HPA Axis Dysfunction: Cortisol and Stress

When your cortisol levels are chronically out of whack, you can feel like you’re falling apart – like things aren’t right in many different ways.  Cortisol is a hormone produced by the adrenal glands in times of stress, and it also plays many roles in your normal bodily functions. It is a multi-purpose hormone that needs to be in the right amount (not too high, not too low) and at the right time.

Your genes play a significant role in how likely you are to have problems with dysregulated cortisol levels. But this isn’t a solely genetic problem! Life stressors, diet, and environmental factors also come into play here, interacting with genetic susceptibility to mess up your cortisol regulation system. Let’s dig into the details on how the system works and how your genes can influence your susceptibility to problems here.

HPA Axis Dysfunction:

When you are stressed (emotional or physical stress), your adrenal glands produce cortisol. Your brain controls the release of cortisol from the adrenal glands.

Specifically, a region of the brain called the hypothalamus sends a signal (corticotrophin-releasing hormone) to the pituitary gland. The pituitary then releases adrenocorticotropic hormone, which increases the production of cortisol in the adrenal cortex.[ref]

All of this – the Hypothalamus signaling the Pituitary which signals the Adrenals – is called the HPA axis.

The hypothalamus releases corticotropin releasing hormone (CRH). The higher levels of CRH cause the pituitary to release adrenocorticotropic hormone (ACTH). When the ACTH signal reaches the adrenal glands, it stimulates the melanocortin 2 receptor, which initiates the synthesis and release of cortisol. It takes about 3-5 minutes for all of this to happen and cortisol levels to rise.[ref]

What is cortisol?

Your adrenal glands produce cortisol as a way to let your whole body know what is going on in your environment. It is a signal that a stressful situation is occurring. Stress can take many forms, from physical pain to mental worry to even something you might enjoy, like exercise.[ref]

At lower levels, cortisol is secreted all the time. It has a ‘diurnal’ rhythm, which means it goes up and down over a 24-hour day in a predictable pattern.

Normal cortisol levels rise quickly around the time that you wake up in the morning. CC https://doi.org/10.3390/ijerph18020676

Cortisol is a ‘steroid hormone’ which is synthesized in the adrenals from cholesterol. The signal sent by the pituitary gland for creating cortisol causes an increase in the enzyme for converting cholesterol into pregnenolone, which is the rate limiting step in creating cortisol.[ref]

Most of the time, a cortisol precursor is circulating in an inactive form, which can quickly be activated by an enzyme called hydroxysteroid dehydrogenase 1.

What does cortisol do in the body?

Cortisol has many functions:[ref]

  • mediating the stress response
  • regulating metabolism (weight gain…)
  • tamping down the immune response

I’ll go into these in more detail in just a minute…

Cortisol signals for actions to take play by binding to two different receptors: mineralocorticoid and glucocorticoid receptors.

These receptors allow for the different functions of cortisol during normal vs. stress situations:[ref]

  • Mineralocorticoid receptors (MR) – low circulating levels of cortisol activate and regulate a bunch of normal functions in the body.
  • Glucocorticoid receptors (GR) – only activated with high levels of cortisol (stress situation). GR activates the flight-or-fight response.

Let me give you an illustration: When a tiger is chasing you, cortisol is elevated to a high level. It activates the GR receptors, which kick you into high gear. While you’re escaping with your life, your body doesn’t need to waste energy on things like reproduction or even much of the immune system. Those functions can be tamped down, put aside, until the crisis has passed, and your energy can be devoted to survival for the time being.

Cortisol levels can ramp up quickly (within minutes) in times of stress, but the half-life of cortisol is also pretty quick. Within 15 minutes, half of the cortisol is metabolized into a form that is excreted in the urine.

What happens when cortisol levels are too high or too low?

The problems with cortisol come when levels are chronically elevated – or – when the response to a new stress is exaggerated and out of proportion.[ref]

There are two defined diseases for extreme cortisol dysregulation:

  • Cushing’s syndrome
  • Addison’s disease

Cushing’s syndrome is due to too much cortisol, either from glucocorticoid medications or too much cortisol produced by the adrenals due to a pituitary tumor. Symptoms of Cushing’s include high blood pressure, abdominal weight gain, round face, stretch marks, thin skin, and, in women, facial hair, and menstrual irregularities.

Addison’s is due to too little cortisol production. Symptoms include weight loss, muscle weakness, nausea, and mood changes.

While Cushing’s and Addison’s show the extremes of cortisol disorders, milder manifestations plague many of us.

Symptoms of HPA (hypothalamic–pituitary–adrenal) axis dysfunction

HPA axis dysfunction can mean that cortisol is chronically elevated and/or doesn’t respond appropriately to stress. It can also be due to a disrupted rhythm of cortisol production over a day.

HPA axis dysfunction can mean:

  1. chronically elevated cortisol
  2. inappropriate stress response
  3. the rhythm of cortisol is out of sync

Chronically elevated cortisol can be due to repeated stress (physical or mental), genetic susceptibility (below), and traumatic childhood events (epigenetic trigger).[ref]

Chronically elevated cortisol is linked to:

  • elevated blood glucose, diabetes, insulin resistance[ref][ref]
  • immune dysfunction[ref]
  • mood disorders such as depression and anxiety[ref][ref]
  • coronary artery disease (heart disease)[ref]
  • infertility[ref]
  • weight gain[ref][ref]

Another aspect of HPA axis dysfunction is that repeated stress and high cortisol causes ‘habituation’, essentially a downregulation of the cortisol receptors and decreased acute stress response.[ref]  While this could seem like a good thing, the acute stress response is needed in times of, well, acute stress -like running from a tiger. And the downregulation can also apply to normal cortisol function during times of non-stress as well.

Let’s dig into the negative effects of HPA axis dysfunction in more detail:

Immune dysfunction:

Chronic stress can also lead to an increase in autoimmune diseases and to a decrease in normal immune responses.[ref][ref]

When acute stress occurs, the body cannot mount a normal stress response because of decreased GR receptors. It can lead to an increased susceptibility to infections, including colds.[ref]

Depression due to HPA axis dysfunction:

Reduced glucocorticoid receptor function along with altered cortisol circadian rhythm is found in women who have depression.[ref]

Several other studies show that higher basal levels of cortisol along with altered cortisol circadian rhythm is associated with major depressive disorder. It seems to be a two-way street — treating depression can reduce elevated cortisol levels.[ref][ref]

Metabolic syndrome, weight gain, and cortisol:

Hypertension, insulin resistance, and high cholesterol add up to metabolic syndrome. And obesity goes hand-in-hand here…All together, a problem that many of us face.

So what does research show about obesity and cortisol?

Activating the glucocorticoid receptor (GR) can increase blood glucose levels by stimulating the liver to create more glucose (gluconeogenesis).[ref]

Hair cortisol levels, which give an average cortisol reading for the past few months, were tested in a group of British adults. The cortisol levels in hair were higher in those who were obese (BMI >30) and with larger waist circumferences. Higher hair cortisol levels also correlated to being overweight for a longer period of time (>4 years).[ref]

This doesn’t mean that weight gain is due to high cortisol levels for everyone, but it could be part of the problem for many of us.

Infertility from stress:

Constant activation of the HPA axis can cause problems when trying to conceive. It is due to cortisol shifting the ratio of follicle stimulation hormone to luteinizing hormone (FSH:LH).

The altered hormone ratio causes decreased egg quality and an increased risk of infertility.[ref][ref] Read more details here.

Additionally, chronic and unpredictable mild stress can alter menstrual cycles and decrease estradiol levels.[ref]

Childhood trauma alters cortisol levels in adults:

I mentioned above that cortisol levels are controlled by three factors: genetics, chronic stress, and childhood trauma.

There is quite a bit of scientific evidence showing childhood trauma can cause persistent changes in the HPA axis. One study describes it as the brain becoming sensitized, thus allowing episodes of depression to occur more frequently.[ref]

Childhood trauma can be mental or physical – from child abuse to a parent dying to having childhood leukemia. Genetics interacts with this, and some people are more resilient to childhood trauma than others. Certain genetic variants cause a higher basal cortisol level with a blunted response to actual, acute stress. It increases the risk of depression, anxiety, and PTSD.[ref]

Adrenal fatigue isn’t real?

I wanted to address adrenal fatigue because many people may confuse it with HPA axis dysfunction. It isn’t really the same thing.

Adrenal fatigue is an idea promulgated by alternative medicine practitioners. The idea is chronic stress causes the adrenals to wear out – become exhausted – and not produce enough cortisol. It is thought to cause overall fatigue, depression, weight gain, brain fog, etc. Examples of alternative health sites writing about adrenal fatigue: Dr. Northrup’s adrenal fatigue articleDave Asprey chiming in on the adrenal fatigue idea. These are just a handful of examples, and all the big alternative health websites used to be on the adrenal fatigue band-wagon.

Most endocrinologists don’t think that ‘adrenal fatigue’ is real. And research studies back up the idea that the adrenal glands aren’t worn out, exhausted, or not producing enough cortisol.[ref][ref]  In fact, some alternative medicine practitioners seem to be revamping how they talk about adrenal fatigue and are now morphing their articles to talk about HPA axis dysfunction.[article][article]

 


Genetic Variants in the HPA Axis

Read more

ANK3: Bipolar Disorder and Brain Development

The genetic variants in the ANK3 gene impact the risk of psychiatric disorders that include bipolar disorder and autism spectrum disorders, and heart arrhythmia. Discover how ANK3 impacts neuronal formation and transmission and how this ties into an increased risk of psychiatric disorders.

Serotonin: How your genes affect this neurotransmitter

Serotonin… a word that brings to mind a commercial that might show our happy brain neurons bouncing serotonin between them.

There is a lot more to this molecule than most of us realize! This article covers how the body makes and transports serotonin and the needed receptors to complete its pathway. I’ll explain the genetic variants that impact the serotonergic system and then go through diet, supplement, and lifestyle changes that impact serotonin.

What does serotonin do?

In the brain, serotonin acts in several ways:

  • as a neurotransmitter, sending a chemical message between neurons.
  • as the precursor molecule for melatonin
  • in sleep quality, including sleep hallucinations[ref][ref]

But there is more to serotonin than just its impact on the brain.

About 90% of serotonin is made in the gut and helps to regulate motility.[ref] Serotonin also regulates other functions such as; bone mass, cardiovascular health, the endocrine system, and appetite.

Serotonin is also important in energy metabolism, heart rate, cell growth, and immunity.[ref]

 

Depression:

Some researchers believe that imbalances in serotonin may play a role in depression or anxiety. Common antidepressants include SSRIs (selective serotonin reuptake inhibitors) and are thought to increase serotonin levels in the brain. However, the method through which they work is still not completely understood.[ref]

Another link between serotonin and depression is that serotonin modulates immune function.[ref] Increased inflammation is implicated in causing major depressive disorder for some.

Recent animal research shows that one reason that SSRIs may not work for everyone is due to increased inflammation. The study showed that in inflammatory situations, histamine is upregulated and SSRIs act in off-target actions on histamine instead of increasing serotonin. In this study, decreasing histamine levels increased the SSRI effectiveness.[ref]  (Read more about histamine and check your histamine intolerance genes.)

Serotonin Synthesis and Transport:

Like most signaling molecules and neurotransmitters, serotonin first needs to be created (synthesized), then it needs to be transported, and finally the signal needs to be received by a cellular receptor.

Synthesis: Serotonin, also known as 5-hydroxytryptamine or 5-HT, is synthesized from the amino acid tryptophan using tryptophan hydroxylase. The TPH1 and TPH2 genes encode the tryptophan hydroxylase enzymes.

Transport: Serotonin is transported by SLC6A4, which is also known as SERT or sodium-dependent serotonin transporter.

Receptors: Serotonin receptors on the cell membrane, HTR1A, HTR1B, and HTR2A receive the serotonin signal.

All of these work in concert: from the creation of serotonin from amino acids to the transport of serotonin to the receptors that are necessary to receive this chemical messenger.

Serotonin Syndrome: Too much serotonin

Ultimately, balance is the key to serotonin. Too much serotonin can result in serotonin syndrome. Symptoms include restlessness, confusion, shivering, diarrhea, and, potentially, death.[ref]

Serotonin syndrome is usually caused by drugs such as MAOIs or SSRIs that affect the rate of serotonin break down.[ref]


Genetic Variants that Change Serotonin Levels:

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Below is a compilation of studies on genetic variants that affect serotonin synthesis, transport, and receptors. Please treat this as a starting point for learning more about your genes and serotonin. Talk with your doctor if you have any medical questions.

Serotonin Synthesis: Tryptophan Hydroxylase (TPH1 and TPH2)

Tryptophan hydroxylase is an enzyme that catalyzes the reaction that produces serotonin from the amino acid tryptophan. Iron is a co-factor, and BH4 is also used in the reaction.

There are two genes that code for tryptophan hydroxylase:

  • TPH1 is found mainly in the gut, skin, and pineal gland.
  • TPH2 works in the central nervous system.

(Learn more about tryptophan and how it converts to serotonin or kynurenine.)

Several TPH2 genetic variants have links to psychiatric issues such as obsessive-compulsive disorder, depression, and bipolar disorder. These variants affect the production rate of serotonin in the brain.

Check your genetic data for  rs4570625 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • G/T: decreased risk of depression[ref], less anxiety, and aggression[ref][ref]
  • T/T: decreased risk of depression, less anxiety, and aggression, more likely to be honest[ref]

Members: Your genotype for rs4570625 is .

Interactions between different genetic variants can be important as well. There are a couple of interesting studies that look at the combination of carrying the rs4570625 genotypes with the BNDF Val66Met (rs6265) genotypes. Those with rs4570625 G/G and rs6265 T/T were more likely to have “impaired inhibition of negative emotional content”.[ref] (The next time you start yelling at someone, be sure to think about your “impaired inhibition of negative emotional content“!)

Read more

COMT: Interactions with Supplements

Some supplements interact with COMT variants to impact the rate at which neurotransmitters are broken down. Check your COMT genotype and discover how this may affect your reaction to different supplements or combinations of supplements.

Is Anxiety Genetic?

This article covers genetic variants related to anxiety disorders. Genetic variants combine with environmental factors (nutrition, sleep, relationships, etc) when it comes to anxiety. There is not a single “anxiety gene”. Instead, there are many genes that can be involved – and many genetic pathways to target for solutions.

CBD Oil: Genes and Receptors

According to the marketing geniuses, CBD oil is the hottest new health hack for everything from anxiety to pain to cancer. While my skeptical side tends to go ‘yeah, right…‘ when I see some of the claims, there is actually some fascinating research that has come out recently.

Why do some people get such great benefits from CBD while others notice nothing? Your genes likely 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): Doesn’t work the same for everyone

Cannabidiol, abbreviated CBD, is a phytocannabinoid 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 many places, but state laws can vary depending on whether the CBD is derived from hemp or cannabis. CBD derived from cannabis is often called ‘full spectrum’.

Cannabis research initially focused on THC, the psychoactive part of the plant, and the CBD component was pretty much ignored for many years. The past decade has seen an explosion of research on CBD,  with several thousand studies referencing it now.

TIL: Cannabis has been used for thousands of years. Researchers have analyzed 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 (why cannabis gives some people the ‘munchies’).[ref]

The 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 oil doesn’t really activate the cannabinoid receptors. Instead, it acts on several other receptors and modulates 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 prevents 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. It may go along with the anti-inflammatory properties or may act 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 might 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 effectively relieve 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 on 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 effectively treat acne vulgaris.[ref]

Caution and Safety:
A cell study published in 2019 shows that CBD could cause DNA damage. DNA damage is never good. Of course, the study needs to be replicated, but it does raise some questions about 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 regarding interactions with other meds you are taking.[ref][ref]

CBD receptors:

Cannabidiol interacts with various receptors in the body — which explains the great variety of different conditions that it treats. Due to genetic variants in the receptors, these different receptors may also explain the differences in effect that people see when using CBD oil.

CC Image PMC8472755

A little background on receptors:
Receptors are made up of a protein complex. The molecule that binds to the receptor and activates it (e.g., cannabidiol) is 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.

CBD binds to a serotonin receptor

Cannabidiol interacts with the serotonin receptor, 5-HT1A. It 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 acts 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 serotonin uptake.[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 anxiety from the pain. The anti-anxiety effects were shown to be due to the interaction with the serotonin receptor.[ref][ref][ref][ref]

Reducing nausea: 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. It 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): Activated by CBD

CBD also activates and desensitizes the vanilloid 1 receptor (TRPV1).

The vanilloid 1 (TRPV1) 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 causes the hotness from wasabi and mustard, also activates 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 TRPV1 receptors.[ref][ref]

CBD binds to GPR55

The G-protein coupled receptor 55  (GPR55) is a receptor found in the central nervous system and also in 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: CBD and ADORA2A

The adenosine 2A receptor is one of several different adenosine receptors in the body. Adenosine is a molecule found in the body that does many different things, including being a part of ATP (adenosine triphosphate) and cellular energy.

Adenosine also acts in cellular signaling and is a neuromodulator that promotes 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 adenosine levels 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). It was shown to be through the activation of the adenosine A1 receptor.[ref]

CBD and GABA

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 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]

Platelets, Arachidonic Acid Release, and CBD

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 to synthesize anandamide, the endocannabinoid our body produces that binds to the cannabinoid receptor.[ref] The release of arachidonic acid may increase 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 no 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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