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Schizophrenia, Cannabis, and the AKT1 Gene

We’ve written several articles on the Cornerstone blog about cannabis and schizophrenia. The association between the two is one of the most fascinating puzzles of cannabis science. What we know is that people suffering from schizophrenia are more likely to use cannabis than non-users, and daily cannabis users have a small but doubled risk of developing a psychiatric disorder. Like all psychoactive substances, medical or recreational, cannabis is not for everyone. What makes someone more susceptible to an adverse reaction to cannabis? Or any substance for that matter? What increases someone’s likelihood of being a daily user?

At the turn of the century, the idea that anyone could be predisposed to a particular psychoactive reaction was largely disregarded. In fact, many physicians did not accept alcoholism as a valid illness when it was originally added to the Diagnostic and Statistical Manual of Mental Disorders. However, genetic research has changed so much of our understanding of psychiatric health. Rather than imagining everyone to have the same psychological operating system, we know that genes dictate large differences from person to person. Even within an individual, genes can be activated and deactivated throughout a person’s lifetime due to environmental factors and stress. Readers may be able to identify with having a friend who cannot or does not smoke cannabis due to repeatedly unpleasant experiences. “It just doesn’t sit well with me.” Such people are unknowingly referring to their genetic make up and general neurological condition. Of course, knowing that there is a genetic difference is not the same as understanding the physical way in which that difference occurs, and in the case of cannabis, the specific genetic interaction is unknown.

Fortunately, the gene AKT1 has been recently targeted. Several studies involving genetic testing of patients with schizophrenia, as well as their siblings (so as to have otherwise similar genetic makeup), have shown that AKT1 gene carriers are at a two-fold risk of being “diagnosed with a psychotic disorder” *if* they have used cannabis. Co-researchers working at the University College of London, University of Exeter, and Kings College decided to explore these findings further by examining acute reactions to cannabis in individuals with and without the AKT1 gene polymorphism. To do this, they purposefully selected participants with no family history of schizophrenia, which helped to answer the question of whether these findings hold true in individuals without family histories. If they do hold, then it seems to suggest AKT1 is pivotal in the psychological reaction to cannabis.

In the end, a total sample of 422 cannabis users (308 males, 114 females), aged 16-23 (an age when neurological disorder can develop), participated. Participants were tested twice, once without any alcohol or cannabis within 24 hours beforehand, and once immediately after using their own cannabis. Participants provided 0.3 gram samples of their cannabis to the lab for testing and were instructed to get “stoned” to an average level in regard to their individual pattern of usage. During testing, urine samples confirmed self-reported cannabis use patterns, and participants answered standard questionnaires designed to evaluate degree of schizophrenia, such as the Psychotomimetic States Inventory and the Schizotypal Personality Questionnaire.

Ultimately, years of cannabis use, gender, ethnicity, and cannabis dependence (daily use) seemed to have little impact on observation of acute pscyhotomimetic symptoms, suggesting that these things have little to do with susceptibility to an adverse reaction to cannabis. However, having the AKT1 genotype was indeed a significant predictor of acute psychotomimetic symptoms, with an increased expression of the gene also corresponding to increased observation of symptoms. In other words, even in individuals without family histories of schizophrenia, having this gene polymorphism increases the schizophrenic-type reaction to cannabis directly after usage.

How does this occur? “AKT1 codes for a protein that…has a variety of functions, one of which is as a signaling molecule downstream of the dopamine D2 receptor.” Since dopamine issues are related to the development and pathology of schizophrenia, and cannabis can affect dopamine levels, this seems a likely avenue for AKT1 to influence the brain’s reaction to cannabis. Additionally, regardless of the pathway, THC has been shown to activate AKT1 both in cell cultures and in living mammals. Of course, this may not be the whole story. In many complex neural situations, multiple genes interact or are responsible for response, meaning that AKT1 may not be the only genetic marker at play. Regardless, we know that there is a high probability of this genetic trait being involved in adverse reaction to cannabis.

As medical cannabis continues to help more and more individuals, early detection of patients whom it might cause a problem for also grows in importance. The idea that individuals could be screened for genetic traits that could cause adverse interactions seems promising, and in some cases, could save lives. In the same way that the societal gain from using something as simple as Advil is greater than the collective societal loss from Advil’s adverse interactions, the societal gain of medical cannabis is certainly worth it. Cannabis offers promise for literally hundreds of serious conditions, as well as numerous new research pathways. However, on an individual level, the decision to use or not use a psychoactive medication is a difficult one with real consequences, and all individuals should have access to as much information as possible when making that decision. Research studies such as the one above will help pave the way for an even safer application of medical cannabis and in turn, allow more people the confidence to give it a try.

One less risky and perhaps more helpful alternative is CBD (cannabidiol). Unlike THC, CBD has virtually no bad interactions and is often more helpful, specifically in the area of pain management. Additionally, CBD counteracts some of the more extreme side effects of THC for patients needing a clear head. Patients with a history of schizophrenia or related disease should always consult their primary physician before taking any new substance and should focus that discussion on CBD rather than THC. For more information on CBD, readers may be interested in referring to the posts below:





Works Cited

CJ Morgan, TP Freeman, J Powell, and HV Curran. AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers. Translational Psychiatry (2016) 6:E738. DOI: 10.1038/tp.2015.219.