CBD Oil and Your Genes: Will it work for you?

CBD oil is the hottest new health hack for everything from anxiety to pain to cancer -- according to the marketing geniuses.  While my skeptical side tends to go 'yeah, right...' when I see some of the claims, there is actually some really interesting research that has come out recently. Why do some people get such great benefits from CBD while others notice nothing? It is likely that your genes play a role in how your body responds to CBD. This article covers the research studies on CBD, the receptors that CBD binds to, and how your genetic variants could be influencing your response (or lack thereof) to CBD oil.

Cannabidiol (CBD) and Endocannabinoids

Cannabidiol, abbreviated CBD, is a phytocannabinoid that is part of cannabis (marijuana) and hemp plants. It was first isolated from the plant in the 1940s, and scientists unraveled its structure in the 1960s.  It is a colorless solid at room temperature and is insoluble in water. CBD does not cause psychoactivity (feeling high). Instead, it is being used for various anti-inflammatory and antiepileptic properties.[ref] It is legal to buy cannabidiol oil in most states in the U.S. now. But state laws vary depending on whether the CBD is derived from hemp or cannabis. Cannabis research initially focused on THC, the psychoactive part of the plant, and the CBD component was pretty much ignored for many years. Research on CBD has exploded in the past decade with several thousand studies referencing it now. Fun fact: Cannabis has been used for thousands of years. Researchers have been able to analyze cannabis found in a 2700-year-old grave of a shaman in China.[ref]

Your Endocannabinoid System

The psychoactive component of cannabis, Δ9-THC, binds to cannabinoid receptors in the body. These receptors are part of our endocannabinoid system. Cannabinoid receptors aren't there just to bind to cannabis, of course. The endocannabinoid system regulates endocrine, immune, and brain functions. For example, it is involved in appetite control (which is why cannabis gives some people the 'munchies').[ref] Our body produces an endocannabinoid called anandamide, which is a lipid-based neurotransmitter. Anandamide binds to the cannabinoid receptors in the central and peripheral nervous systems. It plays a role in regulating mood, appetite, memory, sleep, temperature, and the development of an embryo. But... CBD doesn't activate the cannabinoid receptors. Instead, it acts on several other receptors, as well as modulating the response of the cannabinoid receptors.

Studies on Cannabidiol (CBD oil):

Looking beyond the advertising hype, here is what research studies on CBD show: Anti-inflammatory: CBD is anti-inflammatory in the colon. A study used sections of inflamed colons from IBD, appendicitis, and bowel cancer patients to test the effects of CBD. The study found that CBD acts as an anti-inflammatory and prevented an increase in cytokine production in inflamed colon cells. It did not affect cancer cells in this study.[ref] Pain: CBD has been shown in animal studies to reduce pain. This may go along with the anti-inflammatory properties or may be acting through a different mechanism.[ref] CBD has also been shown to affect pain and inflammation when applied topically.[ref] Addiction: Animal studies indicated that CBD may be able to change behavior in heroin addiction. More research is needed on this, but CBD may be something to add to addiction rehab programs. [ref] Intestinal Barrier:  Studies show that CBD can improve intestinal barrier function (reduce leaky gut!) for people with c. difficile infection.[ref] Anxiety and Depression: Several animal studies show that CBD may be effective in relieving some symptoms of anxiety.  A case study of a child with PTSD and sleep problems found that CBD was safe and effective for reducing anxiety. (More research needs to be done to know the full effects in kids!) [ref][ref][ref] Several animal and human studies have shown that CBD has an antidepressant effect for some people.[ref][ref] Epilepsy: Some specific types of epilepsy can be treated using CBD.[ref][ref][ref] Apoptosis: Research shows that CBD oil induces apoptosis (cell death) in cervical cancer cells.[ref] Acne: A cell culture study shows that CBD oil may be an effective treatment of acne vulgaris.[ref] Caution and Safety: A cell study published in 2019 shows that CBD could cause DNA damage. DNA damage is never good.  The study needs to be replicated, of course, but it does raise some questions on CBD being entirely safe.[ref] Most animal and human studies show CBD oil to be safe and well-tolerated (even at high doses of up to 1,500mg/day). There have been side effects shown such as interactions with medications. It is easy to think - 'oh, this is just something natural from a plant' - but instead consider it as a medication in regards to interactions with other meds you are taking.[ref][ref]

CBD receptors:

Cannabidiol interacts with a variety of different receptors in the body -- which explains the great variety of different conditions that it treats! These different receptors may also explain the differences in effect that people see when using CBD oil. A little background on receptors: Receptors are made up of a protein complex. The molecule that binds to the receptor and activates it is known as the ligand. The metaphor commonly used to describe receptors and ligands is a lock and a key. The ligand binds to a binding site on the receptor and activates it - like a key fitting into a lock. A  molecule that fits into the receptor but doesn't activate it - blocks the keyhole - is referred to as an antagonist of the receptor. A molecule that fits in the keyhole and activates the receptor (but isn't the normal ligand) is an agonist. This lock and key concept can get a little more complex when a molecule can bind to part of a receptor and cause the natural ligand to be either more active or less active -- this is called an allosteric modulator.  A positive allosteric modulator causes the receptor to be more active.

Serotonin receptor:

Cannabidiol interacts with the serotonin receptor, 5-HT1A. This may be why, for some people, CBD oil reduces depression. There is some question as to whether CBD binds directory to the serotonin receptor or whether it is acting as an allosteric modulator, enhancing the signal of endogenous serotonin. Most of the recent studies point to it being an allosteric modulator, binding to the receptor, and modifying the uptake of serotonin.[ref] Animal studies show that the effect on the serotonin receptor is not due to any effect from the cannabinoid receptor (CB1). One study showed that repeated CBD dosing for seven days "reduced nerve injury-induced anxiety-like behavior". In other words, surgery was performed on the animals to produce nerve pain, and seven days of CBD decreased the nerve pain and decreased the anxiety from the pain. The anti-anxiety effects were shown to be due to the interaction with the serotonin receptor.[ref][ref][ref][ref] While people commonly think of serotonin receptors in the context of neurotransmitters and depression, the body also has serotonin receptors in the gut. For people with cancer, chemotherapy often causes nausea. This is triggered by serotonin released in the small intestines. Cannabis (with THC and CBD) is often used by cancer patients to counteract nausea. An animal study showed that CBD suppresses vomiting.[ref]

Vanilloid receptor (TRPV1):

CBD also activates and desensitized the vanilloid 1 receptor (TRPV1). The vanilloid 1 receptor is involved in the regulation of body temperature and in sensing heat and pain. Temperatures over 109 degrees F also activate the receptor. Capsaicin, the hot spice in chili peppers, and isothiocyanate, which cause the hotness from wasabi and mustard also activate the TRPV1 receptor. Desensitization of the receptor, such as through repeated exposure to capsaicin, decreases its activity (and pain such as from neuropathy).[ref] CBD only acts on the vanilloid receptor at certain dosages, and the dose-effect is thought to be a U shaped curve. High doses of CBD show no effects on the TRPV1 receptors.[ref][ref]

GPR55:

The G-protein coupled receptor 55  (GPR55) is a receptor that is found in the central nervous system as well as the intestines, bone marrow, endothelial cells, and platelets.  It is similar to the cannabinoid receptors (CB1 and CB2) but differs structurally in a couple of ways.  CBD is a GPR55 antagonist -- it blocks the function of the receptor. GPR55 is involved in axon growth and the wiring of the brain.[ref] It is thought that CBD's benefit in treating epilepsy is due to blocking GPR55 and decreasing the excitation of certain neurons. A lot of research is still going on about this topic, but it is exciting to see how a natural substance can be used for children with epilepsy.[ref]

Adenosine 2A Receptor:

The adenosine 2A receptor is one of several different adenosine receptors in the body.  Adenosine is a molecule found in the body that does a bunch of different things, including being a part of ATP (adenosine triphosphate) and cellular energy. Adenosine also acts in cellular signaling and is a neuromodulator involved in promoting sleep.  Caffeine binds to the adenosine 2A receptor, causing people to feel more awake. Additionally, the adenosine 2A receptor is involved in the immune system and in the immunomodulation of cancer.[ref] CBD has been shown in several recent studies to bind to the adenosine 2A receptor. In cannabis use, CBD blunts cognitive impairment that Δ9-THC causes -- through its effects on the adenosine 2A receptor.[ref] An animal study of lung inflammation found that CBD decreased the effects of the pro-inflammatory cytokines (TNF and IL-6) as well as other inflammatory pathways. This study clearly showed that the anti-inflammatory effects of CBD were due to the adenosine 2A receptor.[ref][ref] A study showed that injecting CBD into the hypothalamus increases the levels of adenosine in the brain.[ref] This may affect sleep...  One trigger for feeling the need to sleep is the accumulation of adenosine in the brain. And increased adenosine has been shown to increase non-REM sleep while decreasing REM sleep.[ref] A rat study of CBD oil at two different concentrations showed that the total amount of sleep increased, while higher doses delayed the onset of REM sleep.[ref] CBD has also been shown to protect against heart arrhythmia (ventricular). This was shown to be through the activation of the adenosine A1 receptor.[ref]

GABA receptors:

There is some evidence that CBD acts on the GABA receptors also. GABA is the inhibitory neurotransmitter that blocks neurons from firing. It keeps the neurons from being overexcited. A study using magnetic resonance spectroscopy to measure both glutamate and GABA levels in the brain showed some interesting results.  The study compared 17 neurotypical men and 17 autistic men both at baseline and after a single dose of 600mg of CBD oil. The CBD increased subcortical glutamate but decreased cortical glutamate in both groups. But the results for GABA showed significant differences between neurotypical and autistic men. The GABA levels in neurotypical men increased after CBD, but the opposite happened for autistic men with a (statistically) significant decrease.[ref]

Arachidonic Acid Release:

Both CBD and THC stimulate the release of arachidonic acid in platelets. CBD is a more potent activator of arachidonic acid than THC.  Arachidonic acid is a polyunsaturated fatty acid that can be part of the cell membrane. It is also used in the synthesis of anandamide, the endocannabinoid our body produces that binds to the cannabinoid receptor.[ref] It is possible that the release of arachidonic acid increases anandamide, thus creating some of the pleasant effects associated with CBD.

Genetic variants affecting the receptors for CBD oil:

There is a huge variation in how people feel when they take CBD oil -- some people find it has little to know effect, while others swear by it for everything.  The difference is likely to be due to genetic variants, the unique changes that make us all individuals.

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