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Psychedelics and Chronic Pain: A Trip Worth Taking?

May 6, 2025, 08:10 by Emily Burson, DO, RD, and Theresa Lii, MD, MS

Cite as: Burson E, Lii T. Psychedelics and chronic pain: a trip worth taking. ASRA Pain Medicine News 2025;50. https://doi.org/10.52211/asra050125.009.

Introduction

Despite the variety of available analgesic therapies, many individuals with chronic pain remain inadequately treated. Psychedelics, which have been studied for psychiatric and end-of-life conditions, are increasingly being researched for chronic pain. This article provides a brief overview of commonly studied psychedelics and their potential implications in chronic pain management. Because ketamine is considered a non-classical psychedelic and its analgesic effects have been extensively explored elsewhere, it will not be discussed.

Commonly Studied Psychedelics

Lysergic Acid Diethylamide (LSD): Synthesized in 1938, LSD is a serotonergic hallucinogen producing perceptual changes, intensified emotions, and—at higher doses—ego dissolution. LSD is known for its prolonged duration of action, lasting 8-12 hours. Hallucinogenic doses (100-200 mcg) can relieve end-of-life anxiety and depression1,2 while sub-hallucinogenic doses (20 mcg) increase pain tolerance in healthy volunteers.3

Psilocybin: Derived from Psilocybe mushrooms, psilocybin can be synthesized or ingested in mushroom form. Psilocin is the psychoactive metabolite producing visual and emotional alterations lasting 4-6 hours. Synthetic psilocybin at sub-hallucinogenic doses (0.143 mg/kg) shows promise in treating cluster headaches and migraines4,5 while hallucinogenic doses (2-5.5 g of dried mushroom) were effective at treating a refractory case of complex regional pain syndrome.

Ayahuasca: Ayahuasca is a South American brew made from several plants that synergistically enable a psychedelic experience lasting 4-6 hours. Ayahuasca contains N, N-dimethyltryptamine, a serotonergic psychedelic not orally available unless ingested with plants containing monoamine oxidase inhibitors.7 The preparation varies widely among indigenous groups, making it difficult to standardize for research.

Salvia Divinorum: Native to Mexico, this hallucinogenic herb targets kappa-opioid receptors,8 causing brief, intense dissociative effects lasting 5-30 minutes. Its unique receptor profile makes it an intriguing, albeit short-acting, compound for study in pain modulation. Psychedelic effects from salvia occur with doses of 200-500 micrograms orally.9

Ibogaine: Derived from the West African iboga shrub, ibogaine produces an initial visionary “waking dream” state lasting 4-8 hours followed by 8-20 hours of introspection.10 It is studied primarily for substance use disorders at doses of 10-25mg/kg.11

3,4-methylenedioxymethamphetamine (MDMA): A synthetic, non-classical psychedelic related to amphetamines, MDMA enhances feelings of interpersonal connection and reduces fear. Therapeutic doses (40-120 mg) last 3-6 hours with recent research focusing on post-traumatic stress disorder (PTSD).12

Potential Mechanisms of Action

Multi-Receptor Pain Modulation: Classic psychedelics, such as LSD and psilocybin, activate serotonergic 5-HT2A receptors, which are involved in central and peripheral pain modulation.13 In mice, the antinociceptive effects of ayahuasca rely on GABAA and serotonergic signaling.14 Salvia’s analgesic properties are attributed to its activation of kappa opioid, serotonergic, and cannabinoid receptors8,15,16 while ibogaine’s analgesic effects may involve NMDA, kappa and mu-opioid, and sigma receptors.11 For MDMA, the analgesic effects appear to be mediated through serotonergic signaling17. MDMA also boosts oxytocin, a neuropeptide shown to modulate pain.18,19

Anti-inflammation: Activation of 5-HT2A receptors by classic psychedelics may produce an anti-inflammatory cascade via inhibition of tumor necrosis factor (TNF).13 Ayahuasca, salvia, and ibogaine may also induce anti-inflammatory effects by reducing pro-inflammatory cytokine production.20-23 Additionally, ibogaine increases the activity of antioxidant enzymes in human erythrocytes.24

Neuroplasticity: The brain activity of a resting person, known as the default mode network, is reorganized in chronic pain conditions due to persistent pain signaling.25 In rodent studies, psychedelics have been found to stimulate the production of neurotrophic factors, which promote the maintenance, repair, differentiation, synaptogenesis, and survival of neurons.26-28 Psychedelics could, therefore, disrupt the altered networks seen with pain and provide a window of opportunity to reverse central sensitization.13,29

Psychological Effects. Psychedelics can enhance mood and strengthen personal and social interconnectedness, which may mitigate pain-associated suffering. A functional MRI study showed that psilocybin alters blood flow in brain regions that are involved in pain perception and the emotional response to pain.30 The development of persistent pain causes a shift in brain activity from the posterior to the anterior insula cortex, mirroring the shift from nociception to pain perception.31 Thus, psychedelics may transform patients’ experience of pain.

Psychedelic research faces numerous challenges. The Schedule I status of psychedelics remains a significant barrier since securing approval from regulatory bodies can be time-consuming and costly.

Preliminary Evidence of Psychedelics’ Analgesic Effects

Cancer-Related Pain and Palliative Care. In 1964, researchers found that LSD provided superior analgesia to hydromorphone and meperidine after 3 hours in palliative patients.32 While recent trials of psilocybin-assisted therapy in advanced-cancer patients did not primarily evaluate pain, they reported significant, lasting reductions in anxiety, depression, and distress, which are key quality-of-life measures that predict chronic pain outcomes.33,34

Headaches. A case series of five patients found that a non-hallucinogenic LSD derivative can break a cluster headache cycle or considerably improve the frequency and intensity of attacks.35 In two recent double-blind, placebo-controlled, crossover trials for migraines and cluster headaches, participants receiving psilocybin experienced reduced headache frequency and severity.4,5

Fibromyalgia. Polymorphisms in the 5-HT2A receptor gene are linked to fibromyalgia susceptibility, suggesting a possible role for psychedelics in this population.36 In a survey of 354 fibromyalgia patients, 12 reported using psychedelics specifically to manage their pain with 11 of them reporting improvements in their symptoms.37

Phantom Limb Pain. Treatment of seven patients with phantom limb pain with 25-50 mcg of LSD daily for 3 weeks resulted in reduced pain and analgesic medication use.38 Additionally, a case report demonstrated that combining mirror therapy with psilocybin produced sustained pain relief for 3 weeks.39

Neuropathic Pain. Ibogaine shows potential in alleviating severe neuropathic pain as illustrated in a case report of a patient with brachial plexus nerve root avulsion, who experienced significant relief following high-dose inpatient and low-dose outpatient ibogaine treatment.28

Psychological Trauma-Associated Pain. Exploratory data from a phase 2 trial of MDMA-assisted psychotherapy for PTSD showed improved pain outcomes in MDMA recipients, suggesting potential applications in chronic pain.40

Safety

Visual hallucinations, headaches, nausea, dizziness, fatigue, transient anxiety and mood lability, and transient increases in blood pressure are often self-limited acute side effects.41,42 Overall, serious adverse events in psychedelic trials have been rare with none occurring in healthy participants and 4%, including suicidal behavior, psychosis, and convulsive episodes, occurring in participants with preexisting neuropsychiatric disorders.42 The apparent safety of psychedelics should be interpreted cautiously, as clinical trials often have strict selection criteria and thus poorly represent the general population.

Current Challenges

Psychedelic research faces numerous challenges. The Schedule I status of psychedelics remains a significant barrier since securing approval from regulatory bodies can be time-consuming and costly. Other challenges include the difficulty of blinding psychedelic treatments in clinical trials, which can result in heightened expectations and biased results. Psychedelic studies may also attract participants who hold unusually positive attitudes towards psychedelics. Additionally, the therapeutic alliance between participants and therapists can influence outcomes,43 which is especially problematic if therapists can guess which treatment was administered.

As psychedelics can alter consciousness, safeguards must prevent patient abuse during dosing sessions, a serious issue highlighted in recent industry-sponsored MDMA trials that led to the retractions of several papers.44 Additionally, psychedelic-assisted therapy is resource- and time-intensive, limiting accessibility. Psychedelic research and policies must also respect the cultural significance of psychedelics in indigenous traditions.43

Conclusion

Current evidence, albeit limited, suggests that psychedelics may be able to provide relief to individuals with chronic pain. More rigorous clinical trials are necessary to delineate their efficacy and safety and appropriately inform their use in evidence-based pain management. Patients interested in the therapeutic use of psychedelics should be encouraged to seek out clinical trials where patient selection prioritizes safety, and dosing occurs in a supervised setting.

Emily Burson, DO, RD, is an anesthesia resident CA-2 (PGY-3) in the department of anesthesiology and critical care medicine at Johns Hopkins University in Baltimore, MD.
Theresa Lii, MD, MS, is an instructor in the department of anesthesiology, perioperative and pain medicine at Stanford University School of Medicine in Palo Alto, CA.

References

  1. Gasser P, Holstein D, Michel Y, et al. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis 2014;202(7):513-20. http://doi.org/10.1097/NMD.0000000000000113
  2. Holze F, Gasser P, Müller F, et al. Lysergic acid diethylamide-assisted therapy in patients with anxiety with and without a life-threatening illness: a randomized, double-blind, placebo-controlled phase II study. Biol Psychiatry2023;93(3):215-23. http://doi.org/10.1016/j.biopsych.2022.08.025
  3. Ramaekers JG, Hutten N, Mason NL, et al. A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers. J Psychopharmacol 2021;35(4):398-405. http://doi.org/10.1177/0269881120940937
  4. Schindler EAD, Sewell RA, Gottschalk CH, et al. Exploratory controlled study of the migraine-suppressing effects of psilocybin. neurotherapeutics. J Psychopharmacol 2021;18(1):534-543. http://doi.org/10.1007/s13311-020-00962-y
  5. Schindler EAD, Sewell RA, Gottschalk CH, et al. Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: results from a randomized, double-blind, placebo-controlled trial. Headache 2022;62(10):1383-94. http://doi.org/10.1111/head.14420
  6. Jevotovsky DS, Chopra H, Pak DJ, et al. Psilocybin and chronic neuropathic pain: a systematic review. Reg Anesth Pain Med 2024;:rapm-2024-105532. http://doi.org/10.1136/rapm-2024-105532
  7. Frecska E, Bokor P, Winkelman M. The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization. Front Pharmacol 2016;7:35. http://doi.org/10.3389/fphar.2016.00035
  8. Simón-Arceo K, González-Trujano ME, Coffeen U, et al. Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia Divinorum in rats. J Ethnopharmacol 2017;206:115-24. http://doi.org/10.1016/j.jep.2017.05.016
  9. National Drug Intelligence Center. Southwest Region Drug Threat Assessment 2010. U.S. Department of Justice. https://www.justice.gov/archive/ndic/pubs40/40405/sw-saDiv031710p.pdf. Published March 7, 2010. Accessed October 10, 2024.
  10. Santos BA, Barrett B, Borges RM, et al. An integrative framework for understanding the role of resource specialization and spatial distribution of food resources for herbivorous insects. Journal of Plant Interactions 2016;11(1):1-10. https://doi.org/10.1556/2054.01.2016.001
  11. Corkery JM. Ibogaine as a treatment for substance misuse: potential benefits and practical dangers. Prog Brain Res 2018;242:217-57. http://doi.org/10.1016/bs.pbr.2018.08.005
  12. Mitchell JM, Ot’alora GM, Van Der Kolk B, et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med 2023;29(10):2473-80. http://doi.org/10.1038/s41591-023-02565-4
  13. Kooijman NI, Willegers T, Reuser A, et al. Are psychedelics the answer to chronic pain: a review of current literature. Pain Pract 2023;23(4):447-58. http://doi.org/10.1111/papr.13203
  14. Lauria PSS, de Medeiros Gomes J, Abreu LS, et al. Ayahuasca and its major component harmine promote antinociceptive effects in mouse models of acute and chronic pain. J Ethnopharmacol 2024;323:117710. http://doi.org/10.1016/j.jep.2024.117710
  15. Ortiz-Mendoza N, Zavala-Ocampo LM, Martínez-Gordillo MJ, et al. Antinociceptive and anxiolytic-like effects of a neo-clerodane diterpene from Salvia semiatrata aerial parts. Pharm Biol 2020;58(1):620-9. http://doi.org/10.1080/13880209.2020.1784235
  16. Coffeen U, Canseco-Alba A, Simón-Arceo K, et al. Salvinorin A reduces neuropathic nociception in the insular cortex of the rat. Eur J Pain 2018;22(2):311-8. http://doi.org/10.1002/ejp.1120
  17. Crisp T, Stafinsky JL, Boja JW, et al. The antinociceptive effects of 3,4-methylenedioxymethamphetamine (MDMA) in the rat. Pharmacol Biochem Behav 1989 Nov;34(3):497-501. http://doi.org/10.1016/0091-3057(89)90547-9
  18. Boll S, Ueltzhoeffer K, Roth C, et al. Pain-modulating effects of oxytocin in patients with chronic low back pain.Neuropharmacology 2020;171:108105. http://doi.org/10.1016/j.neuropharm.2020.108105
  19. Tracy LM, Georgiou-Karistianis N, Gibson SJ, et al. Oxytocin and the modulation of pain experience: implications for chronic pain management. Neurosci Biobehav Rev 2015;55:53-67. http://doi.org/10.1016/j.neubiorev.2015.04.013
  20. Galvão-Coelho NL, de Menezes Galvão AC, de Almeida RN, et al. Changes in inflammatory biomarkers are related to the antidepressant effects of ayahuasca. J Psychopharmacol 2020;34(10):1125-33. http://doi.org/10.1177/0269881120936486
  21. Santos BWL, Moreira DC, Borges TKDS, et al. Components of Banisteriopsis Caapi, a plant used in the preparation of the psychoactive ayahuasca, induce anti-inflammatory effects in microglial cells. Molecules2022;27(8):2500. http://doi.org/10.3390/molecules27082500
  22. Bhattacharya T, Gupta A, Gupta S, et al. Benzofuran Iboga-analogs modulate nociception and inflammation in an acute mouse pain model. Chembiochem 2024;25(16):e202400162. http://doi.org/10.1002/cbic.202400162
  23. Russo C, Edwards KD, Margetts G, et al. Effects of Salvia Officinalis L. and Chamaemelum Nobile (L.) extracts on inflammatory responses in two models of human cells: primary subcutaneous adipocytes and neuroblastoma cell line (SK-N-SH). J Ethnopharmacol 2021;268:113614. http://doi.org/10.1016/j.jep.2020.113614
  24. Nikolić-Kokić A, Oreščanin-Dušić Z, Spasojević I, et al. Ex vivo effects of ibogaine on the activity of antioxidative enzymes in human erythrocytes. J Ethnopharmacol 2015;164:64-70. http://doi.org/10.1016/j.jep.2015.01.037
  25. Baliki MN, Geha PY, Apkarian AV, et al. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci 2008;28(6):1398-1403. http://doi.org/10.1523/jneurosci.4123-07.2008
  26. Calder AE, Hasler G. Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023 Jan;48(1):104-12. http://doi.org/10.1038/s41386-022-01389-z
  27. Marton S, González B, Rodríguez-Bottero S, et al. Ibogaine administration modifies GDNF and BDNF expression in brain regions involved in mesocorticolimbic and nigral dopaminergic circuits. Front Pharmacol2019;10:193. http://doi.org/ 10.3389/fphar.2019.00193
  28. Dickinson JE, Inzunza JAD, Perez-Villa L, et al. Case report: ibogaine reduced severe neuropathic pain associated with a case of brachial plexus nerve root avulsion. Front Pain Res (Lausanne) 2023;4:1256396. http://doi.org/10.3389/fpain.2023.1256396
  29. Weleff J, Nunes JC, Costa GPA, et al. From taboo to treatment: the emergence of psychedelics in the management of pain and opioid use disorder. Br J Clin Pharmacol 2024:1-18. http://doi.org/10.1111/bcp.16045
  30. Carhart-Harris RL, Erritzoe D, Williams T, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci USA. 2012;109(6):2138-43. http://doi.org/10.1073/pnas.1119598109
  31. Whelan A, Johnson MI. Lysergic acid diethylamide and psilocybin for the management of patients with persistent pain: a potential role? Pain Manag 2018;8(3):217–29. http://doi.org/10.2217/pmt-2017-0068
  32. Kast EC, Collins VJ. Study of lysergic acid diethylamide as an analgesic agent. Anesth Analg 1964;43:285–91.
  33. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry 2011;68(1):71-8. http://doi.org/10.1001/archgenpsychiatry.2010.116
  34. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol 2016;30(12):1165-80. http://doi.org/10.1177/0269881116675512
  35. Karst M, Halpern JH, Bernateck M, et al. The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: an open, non-randomized case series. Cephalalgia 2010 Sep;30(9):1140-4. http://doi.org/10.1177/0333102410363490
  36. Bondy B, Spaeth M, Offenbaecher M. The T102C polymorphism of the 5-HT2A-receptor gene in fibromyalgia. Neurobiol Dis 1999;6(5):433-9. http://doi.org/10.1006/nbdi.1999.0262
  37. Glynos NG, Pierce J, Davis AK, et al. Knowledge, perceptions, and use of psychedelics among individuals with fibromyalgia. J Psychoactive Drugs 2023;55(1):73-84. http://doi.org/10.1080/02791072.2021.2022817
  38. Fanciullacci M, Bene ED, Franchi G, et al. Brief report: phantom limp pain: sub-hallucinogenic treatment with lysergic acid diethylamide (LSD-25). Headache 1977;17(3):118-9. http://doi.org/10.1111/j.1526-4610.1977.hed1703118.x
  39. Ramachandran V, Chunharas C, Marcus Z, et al. Relief from intractable phantom pain by combining psilocybin and mirror visual-feedback (MVF). Neurocase 2018;24(2):105-10. http://doi.org/10.1080/13554794.2018.1468469
  40. Christie D, Yazar-Klosinski B, Nosova E, et al. MDMA-assisted therapy is associated with a reduction in chronic pain among people with post-traumatic stress disorder. Front Psychiatry 2022;13:939302. http://doi.org/10.3389/fpsyt.2022.939302
  41. Yao Y, Guo D, Lu TS, et al. Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis. Psychiatry Res 2024;335:115886. http://doi.org/10.1016/j.psychres.2024.115886
  42. Hinkle JT, Graziosi M, Nayak SM, et al. Adverse events in studies of classic psychedelics: a systematic review and meta-analysis. JAMA Psychiatry 2024:e242546. http://doi.org/10.1001/jamapsychiatry.2024.2546
  43. Muthukumaraswamy S, Forsyth A, Sumner RL. The challenges ahead for psychedelic ‘medicine’. Aust N Z J Psychiatry 2022;56(11):1378-83.http://doi.org/10.1177/00048674221081763
  44. Jerome L, Feduccia AA, Wang JB, et al. Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology (Berl) 2020 Aug;237(8):2485-97. http://doi.org/10.1007/s00213-020-05548-2
  45. Cameron LP, Benetatos J, Lewis V, et al. Beyond the 5-HT2A receptor: classic and nonclassic targets in psychedelic drug action. J Neurosci 2023;43(45):7472-82. http://doi.org/10.1523/JNEUROSCI.1384-23.2023
  46. Guo R, Chen LH, Xing C, et al. Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Br J Anaesth 2019;123(5):637-54. http://doi.org/10.1016/j.bja.2019.07.026
  47. Minerbi A, Shen S. Gut microbiome in anesthesiology and pain medicine. Anesthesiology 2022;137(1):93-108. https://doi.org/10.1097/ALN.0000000000004204
  48. Inserra A, Giorgini G, Lacroix S, et al. Effects of repeated lysergic acid diethylamide (LSD) on the mouse brain endocannabinoidome and gut microbiome. Br J Pharmacol 2023;180(6):721-39. http://doi.org/10.1111/bph.15977
  49. Xu M, Kiss AJ, Jones JA,et al. Effect of Oral tryptamines on the gut microbiome of rats-a preliminary study. PeerJ 2024;12:e17517. http://doi.org/10.7717/peerj.17517
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