McQueeny et al.  showed adolescent girls had larger amygdalae and increased internalizing symptoms when compared to both control and marijuana using boys. Moreover, certain behavioral problems have also been linked to prenatal marijuana exposure in girls, but not in boys.Recent neuroimaging work suggests that young female users may be vulnerable to marijuana-induced alterations in brain volume, given suggestions of greater prefrontal cortex volumes and relatively poorer levels of executive function.Alcohol is similarly disruptive to females’ cognitive function and regional brain morphology,and it has long been recognized that females are more vulnerable to psychomotor sensitization with psychostimulant exposure.Preclinical data are somewhat stronger and indicate that female adolescents are particularly vulnerable to the effects of long-term THC administration on the CB1 receptor system in multiple brain regions, including the prefrontal cortex, striatum, and periaqueductal gray.A recent study of THC in mid-adolescent rats during the period of drug administration and following abstinence indicated greater sensitization of THC-induced locomotor depression in females versus males. Moreover, high doses resulted in increased anxiety-like behaviors during THC administration, particularly in females,although a general tendency is for females to experience greater anxiolytic effects of the drug. Glutamate is critically important in the neuroplasticity that accompanies the transition from drug use to abuse.Under conditions of extreme trauma or stress, its release is associated with neurotoxicity and cell death.Endocannabinoids block glutamate release under such conditions,which could lead to neuroprotection. However, the concomitant observation of high mIns levels argues against this interpretation. Given that mIns is considered to be a glial marker, high levels would be associated with gliosis as well as white matter injury as occurs in the context of neural injury. High mIns concentrations have been observed in early dementia, in frank Alzheimer’s disease,drying cannabis as well as in abstinent methamphetamine users, although this latter observation was in the frontal lobes.

This pattern is intriguing given that deficits in learning and memory represent one of the robust areas of reported cognitive dysfunction in marijuana users.Although our data analyses do not suggest that female marijuana users in this sample are more vulnerable to cognitive impairments,this is a relatively young and high functioning sample. It may be that frank behavioral deficits will emerge more strongly in females over time as chronicity of use progresses. We hypothesize, too, that we may have observed altered NAA levels had we also measured frontal concentrations of each metabolite. Even though our statistical analyses do not show any significant effect of alcohol, it is important to consider the possibility of an underlying biological interaction between the two substances. Male marijuana users in this study had the highest levels of alcohol use, but did not show significant neurochemical alterations relative to controls. Females showed the greatest apparent impact of marijuana use on Glx and mIns, but in the context of lower levels of alcohol use. These findings could suggest a neuroprotective effect in individuals who use both marijuana and alochol, as described by others.Alternatively, previous work has shown greater levels of Glx in the anterior cingulate of chronic alcohol users relative to controls.Considering this, taken together with the findings of the present study, it is possible use of the two substances together may drive metabolite concentrations to “normal” levels via opposing processes, as has also been suggested by others in the context of brain morphology.Differences in metabolic function in heavier versus lighter alcohol users can also impact the conversion of acetate into glutamate.It is possible, then, that the male marijuana users in this study who were heavier alcohol users as compared to females, demonstrated differences in glutamate metabolism, contributing to the observed sex difference. However this assertion is only speculative.

While our data do not fully support these conclusions, the issue of alcohol use in the context of marijuana use requires careful examination in future studies. Sex but not group-related effects were also observed in total choline estimated concentrations.Independent of marijuana use, males showed higher estimated concentrations of tCho compared to females. Numerous choline-containing compounds contribute to the tCho signal measured in this study, complicating the interpretation of this sex difference. For example, phosphatidylcholine plays an important role in the phospholipid bilayer in cell membranes, and choline is essential in the formation of the neurotransmitter acetylcholine. Generally speaking, increases in choline signal in the brain have been demonstrated in cases with pathology .While this study has numerous strengths, it is not without limitations. Given time constraints on the scanning protocol, glutamate and glutamine could not be resolved separately from the acquired spectra. Even though this is a common problem, especially at lower field strengths,it poses limitations on the interpretation of the data because of the different biochemical functions of these metabolites. After release of glutamate into the synapse, cycling between glutamate and glutamine occurs in glial support cells in order to maintain high SNR in glutamatergic neurons, and to protect against adverse excitotoxic effects.Resolution of the glutamate versus glutamine signals would allow stronger interpretations to be offered regarding the meaning of the low levels observed in female users. Given that more extensive spectroscopy scanning is time intensive and requires higher field strengths to be conducted most efficiently, these findings together with other recent studies  suggest that a more in-depth examination of neurochemical metabolism within frontostriatal circuits in heavy marijuana users is warranted. Another limitation of the study is the constrained spatial resolution of the spectra. It would be beneficial to examine additional brain structures, however spectral resolution was chosen over spatial resolution for the current study. Moreover, while the sample sizes are small in relation to the reported group by sex interactions, numerous reports exist which demonstrate a similar a pattern of sex-effects, where females who use or are exposed to illicit substances  are differentially affected.Finally, we did not measure urine or hair concentrations of THC, so it is possible that participants in the study used less marijuana than they reported. We find this to be unlikely given the level of detail that was provided about habits surrounding use in our direct interviews, participants’ consistent reporting regarding their symptoms of DSM-IV marijuana dependence, and concomitant evidence of neurocognitive impairment consistent with marijuana exposure.

Further, the majority of previous studies that collected urine/hair data and quantified cannabinoid concentrations did not show significant associations between these concentrations and brain metabolite data, suggesting such data are perhaps not necessary for this type of analysis in the presence of detailed clinical assessments. Nonetheless, the study would be strengthened by the ability to compare brain metabolic data with cannabinoid levels as obtained by blood, hair or urine analysis.A long-standing observation in clinical and epidemiological research into substance use has been that users of one drug typically do not limit their use to a single substance.For example, alcohol and tobacco are commonly used by the same person and often in the same setting, as are tobacco and marijuana. Though the synergistic effects of these particular drugs have been suggested as a potential explanation,another interesting possibility is that individuals have an underlying liability to drug use within and across different pharmacological classes. Support for this notion has been shown for both licit and illicit drugs in a variety of populations and drug use phenotypes.As poly-substance use is associated with problematic use and reduced treatment efficacy,identifying informative precursors to the onset of abuse and dependence remains a priority. Among the variety of factors that have been examined as a nearly indicator of later, more problematic use patterns, how someone experiences a drug,is one of the most interesting.Factor analytic studies of these experiences frequently yield two main factors: pleasant or positive and unpleasant or negative.Positive subjective experiences often include euphoria, relaxation, and feeling less inhibition. Negative subjective experiences include nausea, difficulty inhaling, dizziness and sadness. Though weakly correlated,users of a drug sometimes report both positive and negative experiences. Alcohol, tobacco, and marijuana are the most commonly used licit and illicit drugs. Studies examining the subjective experiences to these drugs have generally found that how a person responds to a particular drug is predictive of more problematic use of the same drug.

For example, dependent cigarette users more frequently endorse positive experiences than regular smokers and moderate-to-heavy drinkers report experiencing greater stimulant-like effects to alcohol than lighter drinkers.A similar relationship has been demonstrated for marijuana use.Although results are mixed, negative experiences to tobacco and marijuana have also been positively associated with problematic use.For alcohol consumption, low levels of response, primarily measured using negative subjective effects, have been associated with an increased risk of an alcohol use disorder  as lower thresholds to the sedative effects of alcohol protected against developing abuse later in life.A handful of previous studies have suggested that subjective experiences for different drugs may share a common etiology.In particular, subjective experiences to a variety of drugs are correlated and can predict levels of involvement for substances in other pharmacological classes. This observation has been shown for pleasurable experiences of alcohol and tobacco where both drugs were predictive of current alcohol use in a college aged sample.Further, marijuana use has been shown to increase a sense of “liking” among non-smokers whereas alcohol has no effect on the subjective experiences of cigarettes.Lastly, greater rates of alcohol dependence and illicit drug use have been observed among high marijuana users as defined by greater rates of sensitivity to positive and negative subjective experiences.Though additional studies are needed, ebb flow these cross-drug results indicate that how a person responds to a drug is predictive of how they will respond to other drugs. In this report we detail findings from a study of subjective experiences to alcohol, tobacco, and marijuana in a sample of young adults participating in the Colorado Center for Antisocial Drug Dependence. Subjective experiences were collected from both clinical and community participants using a questionnaire developed by Lyons et al..Our analyses were designed to address three questions. First, how do positive and negative subjective experiences across alcohol, tobacco, and marijuana compare? Second, to what extent do subjective experiences to alcohol,tobacco, and marijuana overlap? Lastly, to what degree do subjective experiences to one drug associate with more problematic use behaviors for a different drug?Participants were drawn from the Colorado Center on Antisocial Drug Dependence [CADD] and consisted of 3853 participants  between the ages of 11 and 30 years old and included both community and clinical participants.

Our community-based sample  was drawn from those participating in the Colorado Twin Registry,Colorado Adoption Project,with clinical controls drawn from the Colorado Adolescent Substance Abuse Family Study.Our clinical sample  was drawn from adolescents in treatment for substance abuse and delinquency as a part of the ASA study.Additional clinical participants were drawn from an adjudicated sample from the Denver metropolitan area.Siblings of the clinical subjects  were also included. All participants in the current study met one or more of the following criteria:  they had consumed at least six drinks in their lifetime,  had used tobacco daily for at least one month, or  had used marijuana six or more time in their lifetime.Patterns of alcohol, tobacco and marijuana use, abuse and dependence symptomatology were collected using the Composite International Diagnostic Interview-Substance Abuse Module.Abuse and dependence status as defined by the Diagnostic and Statistical Manual of Mental Disorders  was determined using scoring algorithms based on whole life substance related problems. Retrospective subjective experiences were collected using a 23- item questionnaire developed by Lyons et al..The original Lyons questionnaire was comprised of 23 items. As discussed in Zeiger et al.,due to the CADD interview length the original Lyons questionnaire was shortened after wave 1; a factor analysis was conducted on the Lyons questionnaire and 10 items with lower or mixed loadings were dropped. Subsequently, most subjects received the shortened 13-item questionnaire, thus these analyses were conducted on the 13-item response set from all subjects The 13-items included: social, mellow, creative,top of the world, increased sex drive, energetic, dizzy, nauseous, drowsy, lazy, unable to concentrate, out of control, and guilty. Participants were asked “in the period shortly after you used  did it make you feel…”? Responses were scored as present  or absent  and the item scores summed to make the positive and negative scales.