Our Body’s Response to Cannabis (CNR1 gene): A Look into Dependency Risk

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.

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.


Our body produces several different endogenous cannabinoids derived from fatty acids and bind 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 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 Genes:

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

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