In a May 2020 paper published in the journal Regional Anesthesia and Pain Medicine, researchers from the University of California San Diego reviewed the psychedelic literature and proposed a mechanism by which psychedelics may relieve chronic pain.1
The literature review discusses studies using psychedelics to treat conditions like cluster headaches, migraines, cancer pain, and phantom limb pain. The compounds involved in the studies were psilocybin, LSD, and the LSD analog 2-bromolysergic acid diethylamide (BOL-148).
The authors cover the history of psychedelics, studies on their efficacy, tolerability, and safety, and the chemical classes. In proposing their hypothesis for how psychedelics act as analgesics, the authors reviewed three concepts:
1) The mechanism of action of psychedelics at serotonin receptors (primarily 5-HT2A).
2) The downstream effects of psychedelics in the body leading to modulation of gene expression and inflammation.
3) Changes in brain functional connectivity (FC) brought on by psychedelics.
Psychedelics for Chronic Pain – Making the Case
According to the authors, several mechanisms might contribute to the antinociceptive (detection of pain) effects of psychedelics.
Based on the literature, they observed that activating the 5-HT2A receptor (as the classic psychedelics do) causes upregulation (becoming more active) of the genes that are associated with neuroplasticity. The genes that suppress inflammation via tumor necrosis factor alpha (TNF-α) also experience upregulation when the receptor is activated. Therefore, 5-HT2A receptor activation by psychedelics may lead to rewiring in the brain + reduced inflammation = reduced nociception.