Our Bodies Produce Chemicals Similar to THC in Cannabis

By Drs. Prakash and Mitzi Nagarkatti, University of South Carolina

Over the past two decades, a great deal of attention has been given to marijuana – also known as pot or weed. As of early 2023, marijuana has been legalized for recreational use in 21 states and Washington, D.C., and the use of marijuana for medical purposes has grown significantly during the last 20 or so years.

But few people know that the human body naturally produces chemicals that are very similar to delta-9-tetrahydrocannabinol, or THC, the psychoactive compound in marijuana, which comes from the Cannabis sativa plant. These substances are called endocannabinoids, and they’re found across all vertebrate species.

Evolutionarily, the appearance of endocannabinoids in vertebrate animals predates that of Cannabis sativa by about 575 million years.

It is as if the human body has its own version of a marijuana seedling inside, constantly producing small amounts of endocannabinoids.

The similarity of endocannabinoids to THC, and their importance in maintaining human health, have raised significant interest among scientists to further study their role in health and disease, and potentially use them as therapeutic targets to treat human diseases.

THC was first identified in 1964, and is just one of more than 100 compounds found in marijuana that are called cannabinoids.

What Are Endocannabinoids?

Endocannabinoids were not discovered until 1992. Since then, research has revealed that they are critical for many important physiological functions that regulate human health. An imbalance in the production of endocannabinoids, or in the body’s responsiveness to them, can lead to major clinical disorders, including obesity as well as neurodegenerative, cardiovascular and inflammatory diseases.

We are immunologists who have been studying the effects of marijuana cannabinoids and vertebrate endocannabinoids on inflammation and cancer for more than two decades. Research in our laboratory has shown that endocannabinoids regulate inflammation and other immune functions.

A variety of tissues in the body, including brain, muscle, fatty tissue and immune cells, produce small quantities of endocannabinoids. There are two main types of endocannabinoids: anandamide, or AEA, and 2-arachidonoyl glycerol, known as 2-AG. Both of them can activate the body’s cannabinoid receptors, which receive and process chemical signals in cells.

One of these receptors, called CB1, is found predominantly in the brain. The other, called CB2, is found mainly in immune cells. It is primarily through the activation of these two receptors that endocannabinoids control many bodily functions.

The receptors can be compared to a “lock” and the endocannabinoids a “key” that can open the lock and gain entry into the cells. All these endocannabinoid receptors and molecules together are referred to as the endocannabinoid system.

The cannabis plant contains another compound called cannabidiol, or CBD, which has become popular for its medicinal properties. Unlike THC, CBD doesn’t have psychoactive properties because it does not activate CB1 receptors in the brain. Nor does it activate the CB2 receptors, meaning that its action on immune cells is independent of CB2 receptors.

Endocannabinoids Help Us Feel Better

The euphoric “high” feeling that people experience when using marijuana comes from THC activating the CB1 receptors in the brain.

But when endocannabinoids activate CB1 receptors, by comparison, they do not cause a marijuana high. One reason is that the body produces them in smaller quantities than the typical amount of THC in marijuana. The other is that certain enzymes break them down rapidly after they carry out their cellular functions.

However, there is growing evidence that certain activities may release mood-elevating endocannabinoids. Some research suggests that the relaxed, euphoric feeling you get after exercise, called a “runner’s high,” results from the release of endocannabinoids rather than from endorphins, as previously thought.

The endocannabinoids regulate several bodily functions such as sleep, mood, appetite, learning, memory, body temperature, pain, immune functions and fertility. They control some of these functions by regulating nerve cell signaling in the brain. Normally, nerve cells communicate with one another at junctions called synapses. The endocannabinoid system in the brain regulates this communication at synapses, which explains its ability to affect a wide array of bodily functions.

Research in our laboratory has shown that certain cells of the immune system produce endocannabinoids that can regulate inflammation and other immune functions through the activation of CB2 receptors.

In addition, we have shown that endocannabinoids are highly effective in lessening the debilitating effects of autoimmune diseases. These are diseases in which the immune system goes haywire and starts destroying the body’s organs and tissues. Examples include multiple sclerosis, lupus, hepatitis and arthritis.

Chronic Pain Linked to Low Levels of Endocannabinoids

Recent research suggests that migraine, fibromyalgia, irritable bowel syndrome, post-traumatic stress disorder and bipolar disease are all linked to low levels of endocannabinoids.

In a 2022 study, researchers found that a defect in a gene that helps produce endocannabinoids causes early onset of Parkinson’s disease. Another 2022 study linked the same gene defect to other neurological disorders, including developmental delay, poor muscle control and vision problems.

Other research has shown that people with a defective form of CB1 receptors experience increased pain sensitivity such as migraine headaches and suffer from sleep and memory disorders and anxiety.

We believe that the medicinal properties of THC may be linked to the molecule’s ability to compensate for a deficiency or defect in the production or functions of the endocannabinoids.

For example, scientists have found that people who experience certain types of chronic pain may have decreased production of endocannabinoids. People who consume marijuana for medicinal purposes report significant relief from pain. Because the THC in marijuana is the cannabinoid that reduces pain, it may be helping to compensate for the decreased production or functions of endocannabinoids in such patients.

Deciphering the role of endocannabinoids is still an emerging area of health research. Certainly much more research is needed to decipher their role in regulating different functions in the body.

In our view, it will also be important to continue to unravel the relationship between defects in the endocannabinoid system and the development of various diseases and clinical disorders. We think that the answers could hold great promise for the development of new therapies using the body’s own cannabinoids.

Prakash Nagarkatti, PhD, and Mitzi Nagarkatti, PhD, are Professors of Pathology, Microbiology and Immunology at the University of South Carolina. They receive funding from the National Science Foundation and the National Institutes of Health.

This article originally appeared in The Conversation and is republished with permission.

Cannabis Users May Risk Harmful Drug Interactions

By Pat Anson, PNN Editor

A recent survey found that nearly half of American adults (49%) have tried marijuana, a figure that has risen steadily in recent years as more states legalize medical and recreational cannabis. While the Gallup poll didn’t ask people why they used marijuana, it’s fair to say many are experimenting with cannabis products – and cannabidiol (CBD) in particular – as alternatives to mainstream medical treatment.

And that could be a problem for people with chronic pain and other illnesses, according to researchers at Washington State University, who found that CBD interferes with two families of enzymes that help metabolize pain relievers and other drugs prescribed for a variety of medical conditions. As a result, the medications’ positive effects might decrease or the drugs could build up in the body and become toxic.

“Physicians need to be aware of the possibility of toxicity or lack of response when patients are using cannabinoids,” said Philip Lazarus, PhD, a professor of pharmaceutical sciences and senior author of two new studies appearing in in the journal Drug Metabolism and Disposition.

“It’s one thing if you’re young and healthy and smoke cannabis once in a while, but for older people who are using medications, taking CBD or medicinal marijuana may negatively impact their treatment.”

One study focused on enzymes known as cytochrome P450s (CYPs), while the second study looked at enyzymes called UDP-glucuronosyltransferases (UGTs). Together, the two enzyme families help metabolize and eliminate more than 70 percent of the most commonly used drugs from the body.

The WSU researchers studied three cannabinoids — tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) -- and how they interact with CYP and UGT enzymes. Of particular interest to the researchers are the metabolites produced by cannabinoids as they break down in the body.     

“Cannabinoids stay in your body only for about 30 minutes before they are rapidly broken down,” said first author Shamema Nasrin, a graduate student in the WSU College of Pharmacy and Pharmaceutical Sciences. “The metabolites that result from that process stay in your body for much longer -- up to 14 days -- and at higher concentrations than cannabinoids and have been overlooked in previous studies, which is why we thought we should focus on those as well.”

The researchers found that cannabinoids and the major THC metabolites strongly inhibit several key CYP enzymes in the liver that play a role in metabolizing anti-cancer drugs, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, anti-epileptics and other medications. Cannabinoids also inhibited two of the primary UGT enzymes in the liver.

Atlhough the liver is considered the most important organ for the metabolism of drugs, kidneys also play a vital role, clearing toxins and other drugs from the body. Researchers found that CBD blocked three enzymes that account for about 95 percent of kidney UGT metabolism.

“If you have a kidney disease or you are taking one or more drugs that are metabolized primarily through the kidney and you’re also smoking marijuana, you could be inhibiting normal kidney function, and it may have long-term effects for you,” Lazarus said.

The interactions between CBD and UGT enzymes could be especially risky for patients with acute kidney disease, kidney cancer or HIV, who may be using CBD to treat pain or to try to reduce the side effects from anti-cancer drugs.

“Taking CBD or marijuana might help your pain but could be making the other drug you’re taking more toxic, and that increase in toxicity may mean that you can’t continue taking that drug,” Nasrin said. “So, there could be serious ramifications for anti-cancer drugs, and that’s only one example of the many drugs that could potentially be affected by the cannabinoid-enzyme interactions we’re seeing.”

More research is needed to fully understand the drug-drug interactions that cannabis may have. Drugs.com has a list of 387 drugs that are known to interact with cannabis, with 26 categorized as major interactions and 361 described as moderate.

Medications known to have major interactions with cannabis include several opioids, such as codeine, fentanyl, buprenorphine, hydrocodone, methadone, morphine and oxycodone.

Exercise Reduces Pain by Increasing Beneficial Bacteria

By Pat Anson, PNN Editor

Regular exercise can benefit people in many different ways, helping us lose weight, reduce the risk of heart disease, and boosting overall health.  

But researchers at the University of Nottingham have found that exercise has an unexpected benefit for people with arthritis. Regular exercise increases levels of beneficial bacteria in their digestive tracts, which reduces pain and inflammation by increasing levels of endocannabinoids – cannabis-like substances naturally produced by the body.

The study, published in the journal Gut Microbes, is believed to be the first to find a potential link between endocannabinoids, exercise and gut microbes.

"Our study clearly shows that exercise increases the body's own cannabis-type substances. Which can have a positive impact on many conditions,” says lead author Amrita Vijay, a Research Fellow at Nottingham’s School of Medicine. "As interest in cannabidiol oil and other supplements increases, it is important to know that simple lifestyle interventions like exercise can modulate endocannabinoids."

Vijay and her colleagues enrolled 78 people in their study. Half of the participants did 15 minutes of muscle strengthening exercises every day for six weeks, and the rest did nothing. Blood and fecal samples were collected from both groups.

At the end of the study, participants who exercised not only had lower pain levels, they also had significantly more Bifidobacteria and Coprococcus 3 -- bacteria that produce anti-inflammatory substances and lower levels of cytokines, which regulate inflammation.

These gut bacteria were particularly adept at raising levels of short chain fatty acids (SCFAs), which increase levels of endocannabinoids. About a third of the anti-inflammatory effects of the gut microbes was due to their ability to raise endocannabinoid levels.

Importantly, the exercise group also had lower levels of Collinsella – a bacteria known to increase inflammation that is strongly associated with processed food and diets low in vegetables.    

“In this study we show that circulating levels of ECs (endocannabinoids) are consistently associated with higher levels of SCFAs, with higher microbiome diversity and with lower levels of the pro-inflammatory genus Collinsella. We also show statistically that the anti-inflammatory effects of SCFAs are up to one third mediated by the EC system,” researchers concluded.

Previous studies have also found an association between gut bacteria and painful conditions. A 2019 study at McGill University found that women with fibromyalgia had 19 different species of bacteria that were present in either greater or lesser quantities than a healthy control group.

Bacteria associated with irritable bowel syndrome, chronic fatigue syndrome and interstitial cystitis were also found to be abundant in the fibromyalgia patients, but not in the control group.    

Having a healthy diet can also affect pain levels for migraine, neuropathy and other types of chronic pain. A recent study funded by the National Institutes of Health found that migraine sufferers who ate more fatty fish and reduced their consumption of polyunsaturated vegetable oils — frequently found in processed foods — had fewer headaches.