protected] (E-mail).

Copyright 2003 American Psychiatric Publishing, Inc.

Methamphetamine use is on the rise, with an im-minent upsurge of abuse and dependence reportedacross the United States. Currently, preliminaryevidence suggests that methamphetamine depen-dence may cause long-term neural damage in hu-mans, with concomitant deleterious effects on cog-nitive processes such as memory and attention.This selective review provides an outline and syn-thesis of studies that assess the neurotoxic mecha-

nisms of methamphetamine, as well as those thatevaluate the cognitive sequelae of methamphet-amine abuse.

(The Journal of Neuropsychiatry and ClinicalNeurosciences 2003; 15:317325)

Among the illicit stimulants, cocaine and the am-phetamines are the most widely abused. While co-caine use has had a national distribution and an overalldecrease since the early 1990s, the use of amphetamines,particularly methamphetamine, has been increasing andspreading eastward from its endemic centers in thewestern and southwestern parts of the United States.13

The use and effects of methamphetamine command in-creasing attention from researchers and drug treatmentprofessionals, as well as from drug enforcement officialsand state and national legislators. Using the University

of Californias MELVYL MEDLINE database, a searchfor journal articles indexed under methamphetaminereveals a doubling of the number of articles from theyear 1990 through the year 2000. One hundred six arti-cles are indexed for 1990, whereas 212 articles are foundfor 2000. In contrast, the number of articles indexed un-der cocaine remained essentially constant over thesame time period, at approximately 1,000 per year. From1994 to 2000, the number of underground methamphet-amine labs that were seized by the U.S. Drug Enforce-ment Agency (DEA) increased 590%, with 6,394 lab sei-zures reported.4 Similarly, the amount of the drug seized

by the DEA also increased, from 289 kg in 1996 to 3,163

kg in 2000.4,5 Several acts of national legislation, such asthe Comprehensive Methamphetamine Control Act of


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318 J Neuropsychiatry Clin Neurosci 15:3, Summer 2003

NEUROPSYCHOLOGICAL EFFECTS OF METHAMPHETAMINE USE

FIGURE 1. Chemical diagrams

Methamphetamine

NHCH3 NH2

O

O

O

CH3OCI-

N+

Amphetamine Cocaine

1996 and the Methamphetamine and Club Drug Anti-Proliferation Act of 2000, have focused specifically onthe growing problem of methamphetamine abuse. Thisarticle provides an overview of some of the relevantclinical and historical features of methamphetamineabuse, followed by a discussion of the drugs effect on

different neurotransmitter systems. Particular attentionis given to the issue of methamphetamine-induced neu-rotoxicity. Lastly, the effects of methamphetamine oncognition are also assessed, with particular reference toneurotoxic effects.

Unlike cocaine, methamphetamine is a syntheticallyderived drug, and its synthesis requires only rudimen-tary laboratory equipment (See Figure 1). Until the en-actment of recent legislation, the requisite reagents usedto make methamphetamine could be purchased in drug-stores, hardware stores, and chemical supply houses.According to the DEA, among the controlled substancesmanufactured underground in the United States, meth-

amphetamine is the most prevalent, and it is one of thecommonly abused controlled substances that can bemade in the home.6 For many years, methamphetaminehas been manufactured in small mom-and-pop labsthat can be readily concealed in a shed, storage garage,or large vehicle such as a minivan. Prior to the late 1980s,illicit manufacture of methamphetamine was the pur-view of white motorcycle gangs who used the chemicalphenyl-2-propanone (P2P) to make the drug, which waslegal at the time, as the major precursor. Federal controlswere placed on P2P with the implementation of the Fed-eral Chemical Diversion and Trafficking Act of 1988.Subsequently, underground chemists began using

ephedrine and pseudoephedrine as the main precursorsin methamphetamine synthesis. The use of ephedrineand pseudoephedrine is simpler and more efficient thanthe P2P-based process, as it produces a higher yield ofthe psychoactive D-isomer of the drug. Additionally,Mexican poly-drug trafficking organizations beganmanufacturing and distributing methamphetamine inthe mid-1990s. These organizations created superlabsin Mexico and southern California that were capable of

producing 10 pounds or more of high-purity metham-phetamine in 1 to 2 days. The superlabs are in markedcontrast to the more numerous and widely distributedmom-and-pop labs, which maintain a share of the U.S.market. Because of the varied manufacturing patterns,the purity of street methamphetamine can vary widely,

even within a circumscribed geographic area.3

Methamphetamine is typically ingested (usually dis-solved in a beverage, such as a soft drink or coffee),smoked (vaporized), snorted, or injected intravenously.The amount used at a single administration can varymore than tenfold, depending on individual tolerance,route of administration, and purity. Among chronicusers, dosing patterns tend to be either administrationsof low doses or cycles of high-dose bingeing that lastsfor days, followed by a period of abstinence.

Amphetamines have a longer duration of action thancocaine (813 hours versus 13 hours) and may be morerapidly addicting.7 Methamphetamine has higher lipid

solubility than the unsubstituted amphetamine, andthus larger amounts of the drug rapidly and efficientlycross the blood-brain barrier. Approximately 45% of amethamphetamine dose is metabolized into ampheta-mine, and both drugs are primarily excreted renally.8 Inanimal models the pharmacological effects of metham-phetamine depend greatly upon the dose and pattern ofadministration. In rat models, for instance, different ef-fects are seen with administration of a single dose, re-peated administration of low doses at long intervals, re-peated administration of high doses at short intervals,or high-dose runs superimposed on chronic low-doseadministration.9 In methamphetamine-nave humans,

low doses produce a sense of heightened alertness, at-tentiveness, and energy. Higher dose intoxication pro-duces a sense of well-being, euphoria, and enhancedself-esteem that can approach hypomania and grandi-osity. Initially, sexual activity and pleasure may be in-creased, although longer use is associated withimpairedsexual functioning. Appetite is suppressed. Adverse ef-fects include restlessness, insomnia, bruxism, and exces-sive weight loss. Suspiciousness may occur and can


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is caused by the activation of postsynaptic DA receptor.Hence, DA, glutamate, and perhaps NO may all func-tion in the neurotoxic effects of methamphetamine onthe DA system.

Imaging Studies

Imaging techniques, such as proton magnetic resonancespectroscopy (MRS), have been used to assess the pres-ence of neuronal damage in human subjects. A nonin-vasive magnetic resonance imaging (MRI) technique,MRS uses certain pulse sequences to yield chemicalspectra that reflect relative concentrations of specificneurotransmitters, or their metabolites, in preselected

brain volumes. Using proton MRS, one can obtain mea-sures of N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), and creatine (Cr) content. NAA is presentin axons, dendrites, and the cell bodies of healthy neu-rons, and its levels are thought to be a measure of neu-ronal viability.45 In a wide range of studies, abnormally

low levels of NAA and abnormally high levels of mI (aglia marker) and Cho have been linked to neuronaldamage.46 Using MRS, Ernst et al.46 reported unchar-acteristically low NAA in the basal ganglia of meth-amphetamine-dependent subjects. They also observedan inverse correlation between the prefrontal white mat-ter NAA values and years of use, with evidence of ab-normally high Cho and mI in the frontal grey matter. Ina subsequent MRS study of recently abstinent subjects,Nordahl et al.47 found evidence of abnormally low nor-malized NAA (i.e., NAA/Cr) levels and higher normal-ized Cho (i.e., Cho/Cr) levels in the anterior cingulum(ACC), with no evidence of such findings in the primaryvisual cortex that served as the control region. Taylor etal.48 also found evidence of low NAA in the anteriorcingulum and a trend toward a low NAA value for the

basal ganglia. These findings have been interpreted asconsistent with neural damage to the frontostriatal re-gions. Using MRI analyses, Bartzokis et al.49 reported nooverall tissue loss in frontal gray and white matter. Post-mortem confirmation and longitudinal within-subjectsstudies are necessary in order to confirm these results.Using positron emission tomography [F-18]-fluorodeox-yglucose (FDG PET) techniques, London et al.50 and Vol-kow et al.30 examined brain glucose metabolic changes

in methamphetamine-dependent subjects.

Duration of Neurotoxicity

An emerging body of studies aims to establish the du-ration of methamphetamine damage on neuronal re-gions and processes. In this section, we review recentstudies that were conducted on humans and monkeysand revealed findings pertinent to the continual long-term effects of methamphetamine use. In a study per-

formed on monkeys to assess the persistence of meth-amphetamine exposure effects, Harvey et al.51 used invivo and postmortem techniques. Following a 1-monthexposure to methamphetamine, postmortem character-ization revealed extensive decreases in the immuno-reactivity (IR) profiles of tyrosine hydroxylase, DAT, and

VMAT-2. These decreases were observed in the striatum,medial forebrain bundle, and ventral midbrain dopa-mine (VMD). When assessed at 1.5 years by stereologicalmethods, IR deficits were not associated with a loss ofVMD cell number. At 1.5 years, IR profiles of metham-phetamine-exposed monkeys, throughout the nigrostri-atal dopamine system, appeared to be similar to thoseof controls, although some regional deficits persisted.The lack of VMD cell loss suggests that the magnitudeand extent of dopaminergic deficits may represent tran-sient impairment.

Recent studies conducted on humans suggest thatpermanent degeneration of the DA system does not oc-

cur, and normalization of dopaminergic deficits maytake place over time. In their investigation of the post-mortem brains of methamphetamine users, Wilson etal.52 reported lower levels of the DA nerve terminalmarkers and the DA transporter in the nucleus accum-

bens, caudate, and putamen. They also suggested thatlower levels of striatal DA transporter might explain therationale for the dose escalation and dysphoria that arefrequently found in methamphetamine abusers. Theydid not, however, find decreased levels of the enzyme3,4-dihydroxyphenylalanine (DOPA) decarboxylase orVMAT, which is found in patients with Parkinsons dis-ease who have permanent degeneration of their nigro-striatal DA system.

In a study that used positron emission tomography(PET) to measure DA transporter binding, Volkow etal.53 found evidence of DAT normalization in a pairedstudy of five subjects that were initially examined inearly abstinence and then in late abstinence (1.5 to 2years). These latter findings suggest that chronic expo-sure to methamphetamine does not necessarily causepermanent deficits or damage to the DA system in hu-man users. In the presentation of her data, however, Dr.Volkow reported that the five subjects still had cognitivedeficits following normalization of their DA transporter

binding values.In summary, findings for neuroanatomical, neuro-

chemical, and imaging data support the conclusion thatmethamphetamine abuse causes damage to multipletransmitter systems that are distributed throughout the

brain. Whether the ensuing damage is permanent or re-versible over time has not yet been determined.

Cognitive Effects of Methamphetamine AbuseDrugs that affect the monoaminergic system, such asamphetamine and cocaine, can alter both behavioral and


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cognitive processes in many ways. Although numerousstudies have examined the effects of cocaine on cogni-tion,5460 less is known about the long-term cognitiveeffects of methamphetamine use. As methamphetamineuse has been shown to damage both DA and 5-HT sys-tems, the cognitive effects may differ qualitatively from

those resulting from cocaine use, which has a differentialeffect upon these systems.61 Earlier studies reported thatacute doses of methamphetamine administered to drug-naive subjects produced improvements in cognitive pro-cessing.6264 Studies using sleep-deprived individualsrevealed that administration of amphetamines reducedreaction times and improved performance.62 Other in-vestigations have reported similar results in non-fatigued individuals.65 Fleming et al.66 observed thatsingle doses of dextroamphetamine reduced reactiontimes on a continuous performance test but had no sig-nificant effect on other attentional measures. Additionalstudies reported improvements in verbal memory per-

formance as a result of the administration of metham-phetamine.64 In contrast to the improvements citedabove, some investigations found no cognitive improve-ments associated with amphetamine administration.65,67

More recent studies have shown that long-term meth-amphetamine use is associated with impaired perfor-mance on a number of cognitive tasks.6871 Volkow etal.71 tested a group of methamphetamine-dependentsubjects and found that they exhibited performance def-icits in both verbal memory and motor function. Simonet al.70 observed that the methamphetamine users intheir study did not differ from controls on global Intel-ligence Quotient (IQ) measures, though they did per-form significantly worse on tests of memory recall. Themethamphetamine group in this same study had diffi-culty with tests that measured manipulation of infor-mation (i.e., Digit Span Task and Trail Making Part B),

but had no problems on tasks that measured psycho-motor speed separately (i.e., Trail Making Part A). Themethamphetamine group also displayed deficits in ab-stract reasoning and task shifting strategies. In theirstudy, Ornstein et al.72 reported that methamphetamine-dependent subjects displayed specific deficits in shiftingcategories on a computerized task shifting experimentwhen compared with chronic heroin users and non-

substance using control subjects.Clinically, methamphetamine-dependent individualsappear distractible and exhibit difficulties in sustainingattention. Our lab has examined the attentional perfor-mance in a group of methamphetamine-dependent in-dividuals, using a sensitive, computerized battery of se-lective attention tasks to better understand the natureand specific properties of their cognitive dysfunction.69

A single-trial Stroop priming task; a task switching ex-

periment, with response conflict trials; a spatial primingtask; and a go-no-go task were all used in the assess-ment. When compared with controls, the methamphet-amine-dependent individuals displayed more consis-tent patterns of difficulties in suppressing irrelevant taskinformation. These deficits became apparent in both re-

action time measures and accuracy rates. Although themethamphetamine-dependent individuals exhibiteddeficits in the explicit components of the tasks, they hadpreserved attentional priming, which is a noteworthydissociation in attentional performance. Priming is animplicit component of cognitive processing that remainsintact in some disorders, even when other cognitive abil-ities are impaired, such as in global amnesia. In disor-ders such as schizophrenia, however, priming does notremain undamaged.7374

Dopaminergic Systems and Cognition

The dopaminergic system often exhibits modulatory ef-

fects on many cognitive functions, including memory,attention, task switching, and response inhibition.74 Re-cent studies in humans and animals revealed that DAdepletion in the mesostriatum can lead to both a slowingin reaction time and deficits in overall task perfor-mance.75 Dopaminergic systems within the prefrontalcortex (PFC) are vital to the formation of attentional setsand switching behavior, with DA neurotoxic lesions ofthe PFC disrupting the establishment of attentionalsets.68,75,76 Deficits in task switching have been observedin patients with Parkinsons disease.7779 This suggeststhat, functioning in the mesostriatum, DA may also playa role in the creation of attentional sets.80 As previouslydiscussed, long-term methamphetamine use can impairthe DA system in both humans and animals. Therefore,the logical assumption is that methamphetamine-induced damage to DA systems may contribute to someof the cognitive deficits observed in methamphetamine-dependent subjects.

Serotonergic Systems and Cognition

The depletion of central 5-HT in rats has been shown toincrease the level of premature responding that is in-dependent of the ability to detect and respond accu-rately to visually displayed targets.81 Harrison et al.81

proposed that 5-HT depletion in animals may increaseimpulsivity by altering 5-HT-DA interactions and, pos-sibly, removing the inhibitory effects of 5-HT on DAneurotransmission. Others have suggested that lower 5-HT levels may actually enhance attentional focus underother conditions, although reduced serotonin levels mayincrease impulsive responses and errors of commissionin some circumstances.82,83 In an attentional search taskthat required the suppression of a distracting stimulus,


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Coull et al.82 found that subjects on a tryptophan-de-pleted diet ignored the distractor more promptly thanthose in the placebo control group. Data from theirstudy suggests that reduced serotonin levels may con-tribute more to impulsive patterns of responses ratherthan to deficits in selective attention. Reduced serotonin

levels in humans have been linked to impaired long-term memory performance.84,85 Memory performance in27 tryptophan-depleted healthy subjects was assessed atimmediate and delayed intervals, with specific memoryimpairments emerging in the delayed condition.85 Incontrast, no short-term memory, perceptual, or psycho-motor deficits were observed.

Methamphetamine-dependent subjects show cogni-tive patterns that are similar to those of subjects whohave been on tryptophan-depleted diets.68 Rogers et al.68

used a novel computerized decision making task in or-der to compare the decision making behavior of 1)chronic amphetamine abusers, 2) chronic opiate abusers,

3) patients with focal lesions of orbital frontal cortex ordorsolateral/medial prefrontal cortex, and 4) trypto-phan-depleted normal volunteers. Chronic ampheta-mine abusers and patients with damage to the orbito-frontal cortexbut not other sectors of the PFCshowed suboptimal decisions and deliberated forsignificantly longer periods of time before makingchoices. Subjects with lower plasma tryptophan per-formed similarly to subjects with histories of ampheta-mine abuse. Such a discovery is salient, as studies con-ducted on animals have revealed reduced levels of 5-HTdue to high-dose methamphetamine administration.31

Limbic regions that are innervated by 5-HT projectionsare especially sensitive to the effects of repeated am-phetamine administration in animal studies,17,31 thusone mechanism for altered decision making associatedwith chronic amphetamine abuse in humans might bethe altered serotonergic modulation of the ventral PFCand its interconnected structures. Increased impulsivityand impaired judgment that are associated with meth-amphetamine use may be linked to the depletion of bothDA and 5-HT neurotransmitter systems.

Electrophysiological StudiesDisrupted attentional processing as a result of meth-

amphetamine use has been detected using electrophys-iological techniques in both animals86 and humans.87,88

Effects of repeated administration of methamphetaminein rats were examined using electrophysiological tech-niques to measure an attentional component (P3-like po-tential) of the event-related potential (ERP) while theanimals were performing an active discrimination task.

The rats were trained to press a bar after cessation of atarget tone (1000 Hz) that lasted for 800 ms and to with-hold an overt response to the standard tone (2000 Hz).Following a series of injections with saline or metham-phetamine, ERPs were recorded in rats. In the rats thatreceived methamphetamine, the amplitude of an atten-

tion-related ERP (the P-3 like potential) decreased with-out alterations in latency. These results are consistentwith alteration in catecholaminergic neurotransmissionthat is induced by repeated methamphetamine admin-istration. Human subjects were used in a study in whichauditory ERPs were recorded for 15 methamphetamine-dependent individuals during a selective attentiontest.87 Attention-related negative ERP componentswere reduced and latency was delayed when comparedto normal controls, which suggests impairment in au-ditory information processing. Another experimentrevealed abnormal electrophysiological activity inmethamphetamine-dependent subjects who exhibited

reduced P3a amplitude and delayed P3b latency, bothmarkers of selective attention.88 The authors suggestedthat these findings might be linked to the dysregulationof functioning that is related to impairment of the fron-tal cortex.

The prevalence of methamphetamine abuse hasreached epidemic proportions throughout the UnitedStates. The review of relevant literature supports the as-sertion that cognitive impairments exhibited by meth-amphetamine- dependent individuals may be the resultof the neurotoxic effects of multiple neurotransmittersystems that are distributed throughout the cortex. Def-icits in attentional inhibition, increased impulsivity, andimpaired task-switching strategies may all be conse-quences of collective damage to the DA and 5-HT sys-tems. A convergence of evidence from behavioral stud-ies in humans, animal research, and the field ofneuroimaging is needed to further examine the neural

basis of cognitive deficits in methamphetamine-depen-dent individuals. Increased knowledge of how neuralregions and cognitive functions are affected by excessivemethamphetamine use could benefit both pharmacolog-ical and therapeutic treatment interventions. Targetedand longitudinal research that uses neuroimaging tech-niques, along with sensitive measures of cognitive func-

tion, will have profound implications for the neurosci-ence of drug addiction, which could subsequently guidepharmacological and treatment interventions.

This work was supported in part by a grant from the Uni-versity of California Davis Department of Psychiatry, theNIDA grant DA10641, and the NIDA grant DA14359


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yamphetamine (MDA) on monoaminergic systems in the ratbrain. Eur J Pharmacol. 1986; 128:4148

35. Schmidt CJ, Ritter JK, Sonsalla PK, et al: Role of dopamine in theneurotoxic effects of methamphetamine J Pharmcol Exp Ther1985; 233:539544

36. Callahan BT, Cord BJ, Ricaurte GA: Long-term impairment ofanterograde axonal transport along fiber projections originatingin the rostral raphe nuclei after treatment with fenfluramine ormethylenedioxymethamphetamine Synapse 2001; 40:113121

37. PUB:Zhou FC, Bledsoe S., Methamphetamine causes rapid var-icosis, perforation and definitive degeneration of serotonin fi-bers: An immunocytochemical study of serotonin transporters.Neuroscience NET, 1996; 1

38. McCann UD, Szabo Z, Scheffel U, et al: Positron emission to-mographic evidence of toxic effect of MDMA (Ectasy) on brainserotonin neurons in human beings. Lancet 1998b; 352:14371445

39. Abekawa T, Ohmori T, Koyama T: Effects of repeated adminis-tration of a high dose of methamphetamine on dopamine andglutamate release in rat striatum and nucleus accumbens. BrainRes 1994; 643:276281

40. Nash JF, Yamamoto BK: Methamphetamine neurotoxicity andstriatal glutamate release: comparison to 3,4-methylenedioxy-

methamphetamine. Brain Res 1992; 581:23724341. Sonsalla PK, Nicklas WW, Heikkila R: Role for excitatory amino

acids in methamphetamine-induced nigrostriatal dopaminergictoxicity. Science 1989; 243:398400

42. Sonsalla PK, Riordan DE, Heikkila RE: Competitive and non-competitive antagonists at N-methyl-d-aspartate receptors pro-tect against methamphetamine-induced dopaminergic damagein mice. J Pharmacol Exp Ther 1991; 256:506512

43. Weihmuller, FB ODell, SJ Marshall, JF: MK-801 protectionagainst methamphetamine-induced striatal dopamine terminalinjury is associated with attenuated dopamine overflow. Syn-apse 1992; 11:155163

44. Abekawa T, Ohmori T, Koyama T: Effects of nitric oxide synthe-sis inhibition on methamphetamine-induced dopaminergic andserotonergic neurotoxicity in the rat brain. J Neural Transm 1996;

103:67168045. Pfefferbaum A, Adalsteinsson E, Spielman D, et al: In vivo brainconcentrations of N-acetyl compounds, creatine, and choline inAlzheimer disease. Arch Gen Psychiatry 1999; 56:185192

46. Ernst T, Chang L, Leonido-Yee M, et al: Evidence for long-termneurotoxicity associated with methamphetamine abuse a H-MRS study. Neurology 2000; 54:13441349

47. Nordahl TE, Salo RE, Poissin K, et al: Low N-acetyl-aspartateand high choline in the anterior cingulum of recently abstinentmethamphetamine dependent subjects: a Proton MRS study.Presented at the Annual Meeting of Soc Neuroscience, 2001

48. Taylor MJ, Alhassoon OM, Schweinsburg BC, et al: MR spec-troscopy in HIV and stimulant dependence. J Int NeuropsycholSoc 2000; 6:8385

49. Bartzokis G, Beckson M, Lu PH, et al: Age-related brain volumereductions in amphetamine and cocaine addicts and normal con-

trols: implications for addiction research. Psychiatry Re 2000;98:93102

50. London E, Dong Y, Simon SL, et al: Brain metabolism duringearly abstinence from methamphetamine abuse.Presented at theAnnual Meeting of the Am College of Neuropsychopharma-cology, 2001

51. Harvey DC, Lacan G, Tanious SP, et al: Recovery from meth-amphetamine induced long-term nigrostriatal dopaminergicdef-icits without substantia nigra cell loss. Brain Res 2000; 871:259270

52. Wilson JM, Kalasinsky KS, Levey AI, et al: Striatal dopaminenerve terminal markers in human, chronic methamphetamineusers. Nat Med1996; 2:699703

53. Volkow ND, Chang L, Wang GJ, et al:Loss of dopamine trans-porters in methamphetamine abusers recovers with protractedabstinence. J Neurosci, 2001; 21:94149418

54. Bolla KI, Funderburk FR, Cadet JL:Differential effects of cocaineand cocaine alcohol on neurocognitive performance. Neurology2000; 54:22852292

55. Bolla KI, Rothman R, Cadet JL:.Dose-related neurobehavioral ef-fects of chronic cocaine use. J Neuropsychiatry Clin Neurosci1999; 11:361369

56. Gillen RW, Kranzler HR,Bauer LO, et al: Neuropsychologic find-ings in cocaine-dependent outpatients. Prog Neuro psychophar-macol Biol Psychiatry 1998; 22:10611076

57. Horner MD: Attentional functioning in abstinent cocaine abus-ers. Drug Alcohol Depend 1999; 54:1933

58. Robinson JE, Heaton RK, OMalley SS: Neuropsychologicalfunctioning in cocaine abusers with and without alcohol depen-dence. J Int Neuropsychological Soc 1999; 5:1019

59. Rosselli M, Ardila A: Cognitive effects of cocaine and polydrugabuse. J Clin Exp Neuropsychol 1996; 18:122135

60. Smelson DA, Roy A, Santana S, et al: Neuropsychological defi-

cits in withdrawn cocaine-dependent males. Am J Drug AlcoholAbuse 1999; 25:377381

61. Fleckenstein A, Gibb J, Hanson G: Differential effects of stimu-lants on monoaminergic transporters: pharmacological conse-quences and implications for neurotoxicity. Eur J Pharmacol2000; 406:113

62. Kornetsky C, Mirsky AF, Kessler EK, et al: The effects of d-am-phetamine on behavioral deficits produced by sleep loss in hu-mans. J Pharmacol 1959; 127:4650

63. Seashore RH, Ivy AC: Effects of analeptic drugs in relieving fa-tigue. Psychological Monographs 1953; 67:116

64. Soetens E, Casaer S, DHooge R, et al: Effect of amphetamine onlong-term retention of verbal material. Psychopharmacology1995; 119:155162

65. Grinspoon L, Hedblom P: The Speed Culture. Harvard Univer-

sity Press, Cambridge, Mass 197566. Fleming K, Bigelow LB, Weinberger DR, et al: Neuropsycholog-

ical effects of amphetamine may correlate with personality char-acteristics. Psychopharmacol Bull 1995; 31:357362

67. Burns JT, House RF, Fensch FC, et al: Effects of magnesium pem-oline and dextroamphetamine on human learning. Science 1967;155:849851

68. Rogers RD, Everitt BJ, Baldacchino A, et al: Dissociable deficitsin the decision-making cognition of chronic amphetamine abus-ers, opiate abusers, patients with focal damage to prefrontal cor-tex, and tryptophan-depeleted normal volunteers: evidence formonoaminergic mechanisms. Neuropsychopharmacology 1999;20:322339

69. Salo R, Nordahl TE, Possin K, et al. Reduced cognitive inhibitionin methamphetamine dependent individuals. (Abstract pre-

sented at Society of Neuroscience, San Diego, CA 2001)70. Simon SL, Domier C, Carnell J, et al: Cognitive impairment in

individuals currently using methamphetamine. Am J Addict2000; 9:222231

71. Ornstein TJ, Iddon JL, Baldaccino AM, et al: Profiles of cognitivedysfunction in chronic amphetamine and heroin abusers. Neu-ropsychopharmacology 2000; 23:113126

72. SquireLR, Zola-Morgan S: Memory: brain systems andbehavior.Trends Neurosci 1988; 4:170175

73. Tulving E, Schacter DL: Priming and human memory systems.


9/9


NORDAHL et al.

Science. American Association for the Advancement of Science1990; 4940:301306

74. Cohen JD, Servan-Schreiber DS: A theory of dopamine functionand its role in cognitive deficits in schizophrenia. Schizophr Bull1993; 19:85104

75. Baunez C, Robbins TW: Effects of dopamine depletion of thedorsal striatum and further interaction with subthalamic nu-cleus lesions in an attentional task in the rat. Neuroscience 1999;92:13431356

76. Roberts AC, De Saliva MA, Wilkinson LS, et al: 6-Hydroxydo-pamine lesions of the prefrontal cortex in monkeys enhance per-formance on an analog of the Wisconsin Card Sort Test: possibleinteractions with subcortical dopamine. J Neurosci 1994; 14:25312544

77. Alexander, GE, DeLong ME, Strick PL: Parallel organization offunctionally segregated circuits linking basal ganglia and cortex.Ann Rev Neurosci 1986; 9:357381

78. Cools AR, van den Bercken JHL, Horstinck NW, et al: Cognitiveand motor shifting aptitude disorder in Parkinsons disease. JNeurol Neurosurg Psychiatry 1984; 47:443453

79. Harrington DL, Haaland KY: Sequencing in Parkinsons disease.Brain 1991; 114:99115

80. Downes JJ, Roberts AC, Sahahkian BJ, et al: Impaired extra-

dimensional shift performance in unmedicated and medicatedParkinsons disease: evidence for a specific attentional dysfunc-tion. Neuropsychologia 1989; 26:13291343

81. Harrison AA, Everitt BJ, Robbins TW: Central 5-HT depletionenhances impulsive responding without affecting the accuracyof attentional performance: interactions with dopaminergicmechanisms. Psychopharmacology 1997; 133:329342

82. Coull JT, Sahakian BJ, Middleton HC, et al: Differential effectsof clonidine, haloperidol, diazepam and tryptophan depletionon focussed attention and attentional search. Psychopharmacol-ogy 1995; 121:222230

83. Soubrie P: Reconciling the role of central serotonin neurons inhuman and animal behavior. Behav Brain Sci 1986; 9:319364

84. Park SB, Coull JT, McShane RH, et al: Tryptophan depletion innormal volunteers produces selective impairments in learningand memory. Neuropharmacology 1994; 33:575588

85. Riedel WJ, Klaases T, Deutz NEP, et al: Tryptophan depletion innormal volunteers produces selective impairment in memoryconsolidation. Psychopharmacology 1999; 141:362369

86. Takeuchi S, Jodo E, Suzuki Y, et al: Effects of repeated adminis-tration of methamphetamine on P3-like potentials in rats. Int JPsychophysiol 1999; 2:183192

87. Iwanami A, Suga I, Kato N, et al: Event-related potentials inmethamphetamine psychosis during an auditory discriminationtask. A preliminary report. Eur Arch Psychiatry Clin Neurosci1993; 242:203208

88. Iwanami A, Kuroki N, Iritani S, et al: P3a of event-related po-tential in chronic methamphetamine dependence. J Nerv MentDis 1998; 186:746751

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Neuropsychological Effects of Chronic Methamphetamine Use on Neurotransmitters and Cognition: A Review