Genetics Modify Response to Cannabis: A Look at the COMT Gene

Last week we talked about the need for genetic testing of both the cannabis plant itself and of patients. Speaking in broad terms, we noted that slight alterations in human DNA can lead to noticeable differences in reactions to cannabis. This is something medical cannabis patients can attest to when comparing strains with other medical users. A strain that makes one person feel tired may have little impact on the energy level of another.

Today we can introduce one specific mechanism that seems to influence genetic variation in response to cannabis. Interestingly enough, researchers at Warneford Hospital in the UK actually approached this discovery while searching for causes of psychosis (when thought and emotions are so impaired, patients suffer a disconnect from reality). One of the most debated questions in the scientific community is whether cannabis contributes to the development of psychosis. Believers cite that while many people consume cannabis with no lingering health issue, some develop psychotic symptoms immediately after first exposure. Critics do not necessarily disagree with this observation but believe that many different substances and environmental factors can trigger psychotic illness. Regardless, the data would suggest that if only some patients develop symptoms, the cause might be genetic.

What gene is causing this? Researchers have identified catechol-o-methyltransferase (COMT) as a gene that regulates dopamine in the cortex of the brain. Studies show that cognitive function is improved in animals “with reduced COMT activity”. This pattern implies that the gene is some sort of limiter, perhaps designed to prevent the brain from expending mental resources too quickly. Supporting this, one polymorphism (COMT Met), or one particular gene configuration shared by a significant portion of the population, has limited COMT activity and increased levels of cortical function. This polymorphism is therefore thought to also be a “protective factor against the negative impact of cannabis/THC” (here, negative means reducing activity). To evaluate whether this polymorphism actually has a measurable impact, researchers set out to observe differences in impact of the administration of THC in individuals with and without the polymorphism.

Cleverly, researchers were able to conduct this experiment by examining old data. In particular, researchers used a study testing the psychotic impact of administering THC. By using additional data on the genetic makeup of participants, researchers were then able to split the group into individuals with and individuals without the Met polymorphism. Afterwards, researchers compared the performances of both groups. The research team hypothesized that those with the polymorphism would fare better in cognitive tasks.

In the initial experiment, patients were sorted randomly into placebo or THC administration groups, with the THC administration group receiving 1 mL of THC solution intravenously every minute for 10 minutes (for a total of 10 mL solution or 1.5 mg THC) and the other receiving saline solution. Criticisms of this setup would be the almost borderline ineffective dose of total THC and the ability of patients to easily tell the difference between THC and saline solution by the obvious mental effect. Regardless, ten minutes after administration, patients completed a battery of tests. The two tests most relevant to this study were the CAPE, an “index of psychotic experiences that has previously shown sensitivity to COMT*THC”, as well as the Digit Span Backwards test, a test that establishes working memory by having patients recall strings of numbers in reverse order of presentation.

Results showed that patients given THC had impaired working memory. Additionally, while genotype on its own had no impact on the general level of performance, the interaction between genotype and THC/no THC did, indicating that this polymorphism’s impact may only be observed in the presence of THC. As expected, this data implies that some individuals are more susceptible than others to the negative effects of cannabis on working memory.

Strangely enough, researchers observed no differences on the CAPE test, not even with the interaction between genotype and THC/no THC. While it is entirely possible that the dose of THC given was too small (as previously noted), this would seem to indicate that the Met polymorphism does not have an impact on psychotic episode development.

Although these first results are very basic, this type of study is paving the way for cannabis strains perfectly grown for patients’ needs. In this case, patients lacking the Met polymorphism might benefit from strains with less THC and more CBD. However, as we’ve seen in previous studies, genetic findings are very complicated and subject to change when viewed in new contexts. Perhaps in the context of another enzyme, this polymorphism has no impact at all. Additionally, COMT is not the only gene of interest, and this type of experiment should be repeated with other potential suspects. Over the next two decades, researchers have the job of fully investigating each gene and each gene variation to map how genes control our reaction to cannabis.

 

Works Cited

Elizabeth Tunbridge, Graham Dunn, Robin M Murray, et al. “Genetic moderation of the effect of cannabis: Catechol-O-methyltransferase (COMT) affects the impact of delta-9-tetrahydrocannabinol (THC) on working memory performance but not on the occurrence of psychotic experiences.” Journal of Psychopharmacology 29 (2015) 11:1146-1151.