Adverse structural and functional effects of marijuana on the brain

David E. Mandelbaum, Suzanne M. de la Monte. Adverse Structural and Functional Effects of Marijuana on the Brain: Evidence Reviewed.  Pediatric Neurology.  Article in Press.

Abstract

The growing use and legalization of cannabis are leading to increased exposures across all age groups, including in adolescence. The touting of its medicinal values stems from anecdotal reports related to treatment of a broad range of illnesses including epilepsy, multiple sclerosis, muscle spasms, arthritis, obesity, cancer, Alzheimer disease, Parkinson disease, post-traumatic stress, inflammatory bowel disease, and anxiety. However, it is essential that anecdotal data and the high level of interest in this treatment not obscure objective assessments of any potential and realized short- and long-term adverse effects of cannabis, particularly with respect to age of onset and chronicity of exposure. This critical review focuses on evidence-based research designed to assess both therapeutic benefits and harmful effects of cannabis exposure and is combined with an illustration of the neuropathologic findings in a fatal case of cannabis-induced psychosis. The literature and reported case provide strong evidence that chronic cannabis abuse causes cognitive impairment and damages the brain, particularly white matter, where cannabinoid 1 receptors abound. Contrary to popular perception, there are few objective data supporting preferential use of cannabis over conventional therapy for restoration of central nervous system structure and function in disease states such as multiple sclerosis, epilepsy, or schizophrenia. Additional research is needed to determine if subsets of individuals with various neurological and psychiatric diseases derive therapeutic benefits from cannabis.

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From the article

Neuropsychiatric effects of cannabis vary in severity and can be associated with neuropsychologic deficits, reduced motivation and activity, hallucinations, or symptoms of schizophrenia-like psychotic disorders.  Heavy regular cannabis use, especially in adolescents (before age 15 years), is associated with higher rates of persistent negative outcomes in adulthood, including increased rates of mental illness and cognitive impairment.  Because schizophrenic psychosis and cannabis use share a number of similarities and both begin in late adolescence, a major concern is whether adolescent cannabis use causes or triggers chronic psychosis or schizophrenia and whether the neuroanatomic substrates of cannabis neurodegeneration and schizophrenia are shared.  For example, both heavy cannabis users and schizophrenics have diminished regional gray and white matter volumes, and close relatives of schizophrenics have high cannabis use.  However, in a well-controlled study, Dekker et al.  demonstrated that schizophrenia was not triggered more frequently by adolescent compared with later-onset cannabis use, and that the characteristic white matter abnormalities in the corpora callosa of schizophrenics were not correlated with age of onset of cannabis use. Therefore the schizophrenia-like psychotic disorders associated with heavy cannabis use are likely distinct from schizophrenia.

Another consideration is that cannabis use may precipitate psychosis in susceptible individuals. A study of 410 patients with first-episode psychosis found that those with a history of cannabis use presented with psychosis at a younger age than those who never used cannabis. In addition, those using high-potency cannabis (skunk-type) every day had the earliest onset compared with never users.  The findings in a study of more than 1000 patients with psychotic disorders, their unaffected siblings, parents, and control subjects suggest that gene–cannabis interactions may influence vulnerability to adverse mental health effects of cannabis use.  However, the possibility that individuals with emerging mental illness might seek out psychoactive substances limits the ability to establish a clear cause–effect relationship between cannabinoid use and psychiatric disease based on retrospective studies…

Meta-analysis data show that heavy cannabis using adults exhibit significant deficits in learning, working memory, and attention, but with abstinence, these problems may resolve.  In contrast, adolescence is a critical period of neurodevelopment during which synaptic modulation and myelination are highly active and therefore could be disrupted by exogenous exposures to drugs and toxins.  In this regard, concerns have been raised about chronic heavy cannabis use and cognitive decline in adolescents. To help address this question, a birth cohort of 1037 individuals was followed from birth (1972/1973) to age 38 years in Dunedin, New Zealand. Cannabis use was ascertained at ages 18, 21, 26, 32, and 38 years, and neuropsychologic testing was performed on all subjects at ages 13 and 38 years. This study found that persistent cannabis use was associated with broad neuropsychologic declines across multiple domains of functioning, even after controlling for years of education. Persistent users reported more cognitive problems. Cognitive impairment was mainly associated with cannabis use from adolescence, and more persistent use led to greater declines in cognitive function. The gravity of these problems is highlighted by the finding that cessation of cannabis use did not fully restore neuropsychologic function in adolescent-onset cannabis users…

Besides its adverse effects on cognitive, behavioral, and psychiatric functions, cannabinoid use has been linked to structural changes in the brain. High-resolution MRI with morphometric analysis of gray matter density, volume, and shape was performed on 20 individuals, aged 18 to 25 years, who either had self-report histories of least weekly cannabis use or were abstinent control subjects.   None of the cannabis users met DSM-IV criteria for drug dependence or any current or lifetime Axis I disorder, and all tested negative for alcohol use disorder. The study found a statistical trend effect of higher gray matter densities in the left nucleus accumbens among cannabis users compared with control subjects. In addition, there were statistically significant shape differences in the left nucleus accumbens and right amygdala among cannabis users. Gilman et al. concluded that in adolescent humans, the cannabis exposure-dependent alterations of the neural matrix of core reward structures are reminiscent of the dendritic arborization changes observed in experimental animal studies...

In an open label, uncontrolled study of CBD in children with refractory epilepsy, adverse events were reported in 128 of 162 (79%) of the enrolled subjects.   The most common adverse effects were somnolence (25%), decreased appetite (19%), diarrhea (19%), fatigue (13%), and convulsions (11%). Serious adverse events, including one death, occurred in 30% of patients, and in 12%, the adverse effects were directly attributed to CBD. The most common serious adverse effect was status epilepticus (6%). Mechanistically, some adverse effects such as somnolence and fatigue may have been caused by CBD-induced increases in serum clobazam levels.