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Psychedelics: A Notable Absence in Chronic Pain Management?

Psychedelics have experienced an increase in research interest, particularly in mental health, during the past decade. Despite promising results on the positive impact of psychedelics for chronic pain management, research in this context has been slow.

By Catherine Paré

30 September 2022

PRF News


Psychedelics have experienced an increase in research interest, particularly in mental health, during the past decade. Despite promising results on the positive impact of psychedelics for chronic pain management, research in this context has been slow.

The chronic pain crisis in North America persists and continues to be exacerbated by the opioid epidemic. As such, there is a great need for new and efficacious treatments for chronic pain. Following a 60-year hiatus, there is one such potential pain management therapeutic that is prime for investigation: psychedelics.


Psychedelics, also known as hallucinogens, are a group of psychoactive substances that reliably and significantly alter perception, mood, and/or cognition. Psychedelics can be naturally occurring, such as psilocybin (“magic mushrooms”), or synthesized, such as LSD (lysergic acid diethylamide, or “acid”) and MDMA (a derivative of amphetamine, also known as “ecstasy”). The effects of these substances vary widely and can manifest psychologically with altered perceptions such as the distortion of time, enhanced self-awareness, visual hallucinations, and loss of self-awareness. The mechanistic actions of psychedelics also vary widely, as will be discussed shortly.


Historically, psychedelics have been used by a variety of cultures, often for sacred or religious ceremonies. In the Western world, research investigating the therapeutic viability of psychedelics began in the mid-1940s and lasted until the late 1970s. During this time, empirical research was largely conducted on the effects of LSD and psilocybin for patients with mental health issues such as substance use disorder, depression, wartime stress reactions, and schizophrenia. Researchers, the pharmaceutical industry, and the general population viewed the safety, potency, and efficacy of LSD especially as promising for the treatment of chronic mental health conditions.


Although this early research on psychedelics focused on mental health disorders, some researchers hypothesized a potential role for LSD as a treatment for pain. Early research suggested that LSD might have analgesic properties, and researchers began to conduct empirical studies on its utility for treating specific pain conditions such as cluster headaches, phantom limb pain, and cancer pain. However, this research came to a grinding halt following the enactment of the Comprehensive Drug Abuse Prevention and Control Act of 1970 in the US, a political response to the growing associations between psychedelics and the counterculture movement in the United States. As a result, psychedelics were classified as serving no medical purpose, dangerous, and easy to abuse. The ensuing regulations meant that psychedelics research became incredibly difficult to conduct.


The restitution of psychedelics research

This lapse in research lasted until the 1990s, when researchers renewed their interest in understanding the mechanisms of psychedelics. Interest has grown exponentially since then – a brief literature search reveals an explosion of studies published in the last five years. These studies involve rigorous clinical trials and systematic reviews on the effects of psychedelics (mainly LSD, psilocybin, ayahuasca [a psychoactive South American tea made from plant stalks and leaves], and MDMA) on mental health conditions such as depression, post-traumatic stress disorder (PTSD), anxiety, and substance use disorders.


Most of these clinical trials have shown that when psychedelics (such as LSD, psilocybin, MDMA, and ayahuasca) are taken in a single dose and in conjunction with therapy (also known as psychedelic-assisted psychotherapy, or PAP), they can successfully improve mental health and functioning, both short and long term (Kristoffer et al., 2020Griffiths et al., 2016Hoskins et al., 2021Rodrigues et al., 2021). However, the mechanisms of change resulting in these improved outcomes (whether related to the substance, the therapy, a combination of both, or another, unidentified factor) remain debated and unclear.


The resurgence of interest in psychedelics and pain

Although research involving psychedelics for the treatment of mental health conditions has become increasingly popular over the past two decades, this same enthusiasm has not been seen in the context of pain. There is one chronic pain condition, however, garnering attention within psychedelics research: headaches (i.e., cluster headaches, migraines). Headache patients have reported the successful use of psychedelics such as psilocybin, LSD, and cannabis in treating their condition both proactively and abortively. Case studies and informal surveys have been used to demonstrate the anecdotal success of these substances and led to a substantial increase in empirical clinical trials in recent years. These studies have revealed that a significant number of patients with cluster headaches or migraines are dissatisfied with current treatments and that, for many, psychedelics were a source of significant, long-term pain relief (Andersson et al., 2017Johnson and Black, 2020Schindler et al., 2015). Most recently, a double-blinded, placebo-controlled study explored the effects of a single, low dose (i.e., sub-hallucinogenic) of psilocybin on migraines and found that pain reduction was significantly greater for the treatment group versus placebo (Schindler et al., 2021).


Interestingly, there are also studies on the impact of psychedelics on pain perception in participants without chronic pain. A 2011 study explored the impact of long-term MDMA use on pain perception in abstinent MDMA users, compared to age-matched controls (McCann et al., 2011). MDMA is known to damage serotonin neurons in the brain, which are involved in pain modulation. The study found that abstinent MDMA users were more likely to experience heightened pain, and sooner, in comparison to controls undergoing psychophysical pain procedures. Conversely, a 2021 study by Ramaekers et al. found that a sub-hallucinogenic dose of LSD administered to healthy volunteers increased their tolerance of exposure to cold and reduced perceived pain intensity. Very low doses, as well as placebo, did not alter pain perception.


Exploring the mechanisms of action of psychedelics

These findings beg the questions – how might psychedelics be impacting pain, and do they represent a viable treatment mechanism? Different psychedelics work in different ways and have not been researched equally. Classic psychedelics, such as LSD and psilocybin, work on the serotonergic system. LSD has been found to impact the 5-HT (serotonin) receptors in addition to dopamine (D2) and some amine-related receptors. Psilocybin interacts with 5-HT receptors and decreases activity in the default-mode network, thalamus, and anterior cingulate cortex.


Research on psychedelics and pain has focused on the serotonergic system as the primary mechanism of action. In a 2020 review of the existing literature on psychedelics and pain, Castellanos and colleagues suggested that psychedelics might impact chronic pain through activation of the serotonin 5-HT2A receptor, in turn modulating gene effects, inflammation, and brain functional connectivity (Castellanos et al., 2020). In fact, ergot alkaloids are common for treating cluster headaches, and these substances are thought to act on the serotonergic system similarly to LSD, an ergot alkaloid derivative.


On the other hand, Devon Christie – a medical doctor and psychotherapist specializing in chronic pain and psychedelics at Numinus Wellness Inc. – describes the mechanisms of MDMA as related to the “[downregulation of] the fear response [as well as] fear-based memory reconsolidation.” In contrast, during a PAP session using, “a classical psychedelic like psilocybin, people may spend a lot of that session [internally], not communicating a lot. MDMA [is] more [of a] relational medicine, [so] there’s going to be more interaction with the therapists that are present,” describes Christie.


MDMA is the first psychedelic whose treatment potential was recognized at the federal level in the United States. In 2017, MDMA-assisted psychotherapy was granted Breakthrough Therapy Designation by the Food and Drug Administration for the treatment of PTSD. Interestingly, a recent study conducted by Christie and her team unexpectedly found that patients with high levels of pain who underwent MDMA-assisted psychotherapy for PTSD also experienced significant reductions in their pain ratings.


Another possible mechanism through which psychedelics may have an impact on pain is by affecting or altering the pain experience. In the past 30 years, the biopsychosocial model of pain has become the primary lens through which chronic pain is understood, and the role of psychological distress and psychosocial factors – such as pain catastrophizing and kinesiophobia (the fear of pain during movement) – in the persistence of chronic pain has become undeniable. Christie posits that psychedelics, “have the potential to [impact pain by] addressing these variables that aren’t necessarily the physical experience of nociception [but rather work] around the complex ways that we process pain, [which leads to] the experience of pain and its impact on our lives.” Similarly, Fadel Zeidan, an associate professor at the University of California, San Diego, US, explains that “research points to a reduction of dysphoria, even with a smaller dose of a psychedelic that doesn’t produce a fully realized psychedelic experience.”


This hypothesis is supported by a recent interview-based qualitative study of people self-medicating with psychedelics to manage their chronic pain (Bornemann et al., 2021). The study suggested that pain reduction during and after a psychedelic experience occurred in two manners. First, participants in the study reported that psychedelics helped them shift their negative, pain-related experiences (i.e., depression, pain catastrophizing, anxiety, etc.) toward more positive, accepting, and empowering perspectives. Second, participants in the study were impacted on a somatic level during and following the use of psychedelics. Although the process varied on an individual level, most participants reported experiencing less pain-related disability, then less pain, and finally improved functioning.


Expanding on the findings from the study by Bornemann and colleagues, Christie and Zeidan both believe that psychedelics’ most novel impact might lie with their neuropsychological impact. “Developing chronic pain is a process of neuroplastic changes, [such as] central sensitization, and what might be promising is the ability of a psychedelic – [through] its neurobiological effect – to enhance plasticity and help shape new wiring in the direction that [will] support healing from chronic pain, as opposed to reinforcing the neuroplastic changes that are contributing to chronic pain,” offered Christie.


This might look different for different psychedelics. Zeidan describes that psilocybin might impact chronic pain by creating “a cataclysmic shift in self-referential processing, [meaning how we relate to and identify with ourselves], as it [pertains] to the ascending aberrant sensory input.” This shift could change the way someone with chronic pain experiences their body and their pain. Zeidan believes that “the greater the decoupling between sensory and self-referential processing, the greater the analgesia in the suffering – [as opposed to the] sensory – category of chronic pain.” Simply put, the less we feel “stuck” to the experiences of our bodies, the more pain relief we can experience.


These neuroplastic changes might occur on a more relational level in the context of MDMA. “There’s data supporting the possibility that MDMA opens a critical window [of] neuroplasticity related to social learning,” commented Christie. This is crucial, as many people living with chronic pain have experienced challenges or adversity in their early life. According to Christie, our “neural architecture for self, emotional, and nervous system regulation is absolutely dependent on our early [childhood] experiences because people [need] a safe home to experience their full spectrum of emotions [and develop] social engagement systems that are healthy and robust. [These changes in neural architecture] underlie vulnerability across a range of chronic illness, including chronic pain…. With MDMA-assisted [psycho]therapy, healing relates to [experiencing the] emotional and relational safety that [was] missing during critical periods of development.”



The added complication of dosing

Although the mechanisms of action of psychedelics are still hotly debated, an important factor in understanding the way that psychedelics might help treat or manage chronic pain depends on the dose of the psychedelic. According to Christie, there are two ways that psychedelics might be used in the context of chronic pain: macrodoses, or doses that would bring about the hallucinogenic effects of the psychedelic, or microdoses, more comparable to the routine intake of medication.


As previously mentioned, many clinical trials of psychedelics are conducted using PAP, an established form of psychotherapy for which guidelines and extensive trainings exist. During PAP, a patient participates in several preparatory therapy sessions prior to one extensive (sometimes up to eight hours) session, in which the patient uses a large enough dose of the psychedelic substance to create a hallucinogenic experience (i.e., macrodose) while accompanied by one or two psychotherapists. This extensive session is then followed by several debriefing therapy sessions. In a survey of patients self-medicating cluster headaches using classic hallucinogens (i.e., psilocybin and LSD), 31/53 participants found macrodoses of the psychedelic to be effective for treating cluster headaches (Sewell et al., 2006). In these cases, it seems that the treatment potential of PAP and macrodosing psychedelics might be more closely related to more biopsychosocial mechanisms of action, such as impacting self-referential processing or relational experiences.


It remains unclear, however, whether the hallucinogenic or mind-altering effects of psychedelics are necessary for modulating pain perception or treating chronic pain. An early study on LSD and phantom limb pain used sub-hallucinogenic doses of LSD and found that five of seven patients experienced significant reductions in pain (the other two patients experienced no changes in pain severity) (Fanciullacci et al., 1977). A more recent study conducted in 2010 showed that a non-hallucinogenic formulation of LSD was successfully implemented as a preventative treatment for cluster headaches (Karst et al., 2010). In the case of classic psychedelics, Zeidan offers that, “a smaller dose [could] release serotonin, [which] could elicit pain relief.”


Indeed, the use of low (micro) doses of psychedelics has been endorsed by many people self-medicating their chronic pain using psychedelics (Andersson et al., 2017). In fact, two relatively common substances for treating chronic pain, gabapentin and ketamine, both have psychedelic properties when administered in high doses (i.e., higher than current pain treatment guidelines suggest). However, a recent survey of more than 400 individuals with mental health and/or chronic pain conditions self-medicating with microdoses of psychedelics found that, for chronic pain conditions, no difference in self-reported treatment effectiveness was found between micro- and macrodoses (Hutten et al., 2019). Christie advises that, “we actually have minimal evidence on microdosing, in general, for anything right now … there’s some [survey data] … but they’re not placebo-controlled,” a position which has been corroborated in a recent systematic review of classic serotonergic psychedelics ((Kristoffer et al., 2020).


Should we be concerned?

Whereas some researchers have enthusiastically embraced a scientifically rigorous exploration of psychedelics, others remain hesitant. Taif Mukhdomi, a clinical fellow based in New York City and now practicing in Columbus, Ohio, US, is concerned, and consequently wrote an opinion piece in response to the Castellanos et al. review from 2020 about the pain community’s recent interest in the use of psychedelics for the management of chronic pain. Mukhdomi commented that when he, “read[s] about psychedelics … it reminds [him] … of the [start of] opioid[s] … where this brand-new drug … was able to cure everything, people were not in pain anymore, [where healthcare policy and professionals] started increasing [the] dosing of [opioids] and not really understanding the long-term effects.”


Crucial along this line of thought is another important point made by Mukhdomi – who will “take the reins” when it comes to the clinicians who will be primarily responsible for being the experts on psychedelics for chronic pain management? Mukhdomi also relates this question back to the opioid epidemic, where all physicians could prescribe opioids. It was only once an epidemic had taken hold that pain physicians became the experts on prescribing opioids.


Mukhdomi also worries about the potential for addiction with psychedelics, particularly regarding dosing and psychoactive effects. Although classic psychedelics have virtually no addictive potential, some psychedelics being explored as treatments for chronic pain do, such as MDMA. However, as Zeidan puts it, “we [already] study much more noxious [and] harmful products,” including some with addictive potential. Indeed, there is a rich history of the medical use of substances which are now illegal in many parts of the world, such as cocaine, for pain relief. On the other hand, the rigorous study of psychedelics is limited by legality in most countries.


Where to go from here?

Given the research conducted to date, experts in the field of psychedelics seem to think there is already sufficient empirical support for the theoretical use of psychedelics for pain treatment and management. However, while the mechanisms of action through which psychedelics impact chronic pain are becoming better understood, it does not mean they are a viable treatment option yet. “I also hope that [psychedelics are] useful, not just theoretically but also in practice,” states Julia Bornemann, a PhD candidate at Imperial College London, UK, who published the previously referenced 2021 qualitative study.


According to Bornemann, “[research on psychedelics and chronic pain] will be a really interesting way to reassess our assumptions about mind and body.” Like mindfulness, a topic which has experienced increasing popularity over the past decade, psychedelics bridge our long-held notions of Cartesian dualism, or the presumed separation between mind and body, which are reflected in biomedical treatments of chronic pain. As Zeidan describes it, “the moment-to-moment experience [of living with chronic pain] is contaminated by the self-pain relationship,” meaning there is an inherent connection between the mind and body which deserves further theoretical and empirical exploration.


However, all the researchers and clinicians spoken to for this piece had the same concluding thought – more research is needed, preferably gold standard, randomized, and blinded clinical trials where possible, to determine the extent of the relevance of psychedelics as a treatment for chronic pain. “Very simply, we need human placebo-controlled clinical trials to appreciate if and how psychedelics can modulate more central pain versus more peripheral pain,” or what pain conditions psychedelics may be relevant for, commented Zeidan. Notably, it will also be important to study the less serious side effects and the long-term effects of psychedelics, according to Mukhdomi, as these often garner less attention than more prominent consequences such as death or severe illness.


Additional research will be crucial, given the continued dissatisfaction of pain treatments for those living with chronic pain (Elman et al., 2022). As Zeidan puts it, “I don’t think any of the techniques that we study, especially when considering the complex nature of pain, are a silver bullet. There’s such a wide-ranging spectrum of pain conditions, [in combination] with interindividual variability of [how] people respond to pain [and their] genetics. It’s such a complicated, multimodal problem that it requires a multimodal solution.”


Psychedelics hold a lot of promise, but we also need to learn from past mistakes. Rigorous, high-quality studies combined with continued exploration of the mechanisms of action of psychedelics will help ensure that psychedelics continue to help, but not harm, people living with chronic pain.


Catherine Paré is a PhD candidate at McGill University, Montreal, Canada. Follow her on Twitter – @ImCatherinePare


Featured image:

The chemical structure of lysergic acid diethylamide (LSD)

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