Treating Pain with Psychedelics: Previous Research 

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The little evidence that exists of psychedelics’ pain-relieving efficacy suggests that these compounds, in conjunction with expertly delivered supportive psychotherapy, may have the potential to treat a variety of chronic pain conditions, including cancer pain, cluster headaches, migraine, and even phantom-limb pain — a rather peculiar pain condition in which constant pain is perceived as coming from a limb that has been amputated. 

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Below, we take a deep dive into preliminary evidence from small-scale pilot studies, surveys, questionnaires, and case reports suggestive of psychedelics’ powerful analgesic effects. 

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Treating Cancer Pain with LSD

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In 1954, physician Dr. Eric Kast and his colleague, author of Principles of anesthesiology, Dr. Vincent Collins, compared the analgesic action of LSD with meperidine (Demerol) and hydromorphone (Dilaudid), two opioid medications used to treat moderate to severe pain.

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In a double-blind study, the researchers first administered either hydromorphone or meperidine to 50 sickly cancer patients, before administering whichever drug participants had not received approximately 6 hours later. At least 6 hours subsequent to administration of the second opioid, participants were given 100 micrograms of LSD 

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According to the researchers, hydromorphone was observed to exhibit more effective analgesic action than meperidine with fewer side effects. LSD, however, was observed to outperform both opioids, inducing profound, enduring pain relief that remained for up to 3 weeks.

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According to the researchers, “patients displayed a peculiar disregard for the gravity of their situations, and talked freely about their impending death with an affect most beneficial to their own psychic states.”

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LSD allowed these people stricken with terminal illness to open up and consciously contemplate the oft-terrifying premature termination of their physical existence, and produced pleasant, beautiful sensations which they felt compelled to glowingly describe. The participants reported that they had not previously experienced anything like the effects of LSD. 

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In addition to the study by Cast and Collins, two subsequent investigations examined the analgesic effects of LSD in cancer patients who also had chronic pain. The first trial, conducted in 1969 and featuring renowned psychedelic therapy expert Bill Richards, showcased notable reductions in pain.

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Building upon this research, another study took place in 1973, with the participation of Dr. Stanislav Grof, known for his work in Holotropic Breathwork. This study focused on LSD-assisted psychotherapy and observed a decrease in pain severity, decreased preoccupation with pain, and alleviation of physical suffering in terminally ill cancer patients.

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Psychedelics for Cluster Headache 

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Cluster headache is a rare, treatment-resistant, chronic pain condition characterized by excruciatingly painful paroxysms on one side of the head, usually concentrated around the eye.

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Sadly, current treatments, which include oxygen, sumatriptan, verapamil, lithium, corticosteroids, and other neuromodulators, fail to provide adequate relief for this idiopathic neurological disorder. Cluster headache is widely considered to be the most painful of headache types.

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However, several case series and qualitative studies suggest that psychedelic substances, LSD and psilocybe mushrooms, in particular, may offer a glimmer of hope in what is an otherwise gloomy prognosis. 

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Following an encounter with a man who experienced complete remission of his cluster periods after using LSD and psilocybe mushrooms, a group of researchers became interested and initiated an investigation. Their objective was to explore this phenomenon further, so they conducted interviews with a cohort of patients who met the criteria outlined in the International Classification of Headache Disorders-2 for cluster headache. These patients had also received a cluster headache diagnosis from a medical doctor and reported using psilocybin-containing mushrooms or LSD as a treatment for their cluster headache.

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Interestingly, data analysis found that magic mushrooms were effective in terminating cluster attacks, aborting cluster attacks (ending attacks within 20 minutes), decreasing the intensity or frequency of attacks, and extending remission periods. 

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LSD was reported to terminate cluster periods, something which had never before been observed with any other medication. LSD was also reported to extend remission periods, and produce long-lasting attack-free periods in chronic cluster headache patients. 

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In 2015, assistant professor of neurology and psychedelic researcher at Yale School of Medicine, Emmanuelle Schindler, published the results of a survey that also investigated the phenomenology of self-medicating cluster headache with psychedelics and other drug types. 

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According to the results of this survey study:

• Psilocybin was an effective abortive treatment
• Psilocybin was an effective prophylactic
• Psilocybin and LSD provided meaningful protection against attacks in over 70% of participants
• Psilocybin and LSD prevented the onset of cluster headache in 40% of participants

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Among the co-authors of this study were members of Clusterbusters, Inc., a non-profit organization dedicated to supporting research for better treatments and a cure for cluster headache. 

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The Use of Psychedelics in the Treatment of Migraine

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Approximately 10% of the global population is burdened by migraine, a recurring neurological disorder characterized by moderate to severe throbbing pain typically felt on one side of the head. Migraine can be so debilitating that 9 out of 10 people report not being able to work or go to school while suffering from an attack.

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A lack of effective treatments for migraine has forced treatment-resistant patients to explore alternative treatments online. To better understand the use of unapproved, alternative migraine treatments, researchers at Karlstad University in Sweden conducted a thematic analysis of personal accounts of the use of psychedelics presented in the online forum boards shroomery, bluelight.org, and clusterbusters. 

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Martin Andersson and colleagues found that psilocybin-containing mushrooms, LSD, and related psychedelics were effective as prophylactics and acute treatments — reducing the intensity of migraine pain and the frequency with which migraines occurred. The forum discussions largely revolved around harm reduction practices and maximizing analgesic effectiveness. 

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In 2021, Schindler and colleagues conducted the first-ever placebo-controlled trial to investigate psilocybin’s potential as a migraine treatment. In this first-of-its-kind study, each participant acted as his or her own control, first receiving an oral placebo capsule, before receiving an identically appearing oral psilocybin capsule (0.143 mg/kg) 2 weeks later. 

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In this study, psilocybin was observed to produce:

• Significantly greater reductions in migraine frequency
• Significantly greater reductions in weekly migraine attacks
• Significantly greater reductions in pain severity
• Significantly greater reductions in attack-related functional impairment
• Significantly greater reductions in weekly migraine abortive days

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Interestingly, this study did not find a correlation between the psychedelic effects of psilocybin and positive outcomes, suggesting that its analgesic action in migraine may be independent of acute changes in sensation and perception.

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This observation is consistent with the results of survey studies demonstrating the effectiveness of sub-psychedelic doses of psychedelics and the apparent efficacy of the non-psychedelic lysergic acid derivative, 2-Bromo-LSD (BOL-148), synthesized by chemist Albert Hofmann.

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Magic Mushrooms: A Potential Treatment for Phantom Limb Pain

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Phantom limb pain is a chronic pain condition that occurs in around 80% of amputees in which pain is felt to be coming from a part of the body that is no longer there. Experts surmise that phantom limb pain may be a consequence of miscommunication between the spinal cord and the brain caused by the survival of peripheral nerve connections. 

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Similar to many other chronic pain conditions, current pharmacotherapies offer limited or no relief, while alternative treatments involving direct electrical impulses to the nervous system can be invasive and uncomfortable. However, these alternative treatments also tend to provide only minimal and short-lived relief for most patients.

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A 2018 case report authored by distinguished professor and neuroscientist Dr. Ramachandran and UC San Diego colleagues suggests that psilocybin may be an effective adjunct to mirror visual feedback (MVF), a non-invasive, neurorehabilitation technique first proposed in the 1990s that is used to alleviate phantom limb pain. 

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The researcher's report describes the compelling story of  National Geographic explorer, Albert Lin, whose leg was crushed in a major off-road vehicle accident and required amputation from the knee down. Having received no relief from conventional pain medications, Lin decided to experiment with magic mushrooms, with the fleshy fungi very much living up to its name. 

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For Lin, a single dose of magic mushrooms produced robust and lasting pain relief, which prompted him to try combining psilocybin and MVF. Initially, this combination of psilocybin and MVF produced a 50% reduction in pain that lasted 3 weeks and eventually led to remission.

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The authors suggest that psilocybin may enhance the effectiveness of MVF by upregulating functional connectivity between the visual cortex and the somatosensory cortex responsible for processing somatic sensations. Psilocybin’s promotion of neuroplasticity via 5-HT2A receptor agonism (enhancement of the brain’s ability to form new connections between neurons and modify and adapt its structure and function in response to experience) may enhance the brain’s receptivity to MVF, therefore improving its efficacy. 

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Investigating Self-Medication of Chronic Pain with Psychedelics 

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In 2021, Ph.D. candidate at Imperial College London Julia Borneman led a qualitative investigation in which 11 people were interviewed about their experience of self-medicating chronic pain with psilocybin-containing mushrooms and truffles, LSD, DMT, and ayahuasca. Study participants were suffering from treatment-resistant chronic pain associated with one of the following:

• Traumatic injuries
• Congenital conditions
• Connective tissue conditions
• Chronic back pain
• Fibromyalgia syndrome
• Autoimmune disorders

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Across a range of psychedelic substances and doses, pain scores improved substantially during and after psychedelic experiences. Participants reported lasting pain reduction, improvements in their relationship with pain, improved pain management, improved physical functioning, and increased acceptance of pain.

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In their interviews, participants reported being pleasantly surprised and even shocked at the perceived efficacy of their chosen psychedelic. Notably, participants used the psychedelic in conjunction with physical, psychological, and spiritual mindfulness-based practices including breathwork, journaling, meditation, yoga, and other mind-body-spirit movement practices. 

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Out of thematic analysis emerged two processes in particular that may be integral to the positive outcomes of psychedelic self-medication for chronic pain: Positive reframing and somatic presence (“mindfulness of the body”).

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Positive reframing describes the user’s psychological state from despair toward acceptance and empowerment. Somatic presence, which refers to mindfulness of the physical effects of the psychedelic substance, was associated with lasting analgesia, reduced pain, and increased function. 

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Psychedelic-induced Changes in Pain Perception 

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In 2021, a team of researchers from Maastricht University conducted a study to examine the pain-relieving effects of LSD. The study followed a randomized, double-blind, placebo-controlled design and involved 24 healthy participants. During the study, the participants received different doses of LSD (5, 10, and 20 micrograms) on separate occasions, either 1.5 or 5 hours after undergoing the Cold Pressor Test.

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The aim of the task in this study was to submerge one’s hand in a cold water tank for as long as possible. Participants were allowed to remove their hand from the water as soon as they had enough.

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A single 20 microgram dose of LSD significantly increased participants' pain tolerance by approximately 20% and decreased subjective ratings of painfulness and unpleasantness. Improvements in pain tolerance and subjective pain perception induced by LSD in this study were comparable to those induced by the opioid medications oxycodone and morphine, despite the relatively small dose. 

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In conclusion, the researchers hypothesized that LSD’s activation of serotonin 2A and 1A receptors involved in pain perception may be central to the drug’s analgesic action. Stimulation of these receptors on serotonergic pathways from the raphe nucleus (a structure known to be involved in actions of descending pain inhibitory processes) to the spinal cord may change the way pain is perceived in the body.

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The authors speculate that the analgesic effects of LSD could also be due pharmacological changes in the processing of nociceptive information, psychological changes in coping with pain, or the promotion of self-transcendence. 

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How do Psychedelics Treat Pain?

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Although preliminary evidence suggests psychedelics could be powerful pain treatments, the biological mechanisms by which pain relief is achieved remains unknown.

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Currently, the majority of funding allocated to psychedelic research is primarily focused on achieving positive clinical results and establishing the safety and effectiveness of compounds such as psilocybin and LSD in patient populations. This line of research is crucial for the eventual approval and adoption of psychedelic therapies in clinical settings.

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However, as a consequence, there has been a temporary reduction in the prioritization of mechanistic studies that investigate how psychedelic substances specifically impact pain signaling and processing.

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That said, several possible biological mechanisms have been hypothesized. 

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Epigenetic Changes and Reduced Inflammation 

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When ingested, psilocybin is metabolized in the human liver and converted into its active metabolite, psilocin. Like LSD, psilocin is lipophilic, meaning it can readily cross the blood-brain barrier where it activates serotonin receptors to exert its effects.

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Recent research conducted by LSU professor of pharmacology Charles Nichols suggests that psychedelics’ activation of the 5-HT2A serotonin receptor may upregulate several genes in the prefrontal cortex that are associated with synaptic plasticity (changes that occur at synapses, the junction between neurons that facilitate communication) and synaptogenesis (the formation of new synapses).

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The 5-HT2A agonist psychedelics LSD, DOI (2,5-Dimethoxy-4-iodoamphetamine), and ayahuasca — a DMT-containing Amazonain brew — have also been shown to increase brain-derived neurotrophic factor (BDNF), a protein found in the brain and spinal cord that promotes neuroplasticity. BDNF is commonly referred to as “fertilizer for the brain.”

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Several studies have also examined the effects of certain psychedelics on inflammatory processes. In animals, DOI has been shown to suppress tumor necrosis factor (TNF), a protein associated with inflammation, with “extraordinary potency,” suggesting that psychedelics may be effective anti-inflammatory compounds that could in the future be used to treat a variety of autoimmune conditions. 

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Psychedelic-induced Reorganization of Pain Pathways 

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Typically, descending inhibitory serotonin pathways modulate the transmission of pain signals in the spinal cord and decrease the sensitivity of neurons in the dorsal horn — an intermediary processing center for pain perception. Research suggests that malfunction of these descending inhibitory pathways plays a role in the development of hyperalgesia (extreme sensitivity to pain) and allodynia (a type of nerve pain in which people are extremely sensitive to touch).

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Preclinical studies have shown that these descending inhibitory effects of serotonin are mediated by activation of several serotonin receptors, but only activation of the 5-HT2A receptor (the receptor responsible for eliciting psychedelic effects) produced persisting serotonin descending inhibition, suggesting that it may have a role to play in neuropathic pain caused by injury or damage to nerves.

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Brain Network Reorganization 

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Advances in brain imaging have enabled neuroscientists to demonstrate how brain regions are connected and identify the patterns of connection that are associated with neurological and psychological conditions.

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There is mounting evidence that the disruption of efficiently organized, healthy brain networks is associated with several psychiatric illnesses, as well as a variety of chronic pain conditions including somatoform pain disorder, fibromyalgia, rheumatoid arthritis, centralized pain, chronic pelvic pain, lumbar back pain, and phantom limb pain.

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Functional magnetic resonance imaging (fMRI) studies, spearheaded by leading neuroscientist and head of the Centre for Psychedelic Research at Imperial College London, Robin Carhart-Harris, have demonstrated that psychedelics alter established patterns of brain connectivity. Specifically, psychedelics “disintegrate” or reduce the stability of established brain networks, and increase the global integration between topologically distant brain regions.

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Medicinal chemist and co-founder of the Heffter Research Institute, David E. Nichols, and colleagues, have hypothesized that this increase in global connectivity may be consolidated through anti-inflammatory effects that facilitate ‘healthy’ reconnections as the psychedelic wears off. Combining these changes in brain connectivity with co-therapeutic modalities like MVF, physical therapy, nerve blocks, or neuromodulation techniques could reverse negative neuroplastic changes that cause chronic pain conditions. 

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Psychedelics for Pain: Summary

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Preliminary evidence suggests that psychedelic substances, such as LSD and psilocybin-containing magic mushrooms, may be effective treatments for a variety of chronic pain conditions, including cancer pain, migraine, cluster headache, and phantom limb pain.

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The severity of chronic pain and the relative ineffectiveness of conventional pain medications experienced by many patients has forced a significant number of sufferers to experiment with controlled substances for some relief. Despite their illegality, self-medication using psychedelics has become increasingly popular, and, as a result, a growing number of research institutions are investigating the analgesic action of these compounds.

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It has been hypothesized that serotonergic psychedelics may affect pain perception by reducing inflammation, increasing neuroplasticity, causing epigenetic changes, altering the activity of pathways that are central to the processing and modulation of pain, and reorganizing brain circuits involved in maintaining chronic pain states. Further investigation is required to establish a more comprehensive understanding of how psychedelics exert their analgesic properties and improve the lives of chronic pain patients. 

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Psychedelics have demonstrated clinical efficacy for several mental health conditions. If this therapeutic efficacy can be translated into the treatment of chronic pain, patients could experience signifcant pain relief without having to engage in illegal activity or undergo invasive surgery.

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That said, a lack of clinical research means that available evidence should be interpreted as preliminary until more methodologically valid and reliable studies investigating the efficacy of psychedelics for chronic pain are conducted. It is much too early to assume that psychedelics are efficacious treatments for the various forms of chronic pain. However, preliminary evidence looks promising and offers.