Cannabis and your genes: effects, dependency, and risks

Cannabis is now legal for medicinal use or recreational use in many U.S. states and in Canada. Many people are using cannabis (marijuana) for a variety of reasons – from enjoyment to pain management to the side effects of chemotherapy.

This article digs into the science of how cannabis affects your body and how your genes influence your reaction to cannabis. 

Endocannabinoid System

Your body has an endocannabinoid system which involves your own naturally produced molecules that bind to the same receptors as the psychoactive component in cannabis. It’s pretty cool stuff!

Cannabinoid Receptors:

The two cannabinoid receptor genes in the body were first sequenced in the early 1990s. The receptors, called CB1 and CB2, have different roles in the body.

Structure of a typical neuron. Image from Wikipedia.com

CB1 Receptor:
The CB1 receptor is a G protein-coupled receptor that is mainly expressed in the central nervous system.

It is a receptor that is found on the axons and terminals of neurons and glial cells in the brain, with high levels in the amygdala, prefrontal cortex, and hippocampus.[study] [study]  CB1 receptors are also found on the spinal cord, as well as in other cells such as pituitary, thyroid, liver, intestinal, and fat cells.

It is thought that one role of the CB1 receptors in neurons is to “modulate neurotransmitter release in a manner that maintains homeostasis in health and disease by preventing the development of excessive neuronal activity in the central nervous system”.[study]

Basically, the release of endocannabinoids, which bind to the CB1 receptors, keeps the excitatory and the inhibitory neurotransmitters in check.[study]

The CB1 receptor is also involved in processes that regulate food intake and is often studied for its role in obesity.[study]  (Yes, there is a reason why marijuana gives people the munchies…)

CB2 Receptor:
The CB2 receptor is found mainly in immune cells as well as in some neurons. CB2 receptors have been studied in a variety of pathologic conditions including:

  • neuropathy
  • neurodegenerative diseases
  • osteoporosis
  • autoimmune diseases
  • atherosclerosis
  • cancer [study]

CB2 receptors are found in the T- and B-lymphocytes of the immune system, the central nervous system, the peripheral nervous system, and in the gastrointestinal tract.[study]  Activation of the CB2 receptors moderates the release of cytokines from immune cells.

Endocannabinoids:

Our body produces several different endogenous cannabinoids that are derived from fatty acids that bind to the CB1 and CB2 receptors. The fatty acids that are used by the body when synthesizing the endocannabinoids include arachidonic acid, palmitic acid, and oleic acid.

  • Arachidonic acid-derived endocannabinoids include anandamide (AEA), 2-AG, and others.
  • The palmitic acid-derived endocannabinoid is palmitoylethanolamide (PEA).
  • The oleic acid-derived EC is oleoylethanolamide (OEA).

Anandamide (AEA) is made in the body from arachidonic acid, and it is degraded by the fatty acid amide hydrolase (FAAH) enzyme.

Anandamide binds to both the CB1 and CB2 receptors and plays a role in reward, pleasure, and pain relief as well as feeding behavior. It is the ‘bliss’ molecule.

When there is less of the FAAH enzyme around, anandamide is degraded more slowly. This leads to more of the bliss molecule.

Quick Recap:
The body has an endocannabinoid system involved with neurotransmitters, immune function, and food intake.
Two receptors: CB1 and CB2
Our body produces endocannabinoids to bind to receptors.

Active components of cannabis:

THC, Δ9-tetrahydrocannabinol, activates both CB1 and CB2 receptors and is the psychoactive component that makes a person feel high.  It has been shown to be a partial agonist to the CB1 receptor.  It is thought that it may increase dopamine and acetylcholine in the brain.  [study]

Cannabidiol (CBD oil) is still being studied to determine its mechanism of action. While it does not bind to the CB1 or CB2 receptors, it does seem to influence other substances being able to bind to the receptors.[study]

All of the effects of cannabis, both good and bad, point to or exaggerate the endogenous reasons for the endocannabinoids.  For example:

  • endocannabinoids play a role in obesity (cannabis gives you the munchies)
  • anandamide makes you happy and takes away pain (cannabis can do the same)
  • having fewer CB1 receptors can lead to depression and anxiety (cannabis takes away anxiety. )

Side effects of cannabis:

While there seems to be a lot of information available touting the promising medicinal effects of cannabis, such as reduction in nausea for cancer patients, there are some serious considerations in recreational use.

Psychotic states:

  • A recent study states that psychotic-like states “have been documented in numerous case-reports and estimated to occur at least once in about 20-50% of individuals who use cannabis”.  The study (in mice) goes on to show that pregnenolone can block the psychotic-like symptoms.  [study]  Other studies have also shown that pregnenolone protects the brain “from CB1 receptor over-activation”. [study]
  • The ties between schizophrenia and frequent cannabis use are well studied.  Population-wide, frequent cannabis use doubles the risk for schizophrenia.[study]
  • Studies, though, often give conflicting results for schizophrenia as far as risks associated with genetic variants in the CB1 receptor.

Other possible side effects:

  • Extensive use of cannabis can cause cannabinoid hyperemesis, which is cyclical vomiting, nausea, and abdominal pain after prolonged cannabis use.
  • While activation of the CB2 receptors has an anti-inflammatory effect, activation of the CB1 receptors has been tied to serious cardiovascular events including arrhythmia, stroke, and death from heart attacks.  [study]
  • Acute anxiety disorders can be caused by regular cannabis use. [study]

Cannabinoid Receptor Genes:

CNR1 gene (CB1 receptor):

rs806368  – The C allele has been tied in several studies to increased risk of alcohol dependence and substance abuse.  [study] [study] [study]  It has also been associated with obesity in some populations. [study] [study]  Additionally, the C allele has been tied to an increased risk of cannabis dependence. [study]  More susceptible to stress-induced migraines with nausea [study]

Check your genetic data for rs806368 (23andMe v.4 and v.5; AncestryDNA):

  • C/C: higher risk of cannabis dependence, substance abuse, obesity
  • C/T: somewhat higher risk of cannabis dependence, substance abuse
  • T/T: common/normal

Check your genetic data for rs806380 (23andMe  v.4 only):

  • A/A: decreased risk of cannabis dependence[study] [study]
  • A/G: somewhat decreased risk of cannabis dependence
  • G/G: common/normal, but increased risk of cyclic vomiting disorder[study]

Check your genetic data for rs1049353 (23andMev.4 and v.5; AncestryDNA):

  • T/T: decreased risk of cannabis dependence, increased risk of eating disorders [study]
  • C/T: somewhat decreased risk of cannabis dependence
  • C/C: common/normal risk of cannabis dependence

Check your genetic data for rs1406977 (23andMe v.4 only; AncestryDNA):

  • C/C: reduced cannabis receptor (CB1) levels, reduced working memory[study]
  • C/T reduced CB1 receptors, reduced working memory
  • T/T: common/normal

CNR2 gene (CB2 receptor):

The CB2 receptors are prevalent in the immune system.

CNR2 Q63R (rs2501432) [study]  The T allele increases CB2 receptor response. [study]  Those with a T allele were half as likely to develop severe complications from RSV. [study]  Those with the T allele were at a lower risk for schizophrenia.[study]

Check your genetic data for rs2501432 (23andMe v.4 ; AncestryDNA):

  • T/T: increased CB2 receptor response, decreased risk for schizophrenia
  • C/T: increased CB2 receptor response, decreased risk for schizophrenia
  • C/C:  normal

FAAH (fatty acid amide hydrolase) gene:

FAAH breaks down the endocannabinoid anandamide, thus stopping the action of this ‘bliss molecule’.[study]  Currently, inhibitors of FAAH are being developed and studied for their role in treating pain and inflammation.[study]

Check your genetic data for rs324420 (23andMe v.4 and v.5; AncestryDNA):

  • A/A: increased anandamide (decreased anxiety), increased risk of substance abuse[study][study][study]
  • A/C: increased risk of CUD
  • C/C: common/ normal

Check your genetic data for rs4141964 (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk for cannabis use disorder, decreased FAAH activity (increased anandamide) [ref]
  • C/T: increased risk for cannabis use disorder, decreased FAAH activity (increased anandamide)
  • C/C: normal


ABCB1 (multidrug resistance gene):

The ABCB1 gene is involved in transporting toxins (including drugs) out of the cell. The rs1045642 variant changes how fast certain drugs are expelled out of a cell. The G allele expels drugs faster while the A allele causes a drug to stay in a cell longer.

In a study done on heavy cannabis users, those with A allele for rs1045642 had lower plasma levels of cannabis [study] Another study showed that those with the G/G genotype were at a significantly greater risk for cannabis dependence [study]

Check your genetic data for rs1045642 (23andMe v.4 only)

  • A/A: lower serum THC levels, probably stays in cells longer[study]
  • A/G: lower serum THC levels, probably stays in cells longer
  • G/G: increased risk for cannabis dependence.[study]

TCN2 (B12 transport gene):
While this gene doesn’t have much to do with cannabis, per se, there is an interesting study tying maternal B12 levels during pregnancy with adolescent substance abuse, including cannabis use. The study found that estimated higher B12 (meat consumption) by mom while pregnant correlated with a lower risk of substance abuse in teenage offspring. This was stratified by mom’s TCN2 genetic variant, rs1801198. [study]  The G allele is linked to lower plasma B12 levels.  [study]


Lifehacks:

Cacao:  Chocolate contains a substance that inhibits FAAH, thus increasing our natural endocannabinoid anandamide.[study]  From powdered cacao as a new party drug to getting a little happy eating cacao nibs, some people may increase their anandamide levels from the cacao bean.

Sleep:  Circadian rhythms modulate the endocannabinoids, so good sleep on a regular schedule as well as blocking blue light in the evening may impact our natural production of endocannabinoids.  The lowest levels of 2-AG naturally occur in the middle of the night, increase in the morning and peak in the early afternoon.[study]

Substance Abuse: If you or someone you know is struggling with substance abuse, please seek help.  Visit http://drughelpline.org/.

 

6 Comments on “Cannabis and your genes: effects, dependency, and risks

  1. Has there been any new info on the taking of Cannabidiol oil and hives?

    Marilyn P

  2. Marilyn – If you got hives after consuming CBD oil products, you could be allergic to cannabis in general, allergic to the carrier oil or something used in the extraction process, or the CBD oil could be contaminated with something else that’s causing the hives. I would try a different brand and see if it happens again to try to figure out if it’s a contaminant issue or all cannabis for you. I am mildly allergic to cannabis (at least the pollen), but tolerate CBD just fine, which makes me think it could be a contamination issue bothering you…either with pollen or some chemical they used to extract. Good luck to you.

  3. Interesting.
    Interesting. My 23andme report shows rs1045642 as A/G, not T and CC as above mentioned. ???
    I have tried CBD oils(dif. brands and concentrations) for fragmented sleep, anxiety etc. It makes me feel worse: brain-fogged, tired, nauseated. It had not effect on my sleep and anxiety. It elevated my liver enzymes as well. Other than rs806368 C/C , rs2501432 T/T and rs1045642 A/G all other above mentioned genes are normal. I am still confused if I should continue trying CBD oil(s).

    • Hi Sam –
      First – Thanks for letting me know about your confusion on the rs1045642 being A/G and not T and C. I need to clarify that in the blog post.
      Basically, 23andMe always lists the genotype in the plus orientation. The studies on that specific rs id are listing the alleles in the minus orientation. To switch between the two orientations, A=T and G=C. I’ll update the article so that everything is in the plus orientation to match 23andme.
      The question on CBD oil is harder to answer. The cannabinoid receptors are being studied in reference to binding to the THC in cannabis, I think. From what I’ve found in the literature, the terpenes and other constituents of the CBD oil are probably acting on different receptors in the body.
      I need to dig back into the topic and see if there is any new research out on CBD oil. From talking with people, there is a huge difference in the effect of CBD oil, even with the same brands. It seems like there has to be a genetic variant that influences this. For me, I have absolutely no response to CBD oil that I can tell (didn’t test liver enzymes, though). But I know of people for whom it is a total game changer.
      Have you read my other articles on sleep and circadian rhythm? Maybe they will give you some other avenues to try.
      Debbie

  4. I take 550mg CBD oil sublingually at least twice daily as it stops my anaphylactic reactions (any scented product and many pollens). I have recently had elevated liver enzymes so will be bringing this possibility to my doctor’s attention. Thanks, Sam, for mentioning that!

  5. Debbie, thank you for this article. I just started using a hemp oil with CBD and in 3 days my shoulder pain is reduced 80%! Keep up the excellent work.

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