Psychedelics Cannabis has substances that directly target receptors for cannabinoid. Psychoactive substances such as Lysergic Acid Diethylamide (LSD) are aimed at serotonin receptors. Through serotonin pathways LSD influences endocannabinoid synthesis as well as function, as per an article that was published in British Journal of Pharmacology. In the October 20, 2022, BJP study, which included contributions by the Dr. Vincenzo Di Marzo, Gabriella Gobbi, as well as other researchers, attempted to measure serotonin and endocannabinoid-like molecules found in the brains and spinal cords of mice killed after a 7-day LSD regimen. In repeated doses of 30 micrograms of LSD per kilogram of body weight produced anxiolytic and positive social behavior. Researchers in Canada, Italy and Australia also studied the way LSD altered the microbiome of mice following the seven-day, 30-microgram dose routine.
The study found anti-depressant as well as antianxiety effects that were triggered by LSD that affected the endocannabinoid system and the serotonin metabolite kynurenic acid, but not serotonin levels or its precursor, tryptophan. The increased interaction between mice and anxiolytic behavior was triggered, in part, via endocannabinoid signals and corresponded to changes in some major categories of intestinal bacteria. The results were observed after multiple doses LSD but not just after one session.
LSD IMPACTS ENDOCANNABINOID TONE BY BINDING TO SEROTONIN RECEPTORS
Psilocybin mescaline, ayahuasca and LSD induce a euphoric “trip” by binding to 5HT-2A, which is a serotonin receptor. It is one of 14 serotonin receptors which cause a group of enzymes referred to as the phospholipases (PLs). Various serotonin receptors induce different PLs. Additionally, two substances (agonists) which activate the same receptor could stimulate various enzymes.
Through Serotonin Pathways, LSD Effects Endocannabinoid Synthesis and Functions.
Serotonin receptors drive a symphony of endocannabinoid-producing PLs. Research has demonstrated that serotonin assists in the release of 2-AG. An important endocannabinoid, via a phospholipase c (PLC) dependent mechanism. LSD and Psilocin (the psychoactive metabolite of the psilocybin) stimulate various PL enzymes through binding with the 5-HT2A receptor.
Psilocin promotes the enzyme PLA2 via 5-HT2A, which enables the synthesis of the lipid neurotransmitters palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). These endocannabinoid signaling molecules are part of the same group that includes anandamide (AEA) as well as the other major endocannabinoid. They are the molecular cousins of anandamide. However, unlike anandamide, this molecule, known as bliss PEA and OEA are not bound to receptors for cannabinoid. They all belong to an expanded endocannabinoid system referred to by the name of the endocannabinoidome (eCBome) which is closely linked to the microbiome of the gut and a myriad of other fatty acid-derived substances and receptors.
LSD like psilocin does not alter the endocannabinoid like cholesterol OEA and, in fact, decreases PEA. This is because LSD is a binder to the receptor 5HT-2A without encouraging PLA2 or the PLA2 enzyme. Also, LSD 5HT2A activity depend on the synthesis of PLC that is involved in the release of 2-AG. Instead, the seven-day LSD regimen alters the endocannabinoid’s tone by reducing the levels of anandamide in the mice’s brains but not affecting the production of 2-AG in the prefrontal cortex or hippocampus in accordance with this BJP report.
LSD’S ANTI-INFLAMMATORY PROPERTIES & THE GUT MICROBIOME
Why does a seven-day LSD dose regimen decrease Anandamide concentrations in the hippocampus area of the rodent’s head? Dosing the same way negatively affect the levels of anandamide in humans’ brains?
The psychedelics have been known to induce anti-inflammatory properties that are stimulated via the 5-HT2A receptor. It is believed that anti-inflammatory effects of an eight-day LSD regimen could reduce the body’s demand for production of anandamide. This is due to the fact that anandamide that is produced through multiple pathways, and contains a myriad of enzymes, but not PLC, is produced “on demand” in response to inflammation, as well as other forms of stress. LSD decreases the need for anti-inflammatory endocannabinoids, by reducing pro-inflammatory mediators.
The BJP authors note: “Given that inflammatory signaling influences gut microbiome composition, which is … altered in psychiatric disorders, the anti-inflammatory effects of LSD could have a modulatory role over psychopathology-related gut bacteria.”
In fact, Bifidobacterium, Ileibacterium, Dubosiella as well as Rikenellaceae RC9 species increased following the psychedelic treatment. Bifidobacterium is a bacterium that is a recurring LSD dose’s increase, may increase GABA neurotransmitter activity and reduce inflammation. Repeat LSD doses also increased a healthful ratio between two bacteria, known as bacteroidetes and firmicutes. In addition, the anti-inflammatory bacterium is known to have been proven to help improve autism as well as GI symptoms.
Psychedelics as well as serotonin create unique symphonies during the process of synthesis of lipids via several pathways. Each molecular tune is an orchestra with biological function. “Hence it is possible,” the BJP authors conclude, “that the therapeutic effects elicited by psychedelics acting via the [serotonin] system might be mediated by or result in, changes in gut microbiota composition, brain eCBome composition, or brain 5-HT metabolism.”