Depending on which version of the COMT gene you have, you may be protected from (or susceptible to) the memory-impairing effects of THC.

THC can impair many different types of memory. However, cannabis does not affect everyone the same way, and memory is no exception to this. We now have solid evidence that the extent of memory impairment is determined (at least partially) by your genes. This may explain why one person can remain highly functional while high, but another has trouble remembering what they were just talking about.

Although multiple genes have been linked to the cognitive effects of THC, the COMT gene in particular stands out. This gene regulates the dopamine system, which is very important for cognition. As I will show below, which version of the gene you have can determine your susceptibility to the memory impairments of THC.


COMT and the Val158Met Polymorphism

After dopamine is released from a neuron, it can be removed from the synapse through two mechanisms. The first is that it is pumped back into the cell. This is accomplished by the dopamine transporter (DAT), which is a famous in its own right for being the target of cocaine.

The second mechanism of dopamine removal is for it to be degraded. Catechol-O-methyltransferase (COMT) is the main enzyme responsible for the metabolism of dopamine. The role of COMT is particularly important in brain regions where DAT expression is low such as the prefrontal cortex.

The gene for COMT in humans is called…wait for it…COMT. There are are many genetic variants of COMT, but one polymorphism in particular is the most important. In fact, this is one of the most studied polymorphisms in your entire genome.

This is called the Val158Met polymorphism. It is a single nucleotide change that results in the 158th amino acid of the enzyme being changed from a valine to a methionine. Why is this so important? The Val version metabolizes dopamine up to 4 times faster than the Met version. That means that people with the Met version will maintain higher levels of dopamine in their synapse.

This polymorphism has been linked to many personality traits as well as diseases: neuroticism, schizophrenia, anxiety, response to stress, pain, drug dependence, and more. There are too many studies to list – just check this SNPedia article out.

Similar effects were seen in mice when the COMT gene was knocked out or overexpressed. From the National Institute of Mental Health:

Like a seesaw, each of two common versions of the COMT gene was associated with tradeoffs in the way the brain works. Mice in which the val version was knocked out (KO) showed traits associated with the met version — excelling at memory and attention tasks, but at a cost of being more susceptible to stress and pain. Transgenic (tg) mice in which the val version was over-expressed showed an opposite set of attributes.

Regulation by the COMT gene [National Institutes of Health]

Want to find out which versions you have? You can find out using 23andMe. I genotyped myself with 23andMe and I have to say that my result for this polymorphism was by far the one that I spent the most time thinking about.

Below are the key studies showing that the COMT gene may determine whether you are protected from the cognitive impairments of cannabis:


Study #1: COMT Determines Effects of THC on Episodic Memory

This 2006 study was the first to examine the effect of COMT genotype on cognition by administering THC to people in a controlled laboratory setting.

This study examined episodic memory, which is what most people think of as long-term memory – the recollection of personal experiences in your life.

This study used a double-blind crossover design where 74 subjects smoked a 15% THC joint or “placebo joint” (with almost no THC) on different occasions.

Episodic memory was not impaired by THC in the Met/Met carriers, but there was statistically significant impairment from THC in Val/Val carriers.


Study #2: COMT Determines Effects on Working Memory

Similar to the study above, this 2015 study used an interventional approach where THC was administered in a controlled laboratory setting. The difference is that the focus of this study was on working memory. Working memory (what most people think of as short-term memory) allows you to consciously store and manipulate information.

This was a randomized, double-blind, parallel-group study of 78 subjects who were administered either 1.5 mg intravenous THC or placebo.

At baseline (prior to THC or placebo administration), each group of different COMT genotypes had roughly the same working memory ability. However, working memory was significantly worse in Val/Val carriers after THC administration compared to when they received placebo. Importantly, this effect of THC was not observed in people with at least one Met allele (or at least the difference wasn’t statistically significant.)

THC reduces working memory in COMT Val/Val genotype but not in Met carriers

Study #3: A Naturalistic Study of Working Memory in Regular Cannabis Users

2016 study took a different approach to studying cannabis and memory. They used a “naturalistic” study design where 442 healthy young cannabis users were allowed to use their own cannabis.

Working memory was tested after using their own cannabis and after 1 week of abstinence. No effect of COMT genotype was observed while intoxicated, but a trend toward COMT genotype affecting working memory was seen during abstinence.

Although we don’t know why no effect of COMT was seen immediately after smoking, one likely explanation is that these regular cannabis users had developed tolerance to the memory-impairing effects of THC.

There are other explanations as well. There is evidence that different strains may have different effects on memory. Why? CBD may moderate the effect of THC on memory (an article on this is forthcoming). Terpenes may also improve memory. So it is possible that people who are susceptible to memory impairments from THC gravitate to the strains that impair them them the least.


Conclusions on COMT and Memory

Overall, these results indicate that if you carry a COMT Met allele, you are protected from the memory impairing-effects of THC. This seems to occur for multiple types of memory, including episodic and working memory.

Presumably, people with the Met genotype metabolize dopamine in their synapses slower, and this leads to higher dopamine levels and protection from cognitive impairments after cannabis consumption.

Since no effect of the COMT polymorphism was observed in regular cannabis users, it is possible that it has the greatest effect in occasional users who do not have tolerance to the effects of THC.

If you want to know which version of the COMT gene you have, you can use 23andMe to find out. I am about to publish a guide on using 23andMe to determine genotypes important for cannabis users.

[Featured image: Pixabay]

Last modified: September 6, 2017

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