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

Bonnelle and colleagues situate their study in the context of a rising global burden of chronic pain and growing concern about harms associated with conventional analgesics such as opioids and long-term NSAID use. They note that interest in alternative treatments has expanded alongside a renaissance in clinical research on serotonergic psychedelics (for example LSD and psilocybin), which act primarily via 5-HT2A receptor agonism and have shown promise for mood disorders as well as some pain conditions (cancer pain, phantom limb pain, cluster headache). Proposed mechanisms for psychedelic analgesia include modulation of descending serotonergic inhibitory pathways, anti-inflammatory effects (inhibition of TNFα signalling), promotion of neuroplasticity via glutamatergic pathways, and facilitation of affective regulation through amygdala modulation. The study aimed to evaluate self-reported analgesic effects of classic serotonergic psychedelics in a population of chronic pain sufferers who had used these substances. Specifically, the investigators sought to compare perceived pain relief from macrodoses (hallucinogenic doses producing marked changes in consciousness) versus microdoses (sub-hallucinogenic doses that do not impair normal functioning), and to compare both to conventional pain medications. The analysis also explored whether reported analgesia was mediated by mood or driven by expectancy or advocacy for psychedelic use.

This was an online cross-sectional survey conducted between August 2020 and July 2021. Participants were recruited via social media and the Beckley Foundation website; eligible respondents were adults (≥18 years) with chronic pain who had experienced psychedelics at least once. Ethical approval was obtained from Maastricht University's Ethics Review Committee of Psychology and Neuroscience. The questionnaire was implemented in Qualtrics. The survey collected demographic information, detailed psychedelic use history (including most-used compound and dosing pattern categorised as microdose, mixed, or macrodose), frequency and duration of psychedelic use, and endorsement of advocacy statements adapted from prior work. Pain-related items covered type(s) of chronic pain (musculoskeletal, inflammatory, neuropathic, headache/orofacial, cancer-related, visceral or other), pain severity on a 0–10 scale and pain frequency. Respondents reported their most-used conventional pain medication type and rated perceived pain relief from that medication on a 0–10 scale. To separate macrodose and microdose effects, respondents separately reported changes in pain during or after psychedelic use for each dosing category. When reporting a change they provided direction (improvement or worsening), condition(s) affected, compound, extent of change (0–10), and features of pain relief across domains (intensity, acceptance, interference, emotional distress). Duration of analgesic effect, comparisons of undesired effects versus conventional medications, and the perceptibility of psychoactive effects were also recorded. Statistical analysis was performed in SPSS v28. Inclusion criteria excluded those under 18, those who did not consent or did not complete the questionnaire, and those without chronic pain. Normality was assessed with Kolmogorov–Smirnov and Shapiro–Wilk tests; parametric tests (multivariate ANOVA with post-hoc t-tests) were used for conventional medication outcomes, while non-parametric tests (Friedman, Wilcoxon signed-rank) were used for psychedelic-related variables. Automatic Linear Modelling (LINEAR) in SPSS was applied in separate models for macrodoses and microdoses to evaluate predictors of reported pain relief, with predictors including changes in pain characteristics, psychoactive/psychological effects, advocacy and prior experience.

From 976 respondents, 250 met inclusion criteria and completed the survey. The analysed sample comprised 129 females, 117 males and 4 who preferred not to say; age groups were 18–30 (n = 60), 31–40 (n = 84), 41–50 (n = 41), 51–60 (n = 36) and 61–70 (n = 29). Psilocybin was the most frequently used psychedelic for both microdosing and macrodosing, followed by LSD; other compounds (DMT, ayahuasca, mescaline) were marginally represented. Perceived effectiveness of conventional medications varied: OTC/NSAIDs were used by 22.8% (n = 57) with mean pain relief 4.44 (SE = 0.28); opioids by 21.1% (n = 53) mean 5.36 (SE = 0.31); cannabis by 19.6% (n = 49) mean 5.69 (SE = 0.24); anticonvulsants, antidepressants, triptans and other classes were less common. Multivariate ANOVA showed significant main effects of medication type on pain relief (F(7,187)=3.173, p = 0.003), side-effect severity (F(7,170)=4.82, p ≤ 0.001) and satisfaction (F(7,170)=3.57, p = 0.001). Post-hoc tests indicated cannabis users reported greater pain relief than OTC/NSAIDs (p < 0.001); opioid users reported greater side-effect severity than OTC/NSAIDs (p ≤ 0.001); cannabis users reported greater satisfaction than OTC/NSAIDs (p = 0.001) and than opioid users (p = 0.031). Regarding psychedelics, 187 respondents reported microdose use (microdose-only n = 81; mixed-use n = 106); of these, 67.9% (n = 127) associated microdosing with reduced pain, 5.3% (n = 10) with increased pain, and 49.2% (n = 92) reported microdosing specifically for pain. For macrodoses, 163 reported use (macrodose-only n = 57; mixed-use n = 106); 72.4% (n = 118) associated macrodosing with reduced pain, 14.1% (n = 23) with increased pain, and 33.7% (n = 55) used macrodoses specifically for pain. A Friedman test found a significant effect of treatment type on perceived pain relief (Fr(2,81)=59.34, p < 0.001). Mean perceived pain relief was 8.23 for macrodoses, 7.12 for microdoses and 5.36 for conventional medications. Pairwise comparisons showed macrodoses produced greater perceived pain relief than both microdoses and conventional medications (p < 0.001). Microdoses were perceived as superior to conventional medications overall (p = 0.004). When compared to specific conventional classes, macrodosing was superior to OTC/NSAIDs (p < 0.001), opioids (p < 0.001) and cannabis (p < 0.001). Microdosing was superior to OTC/NSAIDs (p ≤ 0.001) and cannabis (p = 0.042), but not to opioids (p = 0.303). There was no significant difference between psilocybin and LSD for perceived pain relief in either dose category (macrodoses p = 0.990; microdoses p = 0.676). Both dosing strategies were associated with qualitative improvements in pain intensity, acceptance, interference and emotional distress. In linear models predicting overall pain relief, two predictors contributed significantly for both macrodoses and microdoses: perceived reduction in pain intensity (macrodoses coefficient = 0.314, p < 0.001; microdoses coefficient = 0.505, p < 0.001) and reduced interference with daily life (macrodoses coefficient = 0.262, p < 0.001; microdoses coefficient = 0.346, p < 0.001). Psychological variables were less contributory: for macrodoses only life satisfaction significantly predicted pain relief (coefficient = 0.383, p = 0.015), while for microdoses none of the tested psychological predictors (mood, vitality, anxiety, mindfulness, life satisfaction, body awareness) reached significance. Macrodoses were reported to produce longer-lasting perceived analgesia than microdoses (Z = 4.697, N = 107, p < 0.001); 33.7% of those reporting macrodose-related pain reduction still perceived benefits after three days, compared with 21.4% for microdoses. Side-effect comparisons were restricted to microdoses versus conventional medications because of difficulty dissociating acute psychedelic experiences from adverse effects in macrodoses; microdoses produced fewer undesired effects across assessed domains (constipation, nausea, sedation, difficulty focusing, memory impairment, indigestion, anxiety), with Kolmogorov–Smirnov tests all p < 0.001. Analyses addressing expectancy and experience found microdosing was more often used intentionally for pain (49.2%) than macrodosing (33.7%). Intention to treat influenced outcomes for microdosing: those who microdosed with the purpose of managing pain reported higher pain relief than those who did not (Z = 2.12, N = 140, p = 0.034); among people who did not intend to treat pain, microdose-related relief did not differ significantly from conventional medication (Z = 1.61, N = 32, p = 0.107). Macrodose-related pain relief did not differ by intention (p = 0.263). Advocacy and prior experience had no significant influence on macrodose-reported pain relief; for microdoses, greater prior psychedelic experience was negatively associated with reported pain relief (coefficient = -0.798, p = 0.045). The sample showed relative overrepresentation of cluster headache, complex regional pain syndrome and fibromyalgia compared with population prevalence, though the extraction does not provide full condition-by-condition counts.

Bonnelle and colleagues interpret the findings as indicating notable self-reported analgesic potential for classic psychedelics in chronic pain sufferers, with macrodoses perceived as producing the most pronounced benefit. They point out that over two-thirds of respondents reported some pain relief following psychedelic use and that macrodoses were perceived as more effective than conventional medications including opioids and cannabis; these observations are consistent with previous surveys and qualitative work in people self-medicating with psychedelics. The authors differentiate microdosing and macrodosing phenomenologically rather than by fixed milligram ranges, defining microdoses as doses that preserve a normal state of consciousness. Regression analyses suggested that reported analgesia was not strongly mediated by measures of mood, mindfulness or body awareness; macrodose-related analgesia was associated with higher life satisfaction, which the authors link to known relationships between chronic pain, mood and life satisfaction. Expectancy effects appear to play a role for microdosing: intentional microdosing for pain was associated with greater reported relief, whereas macrodose-related analgesia persisted among those who did not use psychedelics specifically to treat pain. The investigators acknowledge several important limitations. The data are entirely self-reported, retrospective and subject to recall bias, expectancy effects and selection bias given recruitment from psychedelic-interested online communities. The sample was heterogeneous across pain conditions and not representative of a clinical population, limiting causal inference and the ability to identify which conditions may benefit most. The survey did not collect information about set and setting, which are known to influence psychedelic experiences, nor did it permit disentangling acute psychoactive effects from post-acute side effects for macrodoses. The authors recommend that future clinical research should clarify dose ranges, frequency of use, safety and adverse event profiles in chronic pain populations, examine mechanisms (for example neuroplasticity and inflammatory markers) and determine which pain conditions are most likely to respond.

The authors conclude that survey data provide further evidence of potential analgesic effects of serotonergic psychedelics in people with chronic pain. Hallucinogenic macrodoses were reported less often for analgesic purposes than microdoses but produced higher perceived pain relief than conventional medications, with benefits sometimes lasting beyond a day. Reported relief did not appear to depend on whether use was intended for pain management, prior psychedelic experience or level of advocacy. Microdoses produced weaker effects that may be more influenced by expectancy, yet they offer a practical option that does not impair daily functioning and may warrant further study to identify an optimal balance between efficacy and psychoactive effects. Overall, the findings point to the need for controlled clinical trials to characterise efficacy, safety, mechanisms and condition-specific effects.