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 ‘pshaw…‘ when I see most of the CBD ads, 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.
Background on Cannabidiol
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 scientist 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 system. 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:
Looking beyond the advertising hype, here is what research studies on CBD show:
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]
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]
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]
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]
Research shows that CBD oil induces apoptosis (cell death) in cervical cancer cells.[ref]
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 not good. The study needs to be replicated, of course, but it does raise some questions on CBD being entirely safe.[ref]
While 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 such as interactions with medications. It is easy to think – ‘oh, this is just something natural from a plant’ – but instead consider it a medication in regards to interactions. [ref][ref]
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.
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]
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]
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:
The genetic variants listed below are all well-researched variants in the genes that code for receptors for CBD. BUT – there aren’t any studies (that I can find) that directly investigate the effects of CBD oil on genetic variants. So the actual effects of these variants on CBD response is untested.
Below each variant, I’ve included what I’m going to preface as WAG (standing for ‘wild ass guess’ or ‘wisdom about genetics’ – you decide). Take it with a grain of salt. If you are a CBD or genetics researcher, leave me a comment below if these WAGs are incorrect.
The TRPV1 gene codes for the transient receptor potential vanilloid 1 receptor. This is involved in the body’s thermoregulation as well as pain perception from spicy foods. CBD has been shown to bind to the TRPV1 receptor in a dose-dependent manner.[ref]
Check your genetic data for rs8065080 (23andMe v4, v5; AncestryDNA):
Check your genetic data for rs161364 (23andMe v4 only):
- T/T: decreased risk of diabetes[ref] less TRPV1(should be better able to tolerate spicy foods)
- C/T: somewhat decreased risk of diabetes
- C/C: normal variant
Check your genetic data for rs224534 (23andMe v4, v5; AncestryDNA):
- A/A: less sensitive to capsaicin (skin sensitivity test) [ref]
- A/G: normal sensitivity to capsaicin
- G/G: normal sensitivity to capsaicin
WAG: People with two copies of the ‘risk’ allele that leads to less TRPV1 might not notice as much of an effect of CBD oil on pain.
Cannabidiol has been shown in several recent studies to interact with the serotonin receptor, which is coded for by the HTR1A gene. Mouse studies have determined that CBD is an allosteric modulator of the serotonin receptor. This means that CBD binds to the receptor, blocking serotonin from binding to the receptor. This is how some SSRI’s work (escitalopram, paroxetine).[ref][ref]
Check your genetic data for rs6295 (23andMe v4, v5):
- GG: increased HTR1A receptor activity (in depressed people) which caused reduced serotonin neurotransmission.[ref]
- CG: normal receptor activity
- CC: normal receptor activity*
*note that this is given in the plus orientation to match 23andMe data. Studies may refer to this SNP in the minus orientation. There are several studies that show opposite effects, possibly due to confusion on orientation and major allele here.
WAG: CBD oil might work better for the GG genotype for depression symptoms.
This gene codes for the adenosine 2A receptor. CBD binds to this receptor, changing levels of adenosine in different tissues in the body. Caffeine is an antagonist of this adenosine receptor.[ref] Most recent studies show CBD as an allosteric modulator for ADORA2A, although some show CBD inhibiting adenosine uptake.
Check your genetic data for rs5751876 (23andMe v4, v5; AncestryDNA):
WAG: CBD oil may reduce anxiety better for people with the TT genotype.
This gene codes for what is now known to be an endocannabinoid receptor found in certain areas of the brain. CBD is an antagonist of GPR55, blocking the receptor.
Check your genetic data for rs3749073 (23andMe v5 only)
WAG: If you have a history of eating disorders, I personally would be very cautious using CBD with the AA genotype.
Effective during acute stress:
One animal study showed that without stress (without HPA-axis activation), CBD oil didn’t act as an anxiolytic. But when animals were stressed, low and intermedia doses of CBD oil blocked the effects of acute stress on the HPA axis. [ref]
Dosages for depression:
Animal studies show that the activation of the serotonin receptors occurs at specific dosages. The lower doses do not seem to affect those receptors. [ref]
Dosages for anxiety:
A study of people with social anxiety disorder tested 600mg of CBD vs a placebo. The results showed that those treated with the CBD had considerably less anxiety and were more cognitively alert when faced with a public speaking challenge. [ref] Another test for anxiety found that CBD was somewhat effective at 300mg. [ref]
A retrospective study of case files found that 25-75mg/day was used for sleep problems due to anxiety. All patients had a decrease in anxiety score by the end of the first month of CBD use.[ref]
As you can see, doses vary a huge amount in these studies. But common sense (and financial sense) dictates that most people start with a lower dose and titrate up. CBD is expensive!
What kind of CBD to buy?
Honestly, I am not an expert on this and don’t want to steer anyone wrong. My only advice is to go with a reputable company with reviews from real people (not MLM shills).
Labdoor.com does independent testing of supplements and now has a CBD oil page.
CBD enhances adenosine signaling.[ref] Caffeine blocks the adenosine receptor…
Combining caffeine and CBD oil theoretically might decrease the effects of CBD binding to the adenosine receptor. Perhaps this would cause more of the CBD to bind with an alternative receptor – such as the serotonin receptor for the relief of anxiety/depression or the TRPV1 receptor for pain relief. It may be worth giving it a try?
An animal study tested transdermal CBD gel for protection against alcohol-induced neurodegeneration. The results showed that a 5% CBD gel was effective for stopping part of the neurodegeneration due to alcohol, and it was detectable in plasma at this concentration. The CBD gel included both CBD and several solvents that are made for transdermal medications. [ref]
A dog study, though, found that plasma concentrations were higher when CBD was ingested as a CBD-infused oil rather than applied transdermally.[ref]
CBD has been shown in studies to counteract intestinal inflammation. It does this (at least in part) through acting on the enteric glial cells. Glial cells are part of the nervous system, and they provide support and protection for neurons. The enteric (intestinal) glial cells surround the nerves that control the digestive system. The enteric glial cells also can release pro-inflammatory cytokines to amplify an immune system response in the gut.
Let me explain a bit: Say that you eat some bad potato salad that sat out too long at a picnic… your immune system will respond to the bacteria in the salad, but your enteric glial cells can help out with that immune response by releasing pro-inflammatory cytokines. This is good when your body needs to fight off the bad bacteria. But too much inflammation on a long term basis is bad. Irritable bowel disease bad.
A study both in mice and using human intestinal cells show that CBD can reduce inflammation in the intestines. The CBD oil reduced the hyper-activation of the enteric glial cells. CBD also prevented the activation of mast cells — a type of cell that reacts during inflammation by releasing histamine and other inflammatory cytokines. [ref]
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