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The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT<jats:sub>2A<\/jats:sub>) receptor agonism, to \u2018reset\u2019 areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT<jats:sub>2A<\/jats:sub> activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.<\/jats:p>","DOI":"10.1136\/rapm-2020-101273","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T04:55:25Z","timestamp":1588654525000},"page":"486-494","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":118,"title":["Chronic pain and psychedelics: a review and proposed mechanism of action"],"prefix":"10.1136","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7365-7260","authenticated-orcid":false,"given":"Joel P","family":"Castellanos","sequence":"first","affiliation":[{"name":"Anesthesia Pain, UC San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Woolley","sequence":"additional","affiliation":[{"name":"Anesthesia Pain, UC San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5536-0343","authenticated-orcid":false,"given":"Kelly Amanda","family":"Bruno","sequence":"additional","affiliation":[{"name":"Anesthesia Pain, UC San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadel","family":"Zeidan","sequence":"additional","affiliation":[{"name":"Anesthesia Pain, UC San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Halberstadt","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, UC San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Furnish","sequence":"additional","affiliation":[{"name":"Anesthesia Pain, UC San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2020,5,4]]},"reference":[{"key":"2025090415174395000_45.7.486.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119598109"},{"key":"2025090415174395000_45.7.486.2","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.557"},{"key":"2025090415174395000_45.7.486.3","doi-asserted-by":"publisher","DOI":"10.1177\/2045125316638008"},{"key":"2025090415174395000_45.7.486.4","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1080\/13554794.2018.1468469","article-title":"Relief from intractable phantom pain by combining psilocybin and mirror visual-feedback (MVF)","volume":"24","author":"Ramachandran","year":"2018","journal-title":"Neurocase"},{"key":"2025090415174395000_45.7.486.5","first-page":"22","article-title":"The effect of LSD on the phantom limb phenomenon","volume":"87","author":"Kuromaru","year":"1967","journal-title":"J Lancet"},{"key":"2025090415174395000_45.7.486.6","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.011478"},{"key":"2025090415174395000_45.7.486.7","doi-asserted-by":"crossref","unstructured":"Geyer MA NG , Vollenweider FX . 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