Using Psychedelics to Decrease Reliance of Opioids in Chronic Pain Management

RESEARCH ANALYSIS

Using Psychedelics to Decrease Reliance of Opioids in Chronic Pain Management

Mona Zhang

Temple University School of Podiatric Medicine

SUMMARY POINTS

-       The use of opioids for management of chronic pain has led to increased reliance and adverse risk factors.

-       Psychedelics such as psilocybin have been shown to treat depression, PTSD, and alcohol abuse disorders. However emerging research shows that these serotonergic agonists could act as therapeutic agents for chronic pain.

-       More research needs to be conducted to understand the correct dosage of psychedelic medication for optimal treatment of chronic pain, while limiting side effects such as hallucinations and visual alterations.

ANALYSIS

Background

Pain represents a pressing issue, particularly in the United States (1). Despite the well-researched adverse effects of prolonged opioid use, such as cardiac abnormalities, immune suppression, and accidental opioid overdose, Americans managing chronic pain continue to receive ongoing opioid prescriptions (1). While short-term opioid therapy is beneficial for acute injuries and post-surgical recovery, improper prescription management leads to significant harm. This contributes to a cycle where patients transition from short-term opioid use to long-term dependency and possible addiction (1). Additionally, chronic opioid use can trigger opioid-induced hyperalgesia (OIH), where opioid medications intended to alleviate pain lower pain thresholds (2). OIH then necessitates increasing opioid doses, creating a dependent cycle. Therefore, we need novel therapies with low-risk and low-side-effect profiles to fill that gap in treating chronic pain.

In recent years, there has been a resurgence of interest in psychedelics as potential therapeutic agents, particularly in chronic pain management. Historically marginalized and stigmatized, psychedelics like psilocybin (found in magic mushrooms) and Lysergic Acid Diethylamide (LSD) are now being reconsidered for their effects on pain reduction (3). They are psychoactive substances that alter mood, perception, and cognitive processing (3). Specifically, the classic hallucinogens, such as LSD and psilocybin, are Serotonin (5-HT2A) receptor agonists. Activation of 5-HT2A receptors is involved in inhibition of pain, particularly in peripherally (pro-inflammatory) and centrally (antinociceptive) mediated pain processing (4). Psychedelics acting on 5-HT receptors can induce antinociceptive properties immediately or cause long-term effects peripherally by decreasing the inflammatory response (5). Research suggests that psychedelics can modulate the brain's pain processing centers, leading to reduced pain intensity and improved pain tolerance, which represents a promising avenue in chronic pain management.

Figure 1: Mechanism of action for LSD and Psilocybin [Reprinted with permission from Psych Scene Hub (8)]

Figure 2: Routes of administration of psychedelics, specifically for LSD and Psilocybin. [Reprinted with permission from American Society of Anesthesiologists (4)]

Findings

Studies utilizing LSD and psilocybin have shown significant reductions in pain perception, with effects lasting beyond the acute psychedelic experience. From a combined literature review collecting data from across multiple clinical trials, the most popular route of administration of LSD and psilocybin was oral ingestion, and often small doses provided adequate analgesia (6). LSD doses ranged from 5 to 200 μg orally, and doses less than 50 μg were considered sub- hallucinogenic, meaning patients did not experience the characteristic “psychedelic trip” often associated with seeing hallucinations or other visual alterations (6). Psilocybin doses less than 0.5 grams were considered sub-hallucinogenic, and doses between 2-3 grams were defined as hallucinogenic (6).

Figure 3: Most common pain states studied with psychedelics as the treatment agent [Reprinted with permission from American Society of Anesthesiologists (4)]

Multiple clinical trials and observational studies have also evaluated the efficacy of psychedelics for various pain states. As shown in Figure 3, the most frequent diagnoses were migraines/headaches, followed by phantom limb pain (6). For migraines and headaches, a survey of 53 participants who consumed sub-hallucinogenic doses of LSD and/or psilocybin found that 22 out of 26 psilocybin users reported a decrease in headache frequency, and 4 out of 5 LSD users reported reduced headache recurrence (7). To mitigate the hallucinogenic properties and address the Schedule I drug classification of psychedelics, 2-Bromo-LSD was developed. This modified compound lacks hallucinogenic properties (7). Participants ingested 30 μg/kg of 2-Bromo-LSD every five days, for a total of three single doses, which reportedly decreased headache frequency and intensity (7).

In cases of phantom limb pain, three case studies reported that micro-doses (less than 50 μg) of LSD and macro-doses (2-3g) of psilocybin decreased the intensity of phantom limb pain, sustained pain relief, increased sensation in the affected limb, and reduced recurrence of pain (7). Patients with phantom limb pain often use mirror therapy, in which a mirror is placed in the midsagittal plane and the patient observes the reflection of the non-amputated limb, mimicking the movement of the amputated limb to alleviate pain (7). It was found that the use of psilocybin in conjunction with mirror therapy resulted in amplified pain relief, showing potential for the synergistic use of psychedelics (7).

Regarding fibromyalgia, limited pathophysiological understanding has resulted in few studies investigating psychedelics as a treatment. However, an anonymous survey of 354 participants found that 29.9% had previously used psychedelics; 59.9% were neutral about trying them for fibromyalgia; 36.8% had a positive perception of their use; and fewer than 3% opposed the idea (7). Out of 12 participants who had used psychedelics to manage their pain, 11 noted improvement (7). Most patients were willing to participate in future clinical trials to assess the efficacy of psychedelics for the treatment of fibromyalgia.

Considering the side effects of psychedelics, they appear to have a more favorable safety profile compared to opioids. Specifically, psychedelics have less potential for physiological dependence, addiction, and tolerance (5). However, with frequent use, psychedelics do have the potential to disrupt daily function through acute reactions known as “bad trips,” which include panic attacks, anxiety, or paranoia (6). While rare in controlled settings, such events can pose risks if dosing is incorrect (6). Additional studies are needed to establish safe and effective dosing protocols that minimize side effects.

Discussion

While the potential benefits of psychedelics in pain management are promising, it is important to note that research in this area is still emerging, and more clinical trials are needed to establish safety, efficacy, and optimal dosing protocols. Additionally, psychedelics are potent substances that require controlled administration due to their potential for inducing altered states of consciousness. Psychedelics are classified as a Schedule I drug, and bringing this class of drugs into clinical practice will be a challenge due to the social stigma. However, under the Controlled Substances Act, practitioners with special Drug Enforcement Administration clearance could conduct experiments with Schedule I drugs, which may be an avenue for researchers to explore in the future. Psychedelics may manage pain through serotonin receptor activity, anti-inflammatory properties, and psychological effects. Continued research is essential to determine their mechanisms, safety, and potential integration into chronic pain treatment.

REFERENCES

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7.     Robinson C, Fonseca A, Diejomaoh E, et al. Scoping review: The role of psychedelics in the management of chronic pain. Journal of Pain Research. 2024;Volume 17:965-973. doi:10.2147/jpr.s439348

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