This is not a popular topic amongst pro-cannabis circles... But, I'm going to make the argument that it should be.

If you're committed to education about the positive non-harmful sides of cannabis, you should also be equally educated about the potential risks.

Due to the politicization of cannabis, it's tempting to "take a side" and ignore the evidence contrary to your position. But, understanding complexity is essential to seeing the whole picture.

Scientifically, there’s a well established link between high potency cannabis use and psychosis. As someone who is personally pro drug legalization and pro-cognitive liberty (you should be able to alter your mind however you choose if it's not harming others) I think understanding this is an essential part of the equation for safe and effective cannabis use.

First off, the science is fairly clear there's a link. A 2019 review of 26 other previously published meta-analyses and systematic review articles concluded:

"The scientific literature indicates that psychotic illness arises more frequently in cannabis users compared to non-users, cannabis use is associated with a dose-dependent risk of developing psychotic illness, and cannabis users have an earlier onset of psychotic illness compared to non-users."

It's not an isolated study or two, it's a review of reviews. This is not to say cannabis is fully causative, but it is strongly correlated.

But, the real question is, how much is this a risk? And for whom?

Well, let's look at two big factors, genetics and frequency of use. First, several studies of first-episode psychosis show genetics play a role.

Genetics: AKT1 and DRD2

First, in 2015 Scientists studied 220 people admitted for a first episode of psychosis and 228 healthy controls. People with the “risk” variants in DRD2 and AKT who smoked cannabis had a higher risk of psychosis. Link to the study here.

DRD2 codes for a dopamine receptor, and AKT1 is involved in the dopamine signaling cascade in the striatum, a part of the brain known to be altered in schizophrenia. Cannabis related psychosis is thought to be related to abnormal dopamine transmission, along with imbalances in GABA and glutamate.

Here's a graph of results from showing the correlation between those who use cannabis and multiple "risk" alleles' impact on psychosis.

Those that smoked daily had an even higher risk at roughly 7 times the average.

But, on the flip side, in the graph above, notice how those those with the “risk” variants but didn’t use THC were at lower risk for psychosis than than average. 

What this really means is that people with certain genes are more sensitive... More sensitive to becoming imbalanced from THC. 

And, this is a good example of what our genetic variants really do. There's no such things as good or bad genes, only ones that are more adapted to different environmental inputs.

Genetics: FAAH

In another study of first episode psychosis, a variant in the FAAH gene studied in 321 patients. Scientists associated it with a 10-fold risk of developing psychosis with cannabis use. You can read the abstract here.

They also found no significant difference in psychosis risk for people who did not use cannabis and had that same variant.

These are descriptions of gene x environment interactions. It's not the genes on their own that might create risk, and it's not necessarily cannabis on it's own either. It's the combination (along with other risk factors like positive family history of psychotic disorders, stress, environmental exposures, etc) that really matters.

Frequency of Use: Another Vulnerability Factor

So, just to be clear... this is NOT saying that if you use cannabis every day you're going to develop a psychotic disorder. But, for people that are already vulnerable, the difference between occasional THC use and daily THC use is dramatic.

Check out the results graph from the AKT1 x DRD2 study below, this time stratified by frequency of use. The risk factor is roughly the same for weekly use or less between one or multiple risk alleles, but daily use skyrockets the risk for those with multiple genetic risk factors.

Another 2019 study by Di Forti, et al found that daily frequency of high potency cannabis use was the most significant risk factor for 901 first episode psychosis patients studied in multiple sites around Europe.

They didn't look at genetic variables in this study, but one can infer that the patients studied had some type of genetic vulnerability.

As you can see below, daily use of greater than 10% THC products was associated with a much higher odds ratio of first episode psychosis as compared to those who never used or didn't use THC containing cannabis regularly.

Additionally, the study examined the background rates of psychosis for these individual cities and tracked the relationship between increases in new psychosis cases and availability of high potency cannabis.

In cities where there was predominantly less than 10% THC cannabis available like Spain, Italy and France, there was minimal increase in new cases. But in London, Paris, and Amsterdam, where higher potency cannabis is most readily available, they found the highest rates of new diagnoses of psychosis.

Back to Genetics: A polygenic approach

So, what happens if you have risk variants in both DRD2 and AKT along with the FAAH variant? It's likely that the risk goes up further. Other smaller effects have been found related to genes such as ABCB1 and ZNF804A.

This is the approach I'm teaching in the upcoming CannaDNA training.

And, this is why looking at genetics with someone who can see the connections between multiple genes can be so useful, especially for those just dipping their toes into the water of the cannabis world. For most people, the risks are pretty low, but why not assess this further?

So, as advocates for safe cannabis use, would you agree we should be talking about this? Those with a family history of psychotic disorders should be especially careful. Anyone concerned should consider learning more about these genetic factors. 

Of course, genetics are not the only factor. Stress, adversity, other substance abuse and other factors can influence psychosis risk too. But, knowing your genes may be a piece of the puzzle to help prevent mental health issues.

The Big Picture

Response to cannabinoids has many components. I like to think of it as a combination of:

• Set (Mindset, psychology)
• Setting (Where and when are you using it)
• Genetics (Your baseline tendencies)
• Epigenetics (Your current health status)
• Strain (Combination of cannabinoids and terpenes)
• Method of Ingestion (vaped vs oral vs smoked)
• Dose
• Quality of Product

Some of these factors you may have more control over than others. You can't control your genetics but you can match the right inputs to your genetics.

This means potentially choosing a different food, herb, supplement, or lifestyle choice to create better epigenetic expression.

Having a better understanding of ALL the components listed above can help you optimize you or your client's health in a more strategic, precise way.

If you're curious about analyzing your endocannabinoid genes, send me a message. I helped develop the Apeiron Endocannabinoid Genetic Panel that can give you a better understanding of the dynamics of how you respond to THC, CBD, and naturally create your own endocannabinoids. I look at this and 50+ other variants for a comprehensive look into how to best use cannabinoids.

Or if you're a practitioner and are interested in providing your clients with better answers about cannabinoids, you can learn more about a comprehensive training on precision genetic analysis I've put together with Dan Stickler, MD by clicking here.