Primary Care Corner with Geoffrey Modest MD: Marijuana psych effects

a recent animal study assessed the effects of cannabinoid receptor stimulation on adolescent rats, finding  brain changes similar to those found in schizophrenia (see  here). this study adds physiologic plausibility to the observed increased incidence of psychosis in human marijuana users in observational cohort studies (see below). given the current remarkable increase in marijuana potency, increasing usage overall, and new legalization, i thought it was useful to review some of the newer data on adverse effects, concentrating on the psych ones. it is notable that the onset of both addiction-related syndromes and psychosis typically occur in adolescence. in the rat study (i will not go into all of the gory details):

 –rats with persistent stimulation of the cannabinoid 1 receptor, but only during specific windows of adolescence (ie, only in early or mid adolescence and not during late adolescence or adulthood), develop a long-lasting prefrontal cortex disinhibition, with a functional downregulation of GABAergic transmission. One key finding is that this disinhibition is enduring into adulthood in rats but only if stimulated during these susceptible developmental times of early to mid adolescence.
–other studies find an important role of impaired GABA transmission in schizophrenia

an older lancet study provided a meta-analysis of longitudinal studies to assess the relationship between marijuana use in adolescence and psychosis (see here). although these were observational studies (so can’t really draw ironclad conclusions), these studies were long-term, so as to minimize the likelihood of reverse causality (eg, patients with imminent psychosis using more marijuana) and are not related to the acute, transitory, psychotic-like effect of acute marijuana usage. their findings:

–after thorough literature search, 7 cohort studies identified which were population-based longitudinal studies, including 2 birth cohorts from Dunedin
–there was a consistent relationship in these studies, finding an average 41% increased risk of schizophrenia (or schizophreniform disorder) with cannabis use. the most rigorous studies (swedish study and dunedin study) found an odds ratio of 2.58.
–6 studies looked at cannabis use frequencies, consistently finding that increased usage was associated with increased risk (50-200% increase)
–the Dunedin study found a stronger effect of cannabis on psychotic symptoms in those who used cannabis prior to age 16
–several studies assessed the presence of psychotic symptoms lasting longer than one month and another only looked at hospital admissions for schizophrenia, making acute intoxication as cause of psychotic symptoms unlikely
–by eliminating patients with known psychosis or predisposition to psychosis at baseline, controlling for up to 60 potential covariates (other substance use, mental health problems, personality traits, sociodemographic markers, etc), and following cohort for years before using cannabis, there was less likelihood for reverse causality (eg, Dunedin study adjusted for psychotic symptoms at age 11, looked at cannabis and psychosis measures at age 15 and 18)
–data on depression/affective disorders, suicidal thoughts, anxiety were examined separately, but marijuana usage was less consistently associated than for psychosis

 so, these 2 studies suggest that :

–especially during early adolescence (in rats and humans) there seems to be increased risk of long-term psychotic effects of marijuana use and this increase is dose-dependent.
–the implications seem pretty profound, since 20% of young people report using marijuana at least once a week and this increased use reported now is especially during early adolescence
–there can never be a randomized controlled trial of marijuana use and psychotic outcomes to prove causation.  but, this meta-analysis is one of the most careful i have seen, and the results are consistent over the several studies analyzed.
–in light of the physiologic possibility (in rats) and the potential increase in psychosis for the huge numbers of human marijuana users (40% of young adults report using marijuana in UK, which translates into a possible 14% of all psychotic outcomes might have been avoidable if marijuana not used), the better part of valor would be to inform young patients of psychosis as a potentially very serious complication of marijuana use.

 another review from the lancet (see here) reviewed the adverse effects of non-medical use of marijuana.  for psych effects, they note the well-accepted impairment in cognitive function in regular users, also noting deficits in verbal learning, memory and attention in heavy users (duration, frequency of use, cumulative dose of THC). there seems to be at least partial recovery after 2 years of abstinence in some but not all studies. also reported are structural brain changes (reduced hippocampus and amygdala volume in chronic users), as well as poor school performance, and early school leaving, with their attendant social consequences. again, most of this is based on observational studies, so cannot posit a direct causal relationship.

but, on the other hand, the American Academy of Neurology published guidelines on complementary/alternative medicine in multiple sclerosis, noting that cannabis has been shown to decrease spasticity and pain (excluding central neuropathic pain), and the spray seems to work for spasticity symptoms, pain and urinary frequency, though cannabis unlikely to improve objective measures of spasticity or urinary symptoms (see DOI 10.1212/WNL.0000000000000250).