The objective of this review is to evaluate the evidence that methamphetamine use causes a characteristic brain pathology in human users of the drug for psychoactive purposes.
Information on brain pathology is important from a public health point of view and might also provide clues as to new targets for therapeutic intervention in the methamphetamine user.
The scope of the review is largely focused on questions whether methamphetamine, as suggested by experimental animal data, might change or damage brain neurons that use dopamine as a neurotransmitter and also cause changes in brain suggestive of neurotoxicity (oxidative stress, gliosis, decreased brain size).
The many confounds in human methamphetamine studies make conclusions on brain pathology difficult. There are many generic difficulties and confounds associated with studies of human methamphetamine users designed to establish whether the drug causes harm to the brain. These include lack of proof (e.g. by hair or repeated urine testing) in most investigations that drug users primarily or exclusively used methamphetamine and did not use other drugs that could cause brain pathology, and uncertainty whether changes present in brain were caused by methamphetamine or were a preexisting abnormality. Scatterplots of individual data are also not always provided making it impossible to establish whether brain differences in individual studies are robust.
In addition, there is a continuing uncertainty whether differences in levels of any of the brain biochemical markers of dopamine or other neurons possibly affected, can be equated with actual changes in neuronal integrity. In this regard, readers are cautioned to be skeptical of any conclusion in the methamphetamine literature that a change in a brain biochemical neuronal marker necessarily equals loss of part or all of a dopamine neuron.
To date, no brain pathology of chronic methamphetamine users has been reported that is a characteristic defining, or obligatory feature. Differences in a variety of brain markers in methamphetamine users have been described, but none can absolutely differentiate methamphetamine users from normal subjects, with levels of most markers showing overlap when comparing ranges of control and drug-user values.
Methamphetamine probably causes changes in levels of brain markers of dopamine neurons of some drug users, but it is not clear whether this represents neuronal loss or an otherwise pathological state. A variety of dopamine neuronal markers have been measured in postmortem and/or living brain of methamphetamine users, including dopamine, its metabolites homovanillic acid and dihydroxyphenylacetic acid, the dopamine biosynthetic enzymes tyrosine hydroxylase and dopa decarboxylase, the dopamine and vesicular monoamine (VMAT2) transporters, and several dopamine receptors. Three potentially meaningful findings have been reported:
The first finding, still awaiting replication, is low striatal (caudate, putamen, nucleus accumbens) concentrations of dopamine in autopsied brain of methamphetamine users, all who had recently used the drug. The magnitude of the reduction was near total in some subjects, with little overlap between control and drug user values in caudate, and suggests that high dose methamphetamine, a dopamine releaser, can cause massive release of the neurotransmitter such that tissue stores of dopamine are depleted. Low dopamine might explain some negative aspects of the methamphetamine abstinence syndrome.
A second dopamine-related finding is a reduction, typically of modest magnitude, of the striatal dopamine transporter, a change that probably normalizes to some extent in extended abstinence. The transporter difference is the most replicated finding in studies of dopamine markers in methamphetamine users. It has been reported in two postmortem brain investigations and in six independent imaging studies of living brain. It continues to be debated whether low transporter levels (reputedly lasting up to many years of abstinence in some investigations) has functional significance or is associated with loss of transporter-containing dopamine nerve endings.
The third observation is the lack, at present, of any marked reduction in striatal levels of some other dopamine neuronal markers, including dopamine metabolites, dopa decarboxylase, and VMAT2, as occurs in Parkinson’s disease.
Other dopaminerigic changes reported in brain imaging studies include slightly decreased striatal binding to the dopamine D2 receptor, and a preliminary finding of increased binding to the dopamine D3 receptor—differences that might relate to aspects of addiction to methamphetamine, although this link is not yet established.
Changes in nondopaminergic markers. These differences include a reduction in biochemical markers of serotonin neurons (generally consistent with animal findings) and decreased striatal concentration of the neuropeptide met-enkephalin—findings consistent with either loss of serotonin and met-enkephalin-containing neurons, or neuroadaptation without neuronal loss.
Does methamphetamine cause brain oxidative stress? Animal data suggest that methamphetamine might cause oxidative brain damage, with dopamine-rich brain areas showing higher oxidative stress. Results of a postmortem brain study of methamphetamine users, awaiting replication, support this possibility, with a finding of markedly elevated concentrations of two lipoperoxidation products, 4-hydroxynonenal and malondialdehyde. Changes were most marked in the dopamine-rich striatum and related to drug dose.
Studies of brain gliosis of methamphetamine users: Findings are intriguing but no clear picture yet emerges. Microglial activation and reactive astrogliosis are common features of neurotoxic insult. Information on brain gliosis is primarily limited to two methamphetamine investigations: a postmortem investigation in drug users (who had very recently used methamphetamine) reporting increased number of microglial cells in striatum but no increase in activated microgliosis, and a brain imaging study, employing a putative marker of activated microglial cells, showing high binding to the marker throughout the brain of methamphetamine users, withdrawn for up to 2 years after a last drug use. The two gliosis findings are still too preliminary, difficult to reconcile, and (the imaging study) uncertain because of the first generation radiolabelled probe employed, but the question remains whether methamphetamine might induce a progressive, persistent brain neurodegeneration accompanied by gliosis in some subjects.
Is methamphetamine exposure associated with smaller or larger brain size? Structural imaging investigations generally suggest slightly lower cerebral cortical gray matter density and striatal enlargement (related to gliosis?) in some drug users. However, the findings are not yet definitive or, in the case of the striatal difference, consistent, and the influence of abstinence time and use of other recreational drugs on the outcome measures remains to be resolved.
Increased risk of Parkinson’s disease in methamphetamine users? A large longitudinal population-based cohort investigation employing inpatient hospital databases from California reports increased risk of subsequent development of Parkinson’s disease in methamphetamine users. This is a preliminary finding, requiring replication, and is associated with many confounds; however, the study does suggest that high dose use of methamphetamine might increase risk of developing Parkinson’s disease in later life.
Major Conclusions. There is as yet no characteristic or defining brain pathology of chronic methamphetamine users, with the exception of the still undiscovered pathology responsible for compulsive drug taking in the subgroup of chronic methamphetamine users who are addicted to the drug.
Regarding brain dopamine-related changes, the reported differences that most impress this reviewer are the striatal dopamine depletion associated with acute drug use, because of the striking magnitude of the change and minimal overlap between drug user and control values, and the striatal dopamine transporter reduction, because of the many replications of the finding in the postmortem brain and brain imaging literature. A severe striatal dopamine transporter reduction (below control levels) is unlikely to be a feature of all methamphetamine users, but future studies of representative numbers of drug users are likely to continue to find a modest mean group reduction in comparison with control values. The lack, to date, of any substantial reduction in other dopamine markers (dopamine metabolites, VMAT2) suggests that if there is any loss of dopamine nerve terminals in methamphetamine users, the extent of loss is probably only typically slight.
At present, a statement that methamphetamine causes physical-structural (vs adaptive-neurochemical) damage to dopamine neurons in the human is not justified.
In terms of measures that might be related to physical damage to brain neurons, the postmortem brain finding of increased levels of oxidative stress indices is noteworthy because of the large magnitude of the change and association with extent of dopaminergic innervation and drug dose. The glial and structural brain changes in methamphetamine users are both highly provocative but still early, not yet definitive findings, with more work needing to be done to confirm the extent to which these changes occur and are related specifically to methamphetamine use. Glial changes assumed to occur from brain imaging studies must be confirmed by histopathological analysis in postmortem brain. A statement that methamphetamine causes “holes in the brain” is at present unjustified.
Recommendations: Regarding the question of methamphetamine as a neurotoxin, my review of the literature suggests that an intensive combined longitudinal brain imaging focus on gliosis (microglial activation, reactive astrocytosis) and brain size in which issues of abstinence time and drug specificity are resolved, will likely be rewarding. There needs to be more (admittedly logistically difficult) postmortem brain investigations of methamphetamine users in order to confirm that brain imaging findings are in fact valid. Future investigations of methamphetamine users should also provide confirmation of use by sampling hair and repeated urine testing, disclosure of scatterplots of data so that extent of overlap of values can be assessed, and inclusion of a drug control group (e.g. users of cocaine) to address, in part, the question of drug specificity.