Response to Cannabis (CNR1 gene)

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. It covers the specific 23andMe or AncestryDNA CB1 and CB2 receptor variants linked to cannabis abuse disorder as well as the genes involved in a person’s response to cannabis.

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Your Endocannabinoid System

Before we get into cannabis, let’s look at the body’s built-in system for cannabinoids.

Your body has an endocannabinoid system that involves your own naturally produced molecules that bind to the same receptors as the psychoactive component in cannabis.

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 mainly expressed in the central nervous system.

The receptor 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.[ref][ref] CB1 receptors are also found on the spinal cord, as well as in other cells such as pituitary, thyroid, liver, intestinal, and fat cells.

Possibly, one role of the CB1 receptors in neurons could “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”.[ref]

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

The CB1 receptor is also involved in processes that regulate food intake and is often studied for its role in obesity.[ref] (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[ref]

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

Endocannabinoids:

Our body produces several different endogenous cannabinoids derived from fatty acids and binds to the CB1 and CB2 receptors. The fatty acids 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 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 less of the FAAH enzyme is 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.[ref]

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.[ref]

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 the 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 a reduction in nausea for cancer patients, there are some serious considerations in recreational use.

Psychotic states:

  • A recent study describes 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, a steroid hormone, can block the psychotic-like symptoms.[ref] Other studies have also shown that pregnenolone protects the brain “from CB1 receptor over-activation”.[ref]
  • The ties between schizophrenia and frequent cannabis use are well studied.  Population-wide, frequent cannabis use doubles the risk of schizophrenia.[ref]
  • 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 ties to serious cardiovascular events including arrhythmia, stroke, and death from heart attacks.[ref]
  • Acute anxiety disorders can be caused by regular cannabis use.[ref]

Cannabinoid Receptor Genotype Report

Your genetic variants influence your susceptibility to substance abuse, and variants also impact how your body reacts to cannabis.

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CNR1 gene (CB1 receptor) genetic variants:

Genetic variants in the CNR1 gene affect the body’s response to cannabis, including whether are, not you are likely to become dependent on cannabis. Additionally, the CB1 receptor is important in the way the brain regulates appetite; thus, a variant in CNR1 can affect someone’s susceptibility to obesity.

Check your genetic data for rs806368 (23andMe v4, v5; AncestryDNA):

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

Members: Your genotype for rs806368 is .

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

Check your genetic data for rs806380 (23andMe v4):

  • A/A: decreased risk of cannabis dependence[ref][ref]
  • A/G: somewhat decreased risk of cannabis dependence
  • G/G: typical, but increased risk of cyclic vomiting disorder[ref]

Members: Your genotype for rs806380 is .

Check your genetic data for rs1049353 (23andMe v4, v5; AncestryDNA):

  • T/T: decreased risk of cannabis dependence, increased risk of eating disorders[ref]
  • C/T: somewhat decreased risk of cannabis dependence
  • C/C: typical risk of cannabis dependence

Members: Your genotype for rs1049353 is .

Check your genetic data for rs1406977 (23andMe v4; AncestryDNA):

  • C/C: reduced cannabis receptor (CB1) levels, reduced working memory[ref]
  • C/T reduced CB1 receptors, reduced working memory
  • T/T: typical

Members: Your genotype for rs1406977 is .

CNR2 gene (CB2 receptor) genetic variants:

The CB2 receptors are prevalent in the immune system.

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

Check your genetic data for rs2501432 (23andMe v4 ; AncestryDNA):

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

Members: Your genotype for rs2501432 is .

FAAH (fatty acid amide hydrolase) genetic variants:

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

Check your genetic data for rs324420 (23andMe v4, v5; AncestryDNA):

  • A/A: increased anandamide (decreased anxiety), increased risk of substance abuse[ref][ref][ref]
  • A/C: increased risk of CUD
  • C/C: typical

Members: Your genotype for rs324420 is .

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: typical

Members: Your genotype for rs4141964 is .

ABCB1 (multidrug resistance gene):

The ABCB1 gene involves transporting toxins (including drugs) out of the cell. The rs1045642 variant changes how fast certain drugs expel 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 an A allele for rs1045642 had lower plasma levels of cannabis.[ref] Another study showed that those with the G/G genotype were at a significantly greater risk for cannabis dependence.[ref]

Check your genetic data for rs1045642 (23andMe v4)

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

Members: Your genotype for rs1045642 is .

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 to the risk of of their chilren having substance abuse issues as an adolescent (including cannabis use). The study found that an estimated higher B12 (meat consumption) by a mom while pregnant correlated with a lower risk of substance abuse in teenage offspring. This was stratified by mom’s TCN2 genetic variant, rs1801198.[ref] The G allele is linked to lower plasma B12 levels.[ref]


Lifehacks:

 

Substance Abuse: If you or someone you know is struggling with substance use disorders, please seek help. Visit http://drughelpline.org/, talk to your doctor, talk with family or trusted friends.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.