How do THC, Mustard Oil, and Vomitoxin affect GLP-1?

Fusarium recently began appearing on the radar of cannabis cultivators. The fungi are problematic for human consumption because they release a harmful metabolite known as Vomitoxin. In contrast, certain cannabis varieties produce an ingredient known as tetrahydrocannabinol that can reduce nausea. A deeper review reveals that THC, Vomitoxin, and various ingredients, such as compounds found in mustard oil, affect GLP-1 through one sensory channel. As its name suggests, though, the mycotoxin induces an opposite effect relative to the antiemetic cannabinoid.

Grains and other major food crops can become infected with a fungus known as Fusarium. Deoxynivalenol — or vomitoxin — is a metabolite emitted by the fungus. It can cause a harmful course of symptoms in humans who consume infected foods and herbal remedies. Symptom severity following ingestion depends on dose and exposure time, lasting anywhere from 12 to 48 hours. Nausea and vomiting are often associated with diarrhea and stomach pain.

Sensory receptor channels

THC can reduce nausea because it binds to multiple sites that cooperate in tandem. The cannabinoid functions as a CB1 receptor agonist, but it also targets more primal biological sites. A defined scope of their properties reveals that Vomitoxin and THC nonselectively occupy the same sensory pathway with opposing outcomes. Where the cannabinoid loosely fills a void, the mycotoxin forms a temporary bond with the TRPA1 channel.

Transient receptor potential channels are comprised of protein groups found throughout cell membranes. They help the body detect things such as heat, cold, and irritating chemicals. Sensory pathways quickly open when they are activated, allowing ions to flow into the cell. The response sends signals to the nervous system that help the body sense its surrounding environment.

Hot wing enthusiasts have become more familiar with Vanilloid 1, a well-known sensory channel. That is because TRPV1 receptors respond to heat and capsaicin, the active ingredient in chili oil. TRPA1, its less popular cousin, is a receptor that detects sharp or irritating chemicals. Nauseating compounds, such as mycotoxins or the primary ingredient in mustard oil form a specific bond with the channel.

Desensitizing agonists

THC activates TRPA1 but it does so without causing sensitization. This is because cannabinoids cannot stabilize Transient Receptor Potential Channels. Compounds that irritate the pathway possess an electrical charge that helps stabilize the channel and form a temporary bond. In this position, the irritant will temporarily keep the pain pathway open. Whereas cannabinoids instead fill the pathway but cannot bind to its structural membranes. Without the stable bond, activation leads to an ion influx that closes the channel — a self-regulated system.

Compounds that hold the channel open for much longer periods can essentially cause more pain and nausea. Coevelant bonds allow the mycotoxin to hold the A1 transient receptor in its open, active state. This is how numerous agonists function with varying potencies. In contrast, the pain pathway rapidly closes when THC or cannabichromene enters the channel. Unfortunately, Vomitoxin has not been the subject of any assays that reveal its binding pose within TRPA1.

Why is Vomitoxin worse?

Mustard is one of North America’s most popular condiments. And while it is typically enjoyed in small quantities, its potential to induce vomiting is relatively mute. Moving up the efficacy ladder, nausea and vomiting are more common side effects of tear gas — another TRPA1 agonist. More than efficacy alone, though, the emetic severity of vomitoxin relies on one more receptor. Its ensemble effect might explain why one agonist induces far more severe side effects.

A study conducted by Michigan State University explored how the mycotoxin saturates hormones involved in appetite and gestation. Following the signals to their source, researchers were led to TRPA1 and one other target. They theorized that the Fusarium metabolite depends on a combination of two factors to modify hormones that make you feel full. The sensory pathway is part of the process. Vomitoxin, however, must also activate a receptor that increases the flow of specific molecular ions. Its dual action works in tandem to drive a stronger hormone release, according to the research.

Mink were infected with the toxin. And then groups were either given a drug that blocks TRPA1 or a calcium-sensing receptor antagonist. Results showed that, after infection, doses of either drug decreased hormone levels known to help control appetite. Infected mink given both drugs showed even greater improvement in symptom severity. Furthermore, hormone levels returned to normal after treatment. This indicates that vomitoxin depends on an ensemble effect between the sensory pathway and the ion-sensing receptor.

Sensory channels and GLP-1

Michigan State researchers focused on the hormones CCK and GLP-1. Ozempic, a popular weight-loss drug, agonizes GLP-1. A 2022 study analyzed levels of GLP-1, which is primarily expressed in the colon and lower section of the small intestine. It also assessed another hormone known as Substance P downstream of vomitoxin activation. They fed mice six different trithocene mycotoxins.

Vomitoxin and two other DON subspecies did increase both satiety hormones. Substance P and GLP-1 levels increased one to two hours after mice ate DON-infected grains and returned to normal after six hours. It did not assess the involvement of sensory (ion) channels. But a Genentech study examined a TRPA1 inhibitor in a rodent asthma model. They reported that the drug downregulated Substance P in the test.

These three papers built on older cellular assays that tested a variety of TRPA1 agonists. Channel sensitization can cause appetite loss by increasing levels of satiety hormones, particularly GCPR, Substance P, and GLP-1. THC can, therefore, increase appetite by reducing these hormones through TRPA1 desensitization.

Can THC cause nausea?

Overall, THC reduces nausea through several mechanisms, including CB1 receptor agonism. But a condition now featured in the mainstream press is defined by cannabis-induced nausea. A chronic consumer will suddenly experience extreme vomiting as a response to long-term THC use. The condition is known as Cannabis Hyperemesis Syndrome (CHS).

CHS patients often seek out treatments that desensitize TRPV1 channels. Desensitization facilitates numerous effects, which largely occur downstream of either intracellular calcium (CA²+) or sodium modulation. It will further lead to heterogeneous desensitization of TRPA1 that in turn reduces various satiety hormones. Gene related calcitonin peptide (GRCP), Substance P (SP). High CA²+ further encourages 2-AG and anandamide (AEA) production.

A recent survey distributed via Social Media assessed consumption habits in over 1000 participants who reported having CHS. The results suggest that the condition predominantly occurs in daily smokers of THC-rich products. Nearly two-thirds of the survey respondents reported using cannabis for more than three years before symptom onset. Oftentimes, a person will suffer until they stop consuming THC and cannot restart normal use. Chronic use of the intoxicating cannabinoid leads to extreme discomfort. Common CHS treatments activate the vanilloid channel, which can in turn, desensitize TRPA1. The importance of this discussion, however, is not to unravel a mystery. The underlying mechanism that drives each CHS case remains unknown.

THC should oppose GLP-1 agonists, but the effect occurs through a transient receptor that induces a bidirectional outcome. Mustard oil will work on either side of the axis, depending on dose and epigenetics. Vomitoxin instead sensitizes TRPA1 directly and indirectly, which increases various hormones that control appetite. Unlike THC and mustard, though, Fusarium-borne mycotoxins attack ribosomes and can damage mRNA.

Sources

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