The results and conclusions from this study should be examined within the context of its limitations. First, the data-set examined in this analysis was derived from two larger parent projects,thus, certain variables of interest could not be manipulated or controlled to study more detailed MJ-related effects.In spite of these limitations, MJ users were homogenous in their MJ use due to study inclusion criteria.In addition, we only had one memory measure common to examine across our combined sample. While the WMS-III story memory paradigm is a well-validated and researched instrument, it may not generalize to learning and memory processes in alternative nonverbal modalities. Further, using a memory measure with a somewhat higher executive loading such as an unstructured word list learning task may elucidate some of the differential effects of MJ versus nicotine on memory functioning. Lastly, the between-group differences observed in this study were characterized by small to-medium effect sizes and future research would be needed to replicate these findings in larger samples.Illicit marijuana use in the United States has been a longstanding public health concern for both adolescents and adults. As many as 44% of college-aged individuals endorse having used marijuana at some point in their life, and 21% of college-aged individuals report marijuana use in the past 30 days.Marijuana intoxication is associated with motor coordination deficits, euphoria, impaired temporal estimation, drying racks and a variety of other psychological phenomena.
Marijuana use has also been associated with more specific cognitive deficits, even after acute intoxication has subsided,and with the development of severe psychopathology.Furthermore, chronic marijuana use has been related to adverse physiological consequences in the cardiovascular and respiratory systems.Adolescence and young adulthood represent periods of the lifespan when increased risk-taking occurs, including the use of illicit substances, such as marijuana. The combination of an innate propensity for risk-taking and use of a judgment-altering substance is a striking example of the immediate public health concern over marijuana use in young-adults. This concern is particularly pertinent in light of recent efforts in support of marijuana’s legalization in the United States. A challenge for the field is to identify which chemical systems and associated information processing networks are most affected by chronic marijuana use. The main psychoactive component of marijuana, Δ9 -tetrahydrocannabinol,acts as an agonist in central nervous system cannabinoid receptors and in other peripheral cell types, primarily immune cells. In the CNS, CB1 receptor density is high in the basal ganglia, particularly in the dorsal striatum.Cannabinoid receptor signaling acts on multiple neurotransmitters through a variety of biochemical cascades, including inhibition of voltage-dependent calcium channels and by directly inhibiting vesicle release. Both excitatory and inhibitory neurotransmitters, including glutamate,γ-aminobutyric acid and dopamine, are either directly or indirectly affected by CB1 receptor activation.For marijuana and other drugs of abuse and dependence, the dorsal striatum has been hypothesized to play a key role in the transition from intermittent drug use to compulsive habit-based drug-taking via mechanisms that underlie long-term synaptic plasticity.Exogenous activation of CB1 receptors, as occurs with marijuana intoxication, inhibits the release of glutamate as well as GABA in both the dorsal and ventral striatum.This inhibition facilitates the development of long-term depression in the striatum, which is a critical component in the altered synaptic plasticity that accompanies drug addiction.Thus, the manner in which corticostriatal functional connectivity is altered in the context of marijuana use is of interest, as is metabolic activity within the chemical systems that contribute to those alterations.
Magnetic resonance spectroscopy is a widely used tool, allowing for in vivo characterizations of various brain metabolites. MRS data is acquired either from single voxel or multiple voxels. The SVS method typically benefits from high spectral resolution and signal-to-noise ratio.MRSI has better spatial resolution compared to SVS, but typically has a much more limited spectral resolution.To the best of our knowledge, only four other studies utilizing some form of MRS to examine marijuana users have been published, and the methods of these studies are relatively heterogeneous.The existing studies are summarized in Table 1. Individuals ages 16-to-42 years were studied with either SVS or MRSI. In two of the studies, only males were examined.In most cases, marijuana use was reported at 20 or more days per month. Lower levels of Glu, N-acetylaspartate,and myo-inositol were observed in marijuana users compared to controls in regions known to be associated with substance use, including the basal ganglia,thalamus,cingulate cortex,dorsolateral prefrontal cortex,and the striatum as well as posterior cortical regions.The methods, ages of subjects, and extent of current marijuana use in the samples tested vary considerably across studies as summarized in Table 1. As disruptions in glutamate activity have been implicated in the development of addiction,we hypothesized disruptions in glutamate concentrations in marijuana users compared to controls. Several lines of evidence suggest inhibition of glutamate excitotoxicity by marijuana.In addition, based on the MRS literature described above related to the basal ganglia of adult marijuana users and literature describing the inhibitory effects of CB1 receptors on glutamate release, we specifically hypothesized that young-adult MJU subjects would show lower levels of Glu + glutamine in the basal ganglia compared to their non-using counterparts. We did not have a specific hypothesis regarding concentrations of other metabolites given that other researchers have not concentrated their assessments on the striatum. However, the limited available literature suggested the possibility of altered mIns as well as NAA levels in users versus controls.Twenty-seven marijuana users were recruited into the study through local advertisements on the University of Minnesota-Twin Cities campus. Marijuana users’ ages ranged from 18-to-21 years, with a mean and standard deviation of 19.5 ± 0.6 years.Exclusion criteria are described below.
Twenty-six healthy young adult non-users,who were participants in a large, longitudinal study of normal brain development, served as a control sample. Control participants’ ages ranged from 13-to-24 years, with a mean and standard deviation of 19.3 ± 3.1 years. The recruitment strategy for the control sample has been described elsewhere.Briefly, participants younger than 18 years of age were recruited through a database of research volunteers throughout the Metro community, through post-cards mailed to University of Minnesota civil service employees, and through local advertisements. Participants over the age of 18 years were recruited using on-campus advertisements. During the controls’ third longitudinal follow-up visit, MRS was added to the protocol as time allowed. Thus, the control sample described in this study has a broader age range than the MJU sample, a feature that was considered in the statistical approach described below. A description of the study was initially given to both the MJU and control participants over the phone. Interested participants were then invited to complete a brief phone screening to ascertain study eligibility. Exclusion criteria included major physical, neurological or psychiatric illness, substance use disorders,head injuries resulting in loss of consciousness >20 min, mental retardation, learning disabilities, current use of psychoactive medications, non-native English speaking, vision or hearing that was not normal or corrected to normal, complications at birth, current pregnancy, and MRI contraindications.Inclusion criteria for MJU participants included current use of marijuana at least five times per week for at least one year, and an age of onset of use prior to the age of 17 years. Marijuana users were also excluded if they were daily cigarette smokers, or if their alcohol use exceeded four drinks for females and five drinks for males on more than two occasions per week. Marijuana users were asked to refrain from drug use for at least 12 h prior to their visit to avoid acute intoxication during study procedures. Participants provided written informed consent and all study procedures were approved by the University of Minnesota’s Institutional Review Board.After the phone interview, eligible participants were invited to the University of Minnesota’s Center for Neurobehavioral Development for an in-person screening session to further ascertain eligibility and to verify information given over the phone. The Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version was used to assess for current or past Diagnostic and Statistical Manual, Fourth Edition axis I disorders, including childhood disorders given the relative youth of the sample.
The presence or absence of DSM-IV disorders was confirmed by case consensus meetings with staff members including a license-eligible clinical psychologist. In addition, a two-subtest version of the Wechsler Abbreviated Scale of Intelligence was administered to yield estimated full scale IQ.Participants who met all inclusion criteria after the in-person interview were invited back for a comprehensive neuropsychological testing battery and an MRI scan. This report focuses on spectroscopy findings.In addition to the K-SADS-PL, the Personal Experience Inventory was used to further assess alcohol and marijuana use in both the MJU group and in the healthy controls. Briefly, the PEI consists of two main sections, one focused on patterns and severity of substance use, and the other focused on psychosocial consequences of use. In most cases, participants endorse items from the inventory using a four-point Likert response format.Different versions of the PEI have been developed for adolescents versus adults. Participants younger than 18 years of age received the adolescent version and participants older than 18 years of age received the adult version; both versions were computer administered. All MJU participants received the adult version. Scoring was implemented to create comparable metrics across the two versions. Finally, an in-house questionnaire based on guidelines provided by the National Institute on Alcohol Abuse and Alcoholism was implemented to assess detailed daily, weekly, yearly and lifetime use patterns of alcohol and marijuana in the sample, considering frequency and amount of use.This study examined a cohort of college-aged heavy cannabis drying users and a control group of non-using young-adults. Using MR-spectroscopy, it was shown that females, but not males, who used marijuana heavily starting in mid-adolescence and persisting for several years have lower levels of glutamate and glutamine in the dorsal striatum when compared to controls, even after accounting for age and alcohol use. Similarly, female but not male users differ from controls in their estimated concentrations of myo-inositol, demonstrating higher levels than controls. These patterns are interpreted as pathological in the female users given that male users had comparable levels to controls of both sexes. Female users did not differ from male users in their overall rates of self-reported marijuana use, in their concomitant level of alcohol use,in their numbers of symptoms of marijuana dependence, or presence of other conditions that might impact brain metabolism.These findings have broad parallels in the extant literature, both in relation to the overall patterns observed but also in relation to sex differences.
Decreased glutamate/glutamine concentrations have been reported in two other MRS studies of marijuana users, one that focused on the basal ganglia and one that targeted the anterior cingulate cortex.First, in an older cohort of marijuana users than is described in the current study, Chang et al. reported lower glutamate levels in the basal ganglia, suggesting that heavy marijuana use during young adulthood as well as later in life is associated with disruptions in glutamate signaling as has been shown for other drugs of abuse.Recently, Prescot et al. reported lower glutamate concentrations in the anterior cingulate cortex, which was nonetheless strongest when females were eliminated from the analysis. Interpretation of the current findings is complicated by poor resolution of the glutamate versus glutamine signal. Glutamate is present in all cell types with the largest pools evident in glutamatergic neurons; smaller pools are evident in GABA-ergic neurons and astroglia. Upon release, astroglia convert glutamate to glutamine, which in turn is transferred back to the neuron for conversion once again to glutamate.Glutamine is primarily located in astroglia. Thus, low glutamate levels would be difficult to ascribe to a particular neuronal process. In contrast, if glutamine levels are low, then glial dysfunction may be present, a finding that would be consistent with white matter aberrations in marijuana users.Others have not reported specific metabolic disruptions in female marijuana users; indeed, within young samples, marijuana is more commonly used in males.Although it has been recognized that females are at an increased risk for some behavioral consequences of drug use such as sexual risk-taking and an increased risk of depression and anxiety following a pattern of daily marijuana use,there are relatively few human studies of brain-based sex differences associated with marijuana. Women have shown slightly more severe neurocogntive deficits related to marijuana use compared to men.