Background & Aims

There are over 40 million amputees in the world with approximately 80% reporting phantom limb pain. There is no cure for chronic phantom limb pain (1). Preliminary evidence demonstrates that psychedelics have the potential to alleviate depression, addiction, and pain (2-5). In particular, psilocybin has been found to target default mode network (DMN) and somatosensory circuitry supporting self-referential processing (6, 7). We predict that psilocybin may be particularly efficacious at modulating centralized pain conditions, such as phantom limb pain. To date, there are no placebo-controlled neuroimaging studies that have examined the effects and neural mechanisms supporting psilocybin-induced phantom limb pain relief. The proposed pilot study employed a randomized, double-blinded (NCT05224336) design and combined functional magnetic resonance imaging (fMRI) with psychophysical pain testing in response to high dose psilocybin (n=5) versus niacin (n=5) in chronic phantom limb pain.

Methods

The targeted sample size for the pilot study is 10 individuals diagnosed with phantom limb pain [?3/10; visual analog scale (VAS)]. To date, 8 participants completed the study (anticipated completion date = March 1, 2024). At baseline, noxious heat (eight, 10s plateaus of 46/48°C; calf) was administered during fMRI. Self-reported phantom limb pain (VAS: 0 = “no pain sensation”; 10 = “most intense pain imaginable”) and chronic pain [McGill Pain Questionnaire (MPQ)] was also assessed. After baseline testing, volunteers participated in three psilocybin-focused preparatory sessions. On a subsequent day, participants were administered 25 mg of psilocybin or 100 mg niacin orally. At the post-intervention MRI session, we performed the same methods as in the baseline session. A 2 (group) X 2 (pre vs. post intervention) ANOVA will test hypotheses that psilocybin reduces self-reported phantom pain, noxious heat-induced pain, and DMN connectivity when compared to niacin, respectively.

Results

For the present abstract, paired samples t-tests were performed across all participants and groups (n = 8). Phantom limb pain intensity [-84%, t(7) = 2.29, p = .06, d = .81] and MPQ [-50%, t(7) = 3.69, p = .008, d = 1.30] ratings were reduced post-intervention when compared to baseline. There were no significant differences from baseline to post-intervention in VAS pain intensity ratings in response to 46°C (p = .19) or 48°C (p = .69) heat stimulation. Unblinded between group hypothesis tests will be presented at the World Congress of Pain.

Conclusions

A significant reduction in phantom pain was revealed across all participants. Upon unblinding, we expect that psilocybin, when compared to niacin, will be associated with significant reductions in pain and weaker DMN activation. These pilot findings will provide preliminary evidence for whether psilocybin is a plausible therapy for chronic phantom limb pain.

References

1.Ephraim, P. L., et al. Phantom pain, residual limb pain, and back pain in amputees: results of a national survey. Arch. Phys. Med. Rehabil. 86, 1910-9 (2005).
2.Carhart-Harris, R. et al. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med 384, 1402-1411 (2021).
3.Johnson, M. W., et al. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharm. 28, 983-992 (2014).
4.Kuromaru, S. et al. The effect of LSD on the phantom limb phenomenon. J Lancet 87, 22-27 (1967).
5.Ramachandran, V., et al. Relief from intractable phantom pain by combining psilocybin and mirror visual-feedback (MVF). Neurocase 24, 105-110 (2018).
6.Carhart-Harris, R., et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep 7, 13187 (2017).
7.Makin, T. R. et al. Network-level reorganisation of functional connectivity following arm amputation. Neuroimage 114, 217-225 (2015).

Presenting Author

Jon G Dean

Poster Authors

Jon Dean

PhD

University of California, San Diego

Lead Author

Ethan Hurwitz

MA

Lead Author

Daniel Barrows

BS

Lead Author

Arwynn Mckinty

BS

Lead Author

Briana Farrell

BS

Lead Author

Joel Castellanos

MD

Lead Author

Timothy Furnish

MD

Lead Author

Patrick Coleman

MFA

Lead Author

Cassandra Vieten

PhD

Lead Author

Gabriel Riegner

BS

Lead Author

Lora Khatib

BS

Lead Author

Stephanie Knatz

PhD

Lead Author

Julie Trim

PhD

Lead Author

Elowyn Samadhi

PhD

Lead Author

Gordon Renwick

PhD

Lead Author

Robert Mudge

MA

Lead Author

Albert Lin

PhD

Lead Author

Mark Geyer

PhD

Lead Author

Adam Halberstadt

PhD

Lead Author

Fadel Zeidan

UC San Diego

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Pain in Amputees