As cannabis becomes legal for medicinal use or recreational use in more states across the US and Canada, I thought I would dig into exactly how and why cannabis has an effect on the body. And while cannabis may not be something that is legal or interesting for you, our body’s endocannabinoid system does so much more than just let you feel high when smoking weed.
The two cannabinoid receptors in the body were first sequenced in the early 1990’s. The receptors, called CB1 and CB2, have different roles in the body.
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”. Basically, the release of endocannabinoids that bind to the CB1 receptors are thought to keep 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]
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, and 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.
Our body produces several different endogenous cannabinoids that are derived from fatty acids that bind to the CB1 and CB2 receptors. Arachidonic acid-derived endocannabinoids include anandamide (AEA), 2-A/G, and others. The palmitic acid-derived endocannabinoid is palmitoylethanolamide (PEA), and 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 (FA/AH) enzyme. AEA binds to both the CB1 and CB2 receptors and plays a role in reward, pleasure, and pain relief as well as feeding behavior.
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), and a lack of CB1 is tied to depression and anxiety (cannabis makes you mellow).
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.
- 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 in some populations with obesity. [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 23andMe results for rs806368 (v.4 and v.5):
- C/C: higher risk of cannabis dependence, substance abuse, obesity
- C/T: somewhat higher risk of cannabis dependence, substance abuse
- T/T: common/normal
rs806380 – G allele has been found to be protective against the risk of cannabis dependence. [study] [study] There is an increased risk of a (rare) disorder called cyclic vomiting syndrome for those with the G allele. [study]
Check your 23andMe results for rs806380 (v.4 only):
- A/A: decreased risk of cannabis dependence
- A/G: somewhat decreased risk of cannabis dependence
- G/G: common/normal
rs1049353 = T is the minor allele. Part of a group of variants (haplotype) that is linked to fewer cannabis dependence problems. The T allele is also linked to a higher risk of anorexia and bulimia [study]
Check your 23andMe results for rs1049353 (v.4 and v.5):
- T/T: decreased risk of cannabis dependence
- C/T: somewhat decreased risk of cannabis dependence
- C/C: common/normal risk of cannabis dependence
rs1406977 — A 2015 study found that “individuals carrying a G allele had reduced CNR1 prefrontal mRNA levels compared with A/A subjects”. It also found that G allele carriers who were cannabis users had “reduced working memory behavioral accuracy…” [study]
Check your 23andMe results for rs1406977 (v.4 only):
- C/C: reduced cannabis receptor (CB1) levels
- T/T: common/normal
CNR2 gene (CB2 receptor):
The CB2 receptors are prevalent in the immune system.
CNR2 Q63R (rs2501432, T ) [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 23andMe results for rs2501432 (v.4 only):
- T/T: increased CB2, lower risk for schizophrenia
- C/C: common/ normal risk for schizophrenia
FA/AH (fatty acid amide hydrolase) gene:
FA/AH breaks down the endocannabinoid anandamide, thus stopping the action. [study] Currently, inhibitors of FA/AH are being developed and studied for their role in treating pain and inflammation.[study]
rs324420 – The A allele is associated with a higher risk of cannabis use disorder (as defined by DSM-V). The A allele causes decreased FA/AH activity, thus increasing anandamide.[study] While increased anandamide has some positives (such as decreased fear and anxiety [study]), this variant is also associated with significantly increased risk for alcohol and other substance abuse problems. [study]
Check your 23andMe results for rs324420 (v.4 and v.5):
- A/A: increased risk of cannabis use disorder, substance abuse
- A/C: increased risk of CUD
- C/C: common/ normal
ABCB1 (multidrug resistance gene):
The ABCB1 gene is involved in transporting toxins (including drugs) out of the cell. In a study done on heavy cannabis users, those with T allele for rs1045642 had lower plasma levels [study] Another study showed that those with the C/C genotype were at a significantly greater 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 (estimated by meat consumption) during pregnancy with adolescent substance abuse, including cannabis use. Basically, the study found that 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]
Chocolate contains a substance that inhibits FA/AH, 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.
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-A/G naturally occur in the middle of the night, increase in the morning and peak in the early afternoon.[study]
More to read: