How an LSD regimen affects the endocannabinoid system, serotonin, and microbiome
Updated: Jan 31
Cannabis contains ingredients that directly target cannabinoid receptors. Psychedelics like LSD instead target serotonin receptors. Through the serotonin system, though, LSD affects endocannabinoid synthesis.
A recent study sacrificed mice to quantify serotonin and endocannabinoid-like molecules in the rodent’s brains after a seven-day LSD regimen. Repeated 30 microgram doses of LSD per kilogram of body weight illicit anxiolytic and prosocial behaviour, but not after a single session. They further compared serotonin and endocannabinoid levels with microbiome expression after the seven-day, 30-microgram dose routine. (1)
No 2-AG increase after LSD
Lysergic Acid Diethylamide (LSD) altered endocannabinoid tone and affected the serotonin metabolite, kynurenic acid, without altering serotonin or tryptophan. The study, co-authored by Dr. Vincenzo Di Marzo and Gabriella Gobbi, alongside other colleagues, noted anti-depressant and anti-anxiety properties induced by LSD. Increased interaction with familiar mice and anxiolytic behaviour occurred, in part, through endocannabinoid signalling and a few key families of gut bacteria.
LSD does not affect 2-AG production in either tested region of the mice’s brains, though. The new analysis, therefore, refutes suggestions from previous LSD and endocannabinoid signalling enzyme studies. Psychedelics like psilocybin (2), ayahuasca (3), and LSD uniquely bind to a serotonin receptor known as 5HT-2A.
Endocannabinoid synthesis occurs under acute intercellular calcium levels. The phospholipase, PLC, drives 2-AG synthesis from glycerols under normal conditions. PLA2 synthesizes OEA and PEA from NAEs, whereas anandamide derives from NAEs via phospholipase-D. Serotonin receptors (5HTs) drive a symphony of endocannabinoid-producing PLs. And the psychedelics — psilocin and LSD — uniquely induce PLs through 5HTs. LSD conversely reduces anandamide without affecting 2-AG levels in mouse hippocamp or prefrontal cortex, unlike psilocin or ayahuasca. (1, 2, 5, 7, 8)
LSD targets serotonin receptors
Serotonin receptors induce a family of enzymes known as phospholipases (PLs.) Various serotonin receptors induce different PLs. And two agonists of the same receptor can promote different enzymes. Serotonin helps synthesize 2-AG by promoting Phospholipase Type C through 5HT-2a receptors agonism, for example. (1)
In contrast, psilocybin promotes the enzyme PLA2 via the same serotonin receptor, inducing unique lipid signalling molecules. And psilocybin competes for serotonin at the receptor binding site. LSD conversely binds to 5HT-2a without promoting PLA2 (2) or depending on PLC synthesis. (4)
Anandamide and its relatives after LSD regimen
Unlike psilocin, LSD does not affect the lipids known as oleoylethanolamide (OEA) and LEA, and it insignificantly reduces their relative lipid — palmitoylethanolamide (PEA.) These lipids are in the same family as anandamide. Different phospholipase enzymes, however, drive OEA and PEA synthesis.
Significantly, LSD doses repeated over seven days reduced anandamide levels in the brains of mice but only in the hippocamp region. And keep in mind that anandamide is synthesized by Phospholipase Type D, preferably when intercellular calcium levels are acute. (1)
Endocannabinoid neutrality and receptor competition
LSD, unlike serotonin, does not induce calcium currents through 5HT-2c receptors for unknown reasons. (5) Both compounds conversely inhibit calcium currents in specific neurons, an effect blocked by 5HT-1a antagonists. (6) The Canadian, Italian, and Australian authors predicated that anti-inflammatory effects from a seven-day LSD regimen negated the body’s requirement for anandamide production. This is because the body produces endocannabinoids on demand to maintain balance. (1)
Homeostasis might further explain a lack of 2-AG increase, although LSD’s symbiotic mechanisms depend on a second serotonin receptor. LSD is a 5HT-2C agonist which competes with 2-AG at neuropeptide Y (NPY) receptors. (7) Research on psychedelics and NYP is sadly vague. Chronic LSD does, however, significantly regulate neuropeptide Y (NPY) genes, according to a publication in the Journal of Neuropharmacology. (8)
Anti-inflammatory LSD doses
LSD did not significantly affect microbiota composition. Bifidobacterium, Ileibacterium, Dubosiella, and Rikenellaceae RC9 species did increase after psychedelic treatment, though. Moreover, repeat LSD doses further boosted a healthy ratio of two bacteria known as firmicutes and bacteroidetes.
Bifidobacterium, which repeated LSD doses elevate, can boost the GABA neurotransmitter and reduce inflammation. The anti-inflammatory bacterium, therefore, improves autism and GI symptoms. Alongside mild microbiome support, LSD decreases pro-inflammatory lipid mediators such as PGD2. Overall, Lysergic Acid Diethylamide reduces the demand for endocannabinoids. (1)
Psychedelics and the endocannabinoidome
Psychedelics such as psilocin, ayahuasca, and LSD conduct unique symphonies within the endocannabinoidome through several pathways. And each performance embellishes a melody of biological functions.
Let us know in the comments if you look forward to future LSD research. And check out this story to learn more about natural compounds that protect anandamide.
Inserra A, Giorgini G, Lacroix S, Bertazzo A, Choo J, Markopolous A, Grant E, Abolghasemi A, De Gregorio D, Flamand N, Rogers G, Comai S, Silvestri C, Gobbi G, Di Marzo V. Effects of Repeated Lysergic Acid Diethylamide (LSD) on the Mouse Brain Endocannabinoidome and Gut Microbiome. Br J Pharmacol. 2022 Oct 31. doi: 10.1111/bph.15977. Epub ahead of print. PMID: 36316276.
Rossi, Giordano & Guerra, Lorena & BakerMaroteaux L, Béchade C, Roumier A. Dimers of serotonin receptors: Impact on ligand affinity and signaling. Biochimie. 2019;161:23-33. doi:10.1016/j.biochi.2019.01.009,
Glen & Dursun, Serdar & Bouso, José Carlos & Hallak, Jaime & Dos Santos, Rafael. (2022). Molecular Pathways of the Therapeutic Effects of Ayahuasca, a Botanical Psychedelic and Potential Rapid-Acting Antidepressant. Biomolecules. 12. 10.3390/biom12111618.
Schindler EA, Harvey JA, Aloyo VJ. Phospholipase C mediates (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-, but not lysergic acid diethylamide (LSD)-elicited head bobs in rabbit medial prefrontal cortex. Brain Res. 2013;1491:98-108. doi:10.1016/j.brainres.2012.10.057
Backstrom, J., Chang, M., Chu, H. et al. Agonist-Directed Signaling of Serotonin 5-HT2C Receptors: Differences Between Serotonin and Lysergic Acid Diethylamide (LSD). Neuropsychopharmacol 21 (Suppl 1), 77–81 (1999). doi/10.1016/S0893-133X(99)00005-6
Penington NJ, Fox AP. Effects of LSD on Ca++ currents in central 5-HT-containing neurons: 5-HT1A receptors may play a role in hallucinogenesis. J Pharmacol Exp Ther. 1994;269(3):1160-1165.
Khansari, Mohammad & Panahi, Negar & Hosseinzadeh, Saeid & Zendehdel, Morteza. (2020). Effect of cannabinoid-serotonin interactions in the regulation of neuropeptide Y1 receptors expression in rats: the role of CB1 and 5-HT2C receptor. Comparative Clinical Pathology. 29. 10.1007/s00580-019-03081-z.
Martin DA, Marona-Lewicka D, Nichols DE, Nichols CD. Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia. Neuropharmacology. 2014;83:1-8. doi:10.1016/j.neuropharm.2014.03.013