Analgesic potential of macrodoses and microdoses of classical psychedelics in chronic pain sufferers: a population survey

This survey (n=250) finds that those suffering from chronic pain use, who have used psychedelics, find the most benefit from macrodoses (above that of opioids), though they also still experience (partial) pain relief by microdosing (classical) psychedelics.

Abstract

“Although several studies and reports have shown the potential analgesic use of serotonergic psychedelics in cancer pain, phantom limb pain and cluster headache, evidence supporting their use for chronic pain is still limited. The past years have seen a considerable renewal of interest toward the therapeutic use of these compounds for mood disorders, resulting in a marked increase in the number of people turning to psychedelics in an attempt to self-medicate a health condition or improve their wellbeing. In western countries particularly, this population of users overlaps substantially with chronic pain sufferers, representing a unique opportunity to evaluate the effects these compounds have on pain and wellbeing. Here, we report results from an online survey conducted between August 2020 and July 2021 in a population of 250 chronic pain sufferers who had experience with psychedelics, either in microdoses (small sub-hallucinogenic doses), macrodoses (hallucinogenic doses), or both. Macrodoses, while less often used for analgesic purposes than microdoses, were reported to induce a higher level of pain relief than both microdoses and conventional pain medications (including opioids and cannabis). Although the effects were weaker and potentially more prone to expectation bias than with macrodoses, our results also suggested some benefits of psychedelics in microdoses for pain management. The reported analgesic effect appeared unrelated to mood improvements associated with psychedelic use, or the advocacy of psychedelic use. Taken together, our findings indicate interesting potential analgesic applications for psychedelics that warrant further clinical research.”

Authors: Valerie Bonnelle, Will J. Smith, Natasha L. Mason, Mauro Cavarra, Pamela Kryskow, Kim P. C. Kuypers, Johannes G. Ramaekers & Amanda Feilding

Summary

Analgesic potential of macrodoses and microdoses of classical psychedelics in chronic pain sufferers: a population survey

Although several studies have shown the potential analgesic use of serotonergic psychedelics in cancer pain, phantom limb pain and cluster headache, evidence supporting their use for chronic pain is still limited. A survey of 250 chronic pain sufferers found some benefits of psychedelics in microdoses for pain management.

Introduction

Worldwide, the burden caused by chronic pain is escalating. Ketamine, an antagonist of the N-methyl-D-aspartate receptor, has been used as an analgesic in emergency medicine, as an adjuvant drug in the perioperative setting and as a third-line adjuvant drug for opioid-resistant pain in palliative care and for intractable chronic non-cancer pain.

Ketamine shares some of its effects and mechanisms of action with a class of compounds considered to be one of the safest known classes of CNS drugs: the ‘classic’ serotonergic hallucinogens (psychedelics). These compounds have also shown encouraging analgesic potential, particularly for cancer pain and cluster headache.

A recent double-blind study found that LSD increased pain tolerance and decreased painfulness as well as unpleasantness in healthy volunteers using a Cold Pressor Test.

Psychedelics can exert beneficial effects on chronic pain, but the mechanism of action is poorly understood. We surveyed individuals suffering from chronic pain and compared the analgesic effects of psychedelics to more traditional pain management options.

Design

Participants were recruited online via social media and the Beckley Foundation Web site. They had to be adult (over 18 years old) chronic pain sufferers.

Questionnaire

Respondents were asked whether they had used psychedelic substances in the past, which compound they had the most experience with, what dosing best typified their use, and how long they had been using psychedelics for.

Four items were used to assess the individual’s relationship with psychedelic drugs: active advocate, advanced knowledge, and highly experienced user.

Participants were asked to specify the nature of the pain conditions they were suffering from and to rate the severity of the pain on a scale of 0 – 10.

Perceived effectiveness of psychedelics was assessed by asking respondents to separately report their experiences with both types of dosages.

Respondents were asked if they had noticed a change in pain perception during or after taking a psychedelic. If so, they were asked to report the change in pain perception.

The respondent found most effective psychedelic for pain relief in pain intensity, pain acceptance, pain interference with daily activities and pain-induced emotional distress.

To compare the effects of cannabis compound to that of conventional pain medication, and to determine the extent of psychoactive effects.

To gain a better insight into the relationship between psychoactive effects and analgesia, respondents were asked to describe the effects experienced with the psychedelic compound associated with the most pain relief.

Statistical analysis

A questionnaire was administered to a group of people suffering from chronic pain. The results showed that psychedelics were as effective as conventional pain medication in relieving pain.

SPSS’s Automatic Linear Modelling (LINEAR) was performed to evaluate the contributions of several factors to reported pain relief scores.

Psychedelics use

In our sample, psilocybin was the most frequently used psychedelic for macrodosing and microdosing, followed by LSD.

Self-reported pain conditions

Respondents reported suffering from more than one pain-inducing condition.

Perception of pain relief effectiveness with conventional medication

The frequency and perceived pain relief associated with conventional medications used were over-the-counter (OTC) medications/NSAIDs, opioids, cannabis, anticonvulsants, antidepressants, triptans/migraine medication, and ‘other’. Some respondents reported not taking any pain medication.

The main effects of conventional treatment types on pain relief, side effects and satisfaction with pain relief were significant. Respondents who used cannabis reported significantly greater pain relief than those using OTC/NSAIDs and opioids.

Perception of pain relief effectiveness with psychedelics

Of the 187 respondents who reported using psychedelics, 67.9% reported a reduction in pain, while 5.3% reported an increase in pain.

Of the 163 respondents who reported using psychedelics, 72.4% associated it with a reduction in pain, while 14.1% associated it with an increase in pain.

Comparison of perceived pain relief between psychedelics and conventional pain medication

A non-parametric Friedman test indicated that both macrodoses and microdoses achieved higher pain relief than conventional medications, and that pain relief achieved with macrodoses was statistically significantly more pronounced than that achieved with microdoses.

We looked at how three commonly reported conventional medications (OTC/NSAIDs, opioids and cannabis) compared with microdoses or macrodoses of psychedelics. Microdoses were only statistically significantly superior to OTC/NSAIDs and cannabis, but not to opioids.

Qualitative changes in pain

Macrodosing and microdosing were both associated with perceived improvements in pain intensity, acceptance of pain, interference caused by pain and emotional stress.

To assess which aspects of pain contributed most to pain relief, pain intensity and pain interference with daily life were assessed for macrodoses and microdoses.

Psychological factors

The relationship between pain relief and subjective effects of psychedelics was examined. Only life satisfaction significantly contributed to the model, suggesting that pain relief is not strongly mediated by psychological factors such as mood, mindfulness or body awareness.

Effects duration

Macrodosing provided longer duration of pain relief than microdosing, with 33.7% of people still experiencing benefits three days after the dose.

Side effects

Microdoses of psychedelics produced less side effects than conventional medication in all dimensions assessed, namely constipation, nausea, sedation, difficulty focussing, memory impairment, indigestion and anxiety.

Comparing intentional versus non-intentional use of psychedelics for pain management

Microdoses were more frequently reported as having been used for pain management than macrodoses, but the level of pain relief was not significantly different between those who microdosed with the purpose of pain management and those who did not.

Discussion

Although psychedelics have shown potential benefits in cancer pain, phantom limb pain and cluster headache, their use for the management of chronic pain has received little clinical attention to date.

Effect of psychedelics on pain

Over two-thirds of respondents reported having experienced some pain relief as a result of their psychedelics use, with macrodoses of psychedelics perceived as producing more effective pain relief than conventional medication (including cannabis and opioids) and microdoses.

Microdosing versus macrodosing

A microdose of psychedelics is one-tenth to one-twentieth of a recreational dose, varying within and between substances. A macrodose induces significant alterations to the state of consciousness.

Are the effects on pain mediated by mood?

Depression and chronic pain frequently coexist, with microdoses of psychedelics being associated with better mental health. Although the direct effect of psychedelics on mood does not appear to mediate perceived pain relief, microdoses-mediated pain relief was associated with improvements in life satisfaction.

Expectancy effect

Patients’ expectations about the therapeutic benefit of a treatment represent a major determinant of the placebo response. Although expectancy plays a significant role in pain relief reports, psychedelics can still be used to treat pain with an effect similar to conventional medication.

Respondent sample

Although we cannot draw any rigorous conclusions, people suffering from Cluster Headache, Complex Regional Pain Syndrome and Fibromyalgia seemed to experience more benefits from psychedelics use.

The most widespread pain medications reported by respondents included OTC, opioids, anticonvulsants and antidepressants. A relatively high percentage of respondents reported cannabis as their most effective pain management option, which is also in keeping with previous reports.

In congruence with previous surveys, psilocybin and LSD are the most commonly used psychedelic compounds. Both act via agonism of the serotonin 2A receptor.

Survey data: opportunity and limitations

The use of psychedelics is becoming more widespread and is now expanding beyond purely recreational use towards self-medication for a range of mental and physical health conditions.

These types of surveys are not without limitations, as they are entirely subjective, highly vulnerable to bias and preclude causal inference. In addition, the population assessed was highly heterogeneous, and more work is needed to evaluate which chronic pain conditions are likely to benefit most.

Other limitations

In this survey, we did not collect any data regarding the intention and context in which respondents were using psychedelics.

Psychedelics produce intense effects that make it difficult to compare the side effects of macrodoses to conventional medication.

Conclusion

Data collected through this survey suggested that psychedelics may have analgesic potential. This effect was unrelated to whether or not the intended use was pain management, prior experience with psychedelics or level of advocacy.

Although the effects of microdoses of psychedelics for pain management were weaker and potentially more prone to expectation bias, these results indicate interesting potential analgesic applications for these compounds.