How genetic differences can radically change your cognitive response to THC.

While it's generally agreed that THC-rich cannabis causes some degree of short term memory impairment while you're stoned, the degree to which memory loss occurs, and persists after use, has been debated extensively.

You might know someone who's a daily stoner and functions pretty well. I mean, guys like Snoop Dogg have built an empire while high pretty much the whole time.

But, on the other hand, there's also plenty of people that use cannabis that experience motivation issues and lack of cognitive clarity.

Why It Matters

I'm personally 100% in the pro-cognitive liberty camp and believe that everyone should have the right to put whatever substance they want in their body and alter their consciousness how they choose. But, I'm also a realist when it comes to the potential impacts, both positive and negative of any substance or activity (that ranges from cannabis to processed foods to marathon running to kale to ice baths to LSD to looking at computer screens).

See, while there are very clearly certain things that are harmful to human health and just shouldn't be ingested, most food and drugs are useful to some people in certain situations and harmful to others in other situations. One often overlooked variable is genetic differences that can really cause things to swing in either direction.

Personally, I think that understanding the highly individualized response to substances like THC can help diffuse the obnoxious politicization of them and dismantle blanket statements that don't really reflect reality.

Cannabis is not a miracle drug for everyone nor is it a terrible scourge upon this earth.

And while both those statements will probably trigger people on either end of the spectrum, the complex and not-so-sexy answer lies somewhere in between.

So, if you're passionate about cannabis in any way, becoming genetically literate is pretty helpful in developing a less biased, more objective understanding of its impact on humans.

COMT

Catechol-o-Methyltransferase (COMT) is an important catabolic enzyme that breaks down catechol neurotransmitters (or catecholamines). Catecholamines include dopamine, epinephrine, and norepinephrine and are derived mostly from the amino acids tyrosine and phenylalanine.

Dopamine levels can be loosely characterized by being either tonic or phasic. Tonic means general baseline levels and phasic means how the levels spike during a pleasurable or rewarding event. Keep this in mind as we start looking at the different COMT variants.

Dopamine is converted into Norepinephrine by an enzyme called dopamine-beta hydroxylase (DBH), which is then converted into epinephrine. You totally don't have to know this to understand the impact of COMT on short term memory and cannabis, but it's pretty interesting to understand the chain of events that leads from one neurotransmitter to another. All three of those neurotransmitters are broken down by the COMT enzyme.

The COMT Val158Met Allele

The COMT gene contains the instructions for building the COMT enzyme. And, within that gene there are common naturally occurring differences that are known to change the function and overall amount of the COMT enzyme. These are known as SNPs or single nucleotide polymorphisms.

You can read more in depth about what a SNP is here, but mostly just think of them as slight differences in the recipe that makes you, well, you. They're basically single letter differences from one person's DNA code that occur in the same place in the genome. Most of them are pretty low impact, and it's the combination of lots and lots of them together that really counts (along with epigenetic modifications, but that's a story for another day).

But, some like the COMT Val158Met variant, are high impact on their own. The identifier number for this SNP is rs4680. You can look it up with that number if you have 23andMe or have your genetics done through Apeiron or another provider.

So, there are two more extreme versions of the COMT Val/Met allele and one that's kind of in the middle.

The Val/Val (GG) Allele

The Val/Val variant, which means that there are two valine amino acids in the 158 position in the COMT gene (also called the GG variant), codes for a more functional version of the COMT enzyme that tends to be produced in higher amounts.

This means that people with Val/Val or GG variant tend to have lower overall tonic dopamine and other catechol levels in the brain. This is because more COMT breaks down more dopamine.

However, it's believed that val/val carriers experience higher phasic spikes of dopamine as compared to met/met carriers.

So, they tend to have lower baseline levels, but experience more of a significant increase during pleasurable stimuli.

The Met/Met (AA) Allele

On the flip side of things, people with the Met/Met allele (two methionine amino acids in the 158 position) or AA variant carry a less effective, less abundant, COMT enzyme.

Can you guess what that means in terms of catecholamines?

It means Met/Met or AA carriers tend to have higher tonic or baseline brain levels of dopamine, and subsequently higher norepenephrine and epinephrine.

But, since they are starting out with higher general levels of dopamine, it's thought that they tend to experience less of a drastic difference between tonic levels and phasic spikes.

The Val/Met (GA) Allele

The Val/Met or GA carriers tend to be somewhere in the middle and are associated with relatively average catecholamine levels.

Of course, there are many other factors that influence dopamine and norepinephrine levels, including the DBH gene I mentioned above, but I'll cover that in another article.

So, there are TONS of studies on the implications of the COMT val/met allele - it's an incredibly well studied SNP. Since I'm focusing on its impact on short term memory I'm not going to go further into all the other things it effects, but here's a quick diagram so you can get a picture. Keep in mind that the symptoms of high or low catecholamines listed below can be related to dopamine, epinephrine, norepinephrine, or all three. And, keep in mind this is somewhat of an oversimplification - it's not all about the COMT SNP, but it's important.

COMT's Impact On Short Term Memory And Cannabis

OK, so how does all this play into cannabis?

Well, it's pretty well known that THC both influences the release of dopamine (and over time tends to blunt the reward effects of dopamine) and generally tends to make you forget where you put your keys and wallet. Although new evidence shows it's not so simple - with THC actually showing an ability to improve memory in older animals in an Alzheimers model. This is attributed to what's known as the biphasic response curve to cannabinoids, where both too much or too little can cause issues. You can think of it as goldilocks kind of thing... but I digress...

It's also pretty well known that dopamine influences short term memory and attention. So, scientists decided to look at the COMT gene, which they know influences dopamine, and tested whether it impacts the short term memory impact of cannabis.

What the Data Says

In 2015, Elizabeth Tunbridge and colleagues gave 78 participants intravenous THC, grouped them by their COMT variant, and measured their short term memory using an assessment called the "Digit Span Backwards Test", which consists of remembering increasingly large sequences of numbers and recalling them in reverse order. Not something that seems easy while you're not high, right?

There were several previous studies that suggested that COMT may moderate the impacts of cannabis on short term memory and cognition, but this was by far the most consistent and conclusive evidence yet. So what did they find?

Val/Val (GG) carriers that had lower levels of dopamine and other catechols scored on average 40% lower than baseline, while Met carriers (either Val/Met {AG} or Met/Met {AA}) scored only 11% lower on average but did not technically reach statistical significance.

Below are some graphs from the study:

Those are pretty big differences depending on genotype.

This study also looked at COMT's impact on psychotic-type symptoms with THC and didn't find any correlation, contradicting other studies that previously found small correlations. It is currently believed that COMT does not moderate psychotic liability of cannabis, however, there are several other strong genes that do have positive correlations with psychosis/schizophrenia and cannabis. I'll talk about that in another article.

While this study lumped both the AA and AG allele carriers into one group, other studies looking at different factors such as moderation of brain size in different regions in combination with chronic cannabis use seems to point toward the AA genotype as the most protective overall.

A limitation of the study mentioned is that it only looked at pure THC, not combinations with whole plant cannabis; however, based on other subsequent studies that have examined the impact of lifetime cannabis use and COMT genotypes seem to indicate that the GG variant is still more at risk for impaired cognitive function regardless of type of THC consumed.

Other factors that impact Cannabis and Cognitive Function:
The Polygenic Perspective

Like most SNPs, the COMT Val158Met allele is certainly not the only thing that impacts short term memory. Variations have been found in the CNR1 gene and PTGS2 that also impact short term memory.

And, of course, short term memory isn't the only type of cognitive function affected by cannabis. Psychomotor control, impulsivity and decision making, and attention span are some of the other domains identified in which different genetic factors influence the effect of cannabis.

A polygenic approach is one in which the impacts of multiple genes are considered together.

For example, you could have the protective variants in all those genes (which I've seen in a few clients) or you could have all of the risk-predisposing genes (which I've also seen). Most people fall somewhere in the middle, but what's important to know is that you can't be reductionistic with this stuff. COMT plays a role, but it's just one of many factors, both genetic and epigenetic - I can't stress that enough.

Beyond that, some people are fast or slow metabolizers of THC depending on variants in the CYP2C9 gene, or to a lesser degree the CYP2C19 gene. This makes certain people much more sensitive to THC because it doesn't get broken down as quickly, and so more builds up in the blood stream. If you have a COMT GG variant and are a slow THC metabolizer, it might be that much more impactful. You can read more about genetic variations on THC metabolism here.

Below is a rough sketch I made of some of the other genes and their impact on cannabis' effect on cognitive function. I'm coming out with a course designed for practitioners that goes MUCH deeper into all of this, so if you find this fascinating, sign up for updates and early access here.

Conclusion

Cannabis and short term memory is a complex dance, strongly influenced by genetics. COMT seems to be the most impactful gene we know about. Those with the val/val or GG variants are predisposed to significantly worse short term memory function after cannabis use.

So, next time someone tells you that THC causes cognitive impairments, you'll have some data to explain the complexity.

Interested in getting your genes sequenced with a privacy secure test so you can better understand your relationship to cannabis? I've developed a 50+ SNP test in collaboration with Apeiron Genomics that can give you information on a variety of different factors, along with testing for actionable insights on optimal nutrition, supplementation and more for your body. Contact me here to learn more.