Discussion
CRPS is notoriously challenging to manage, with a substantial need for alternative long-term management strategies, particularly for cases unresponsive to conservative management. It is estimated that 10–20% of patients with CRPS, specifically those with pain confined to the distal extremities, can have pain refractory to both spinal cord stimulation (SCS) and conservative management (10). The urgency for new treatments is underscored by the limitations of existing therapies.
A recent case series from 2023 reported one successful instance of CRPS treated with psilocybin, where a patient with five years of CRPS pain, averaging a baseline pain score of 5 out of 10, experienced significant relief using 500 milligrams microdoses of psilocybin-containing mushrooms daily for 7-10 days, followed by a rest period of 2-3 days to avoid gastrointestinal side effects and rebound pain or withdrawal (11). Each dose provided approximately 80% pain relief for 3-4 hours, which gradually returned to baseline over 12 hours. This regimen yielded sustained pain relief, which was maintained at the 1-year follow-up, emphasizing the potential role of psilocybin in CRPS management. Notably, no other reports in the literature were identified.
The present case reinforces the need to better understand psilocybin’s role in managing CRPS. The mechanisms by which psychedelics could improve CRPS symptoms are not fully understood. Psilocybin’s serotonergic effects, particularly through serotonin 2a receptor agonism, are believed to contribute to its anti-nociceptive properties (9). However, more research is needed to elucidate these mechanisms and determine the most effective dosing strategies.
In comparing dosing regimens, the patient in the previously published Lyes et al. case utilized microdoses, while the current case involved full doses spanning 2 grams to 5.5 grams. The decision between microdosing and taking full doses should consider the balance between transient side effects and the frequency of administration. Lyes et al. reported that the patient initially consumed 2 grams of dried psilocybin mushrooms, resulting in 18 hours of pain remission but also significant psychotropic, audiovisual, and cognitive changes (11). This experience prompted the patient to switch to a microdosing regimen that eliminated psychotropic effects but provided only 80% pain relief (11).
Microdosing may minimize side effects but may require more frequent dosing, while full doses could potentially offer longer-lasting relief with less frequent administration but may cause more pronounced side effects. As research on psilocybin for CRPS expands, special attention should be given to creating population-specific dosing guidelines. Interestingly, many of the higher quality studies on psilocybin utilize a dose of 0.14 milligrams per kilogram (12, 13). However, it is important to consider that these studies focus on headache and migraine populations, not CRPS.
Psilocybin is not FDA-approved and is classified as a Schedule I drug under the Controlled Substances Act, indicating their lack of acceptance for medical use and high abuse potentials (14). Nonetheless, the FDA and several local and state governments are moving toward allowing the use of psilocybin under controlled conditions. This regulatory landscape underscores the importance of continued research into the safety and efficacy of psilocybin for medical purposes. Recent evidence increasingly supports the use of psychedelics including psilocybin for the treatment of chronic pain syndromes (9, 15). As research in this field continues to expand, there is a need for more robust studies with larger sample sizes and protocols designed to reduce bias.
Adjunctive therapies are crucial in managing CRPS, especially since patients often exhibit decreased tactile-spatial processing (16). Functional restoration training activates pre-sensorimotor cortices, progresses to gentle active movements, and culminates in weight-bearing activities (8). Gradual desensitization to sensory stimuli is linked to increased function (17). In this case, neuromechanical techniques, neurovisual modulation, and tactile reprocessing were used alongside psilocybin treatment. These therapies target different aspects of CRPS’s complex pathophysiology and are included in the CRPS Treatment Guidelines. This is the third known case demonstrating the synergistic effects of psilocybin and adjunctive therapies in treating various chronic pain conditions (11, 18). More research is warranted to explore the effect of psilocybin with and without adjunctive reprocessing therapies.
Despite the promising outcomes observed in this case, several limitations must be acknowledged. The generalizability of the findings is limited due to the case report’s nature. Additionally, the lack of blinding and randomization in this context poses a challenge to establishing causality and determining the full extent of psilocybin’s therapeutic potential for CRPS.
In conclusion, this case report highlights the potential of psilocybin as a treatment for CRPS and underscores the need for further research to explore its efficacy, safety, and mechanisms of action. The promising results observed in this case and the 2023 case series suggest that psilocybin could represent a valuable addition to the existing treatment options for CRPS, particularly for patients who have not responded to conventional therapies. As the regulatory landscape evolves, it will be critical to conduct well-designed clinical trials to fully understand the therapeutic potential of psilocybin for CRPS and other chronic pain conditions.
Figure 1. Timeline and corresponding treatments from onset of leg pain to resolution of symptoms.