Building an understanding of genetics is the key to unlocking the potential of both cannabis medicine and personalized medicine with treatments tailored to the individual. It starts with understanding endocannabinoid genes and how individual differences in your genetic profile can affect your endocannabinoid system and its response to cannabis.
So far, most of the research into the genes encoding the endocannabinoid system has been focussed on marijuana addiction. Though a significant minority of pot smokers may develop a serious habit, marijuana addiction is not public health problem number one in the U.S.
Other genetics-based marijuana research has focussed on why cannabis can trigger psychosis in the population of people predisposed to schizophrenia. Once again, an important avenue of research, but a narrow one. About one percent of the population has schizophrenia, and only a fraction of those have marijuana as a trigger or problem in their lives.
Which is why, now that many states have legalized cannabis, researchers are taking a broader look at the genes that code the endocannabinoid system. Medical scientists are setting up more studies in petri dishes, rodents and humans with an eye toward how people with medical conditions respond to cannabis therapies based on their own genetic predisposition.
We know from some meta-analysis studies (basically, studies drawing conclusions from a group of other studies) that the cannabinoid system genes are crucial to neurological function. One PloS One study from 2017 looked at more than 6,000 patients to try to suss out how their endocannabinoid genes varied and how those variations connected with their health problems.
“Rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders—alone or in combination with anxiety—compared to a set of controls without such CNR1 variants,” the study states. “Similarly, … rare variants in DAGLA, which encodes (an endocannabinoid), were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain.”
Mapping the Genetic Basis of the Endocannabinoid System
Like most cannabis science, mapping the basis for the human endocannabinoid system in DNA is advancing rapidly. Researchers every year discover new genes that code for endocannabinoid system components or that affect its function in some way.
As scientists map out these genes and how they produce variations in cannabis response, the data set grows for other researchers to apply to health problems. One way the U.S. National Center for Biotechnology Information is fostering this — not just for cannabis research, but for the entire human genome — is through the ClinVar database. Genetics researchers all over the world can upload their findings every time they find a new genetic variation of any gene.
For example, the CNR1 gene, which codes for the cannabinoid receptor 1, has 17 recorded variant expressions listed on ClinVar. A dozen are listed for FAAH, the gene coding for the enzyme that breaks down the endocannabinoid neurotransmitter anandamide. Perhaps less than a year ago, there were only 15 and 11 listed, respectively. Other researchers can tap this data to test how these variations interact with other genes to govern the body’s response to cannabis.
And because the human body is such a finely tuned system, changes in any component affect the functioning of every other. AKT1, for example, is a gene that governs the neurotransmitter dopamine. Initially, it seems AKT1 doesn’t have much to do with the endocannabinoid system. Dopamine is a workhorse neurotransmitter chemical that’s ubiquitous throughout the brain and central nervous system and has been studied even before the discovery of the endocannabinoid system.
But certain variations in AKT1 can make people’s brains function differently when consuming marijuana. Researchers behind a double-blind 2014 Psychological Medicine study mapped subjects’ DNA, fed them weed, and made them perform tasks while watching their brains work on a functional MRI machine.
One group of subjects with a specific AKT1 mutation totally blew it on the motor skills, suggesting that dopamine function as mediated by the AKT1 gene affected the function and metabolism of the phytocannabinoids in pot.
AKT1 and its role in dopamine pathways can also be indicative of an individual being predisposed to cannabis-induced psychosis.
But that kind of research is tedious, time-consuming and expensive. Only recently, with the wave of marijuana legalization and new discoveries about the potential of cannabis medicine, have mainstream scientists started to explore beyond the substance abuse implications of the plant.
What are the endocannabinoid genes that build and control the endocannabinoid system?
In the meantime, the practical applications for human cannabinoid genetics are limited by incomplete science. There doesn’t seem to be a consensus in the literature about which genes are even part of the endocannabinoid system, but the core few are clearly mapped. They include:
- CNR1
- Codes for CB1 (cannabinoid receptor 1)
- CNR2
- Codes for CB2 (cannabinoid receptor 2)
- DAGLA
- Codes for 2-AG (2-arachidonoylglycerol)
- NAPEPLD
- Codes for Anandamide (AEA)
- MGLL
- Codes for MAGL, the enzyme that breaks down 2-AG
- FAAH
- Codes for FAAH, the enzyme that breaks down anandamide
- ABHD6 and ABHD12
- Codes for enzymes that break down 2-AG, mostly in reproductive organs, but also throughout the body to a lesser degree.
ABCB1 and ABCG2 code for proteins that lock onto other chemicals and carry them around across cell membranes. These membrane transporter chemicals have shown an affinity for cannabinoids and may be necessary for shepherding endocannabinoids around the nervous system.
Learn more about the phenomenon of endocannabinoid transportation
Exactly how this works is up for debate, however. Some researchers believe that FABP5, coding for one of a family of fatty acid binding proteins, is responsible for transporting anandamide and 2-AG once they’re INSIDE a cell, but that FAAH and MAGL break down the cannabinoids there to draw more inside the cell via a concentration gradient — no transporter necessary.
Liver enzymes that break down THC, CBD
Cytochrome P450: This family of genes codes for general-purpose liver enzymes, a few of which are responsible for THC/cannabinoid breakdown in the liver. How much or how little of this enzyme your body produces will govern how fast your high dissipates and the ratios of THC metabolites that circulate through your bloodstream after smoking/eating pot.
Furthermore, several genes in the UGT family break down CBD and cannabinoid metabolites (like THC-OH) and minor cannabinoids (Like CBN). The most important in this process are UGT1A9, UGT1A7, UGT1A8, and UGT1A10 enzymes encoded by genes with the same names
Beyond endocannabinoid genes: Processes tangential to the ECS
FADS1 and 2 code for the delta-6-desaturase involved in the biosynthesis of arachidonic acid from linoleic acid from our diet. Arachidonic acid is the base molecule of both anandamide and 2-AG. It’s crucial for a large class of fatty signaling molecules called eicosanoids that have a bunch of different functions. Linoleic acid comes from meat, milk and vegetable oils, among other sources.
(In case you were about to start supplement hunting, it’s pretty difficult to have a linoleic acid deficiency — this is only seen in people with some sort of severely restricted diet or infants fed skim milk. People who choose their own food seldom get linoleic acid deficiency.)
SLC6A4 and COMT: Some research has shown people with mutations of COMT together with SLC6A4 experience more hallucinations and poorer memory when using marijuana.
COX-2: COX-2 is a pro-inflammatory chemical blocked by aspirin. The COX-2 gene also has an effect on CB1 signaling.
MAPK14 and NGR1: These control, in part, the amount of white matter in the brain — certain mutations of both have been associated with cannabis dependence. These have also been associated with alcoholism and addiction in general.