Can psychedelics help close the gender gap in pain relief?

Sculpture of a woman in a park with skyscrapers

Psychedelics could have roles as pain relievers, or analgesics—this could change how women’s pain, which has so-often been ignored and underplayed historically, is treated. Image credit: JR Harris via Unsplash

Disclaimer: The term “woman” is used for brevity to describe people with uteruses, although this does not encompass the entire population of people who have uteruses, including some trans men and non-binary people.

It seems that having a uterus elicits temporary disappearance without explanation. The debilitating cramps that some people experience, whether from menstrual cycles or endometriosis, mean that lectures are left early, and social events skipped, replaced with clutching pain.

Observing at a sexual health clinic, I saw countless women seek contraception removal due to unbearable cramping induced by their intrauterine devices (IUDs). It struck me as tragic that these women had to give up today’s most effective birth control measures so that they could get pain relief, especially at a time when barriers exist to obtaining contraception in the first place.

Recent medical studies posit that, as compared to their male counterparts, a woman’s experience of pain is more likely to be underestimated and labelled as psychological and emotional. This notion was recently exemplified by the Yale Fertility Center scandal, which involved the clinic systematically ignoring the complaints of agony from women undergoing egg retrieval procedures. It turned out clinic staff chalked up these complaints to patient overreaction, yet they were actually the result of a nurse stealing anaesthetic fentanyl and replacing it with saline.

It turned out clinic staff chalked up these complaints to patient overreaction, yet they were actually the result of a nurse stealing anaesthetic fentanyl and replacing it with saline.

On top of gendered healthcare biases undermining women’s experience of pain, women represent a majority of patients with chronic pain—70%. Chronic pelvic pain affects 26% of women. Survivors of abuse disproportionately suffer from fibromyalgia and endometriosis, underscoring the social determinants of health. Traumatic experiences such as these may cause an inflammatory bodily stress response that contributes to pain symptoms.

Women’s suffering is compounded by the fact that many of the pain disorders that affect women have been historically understudied. In fact, until 2016, 80% of pain studies were conducted on men or male mice. It was only in 1993 when the National Institute of Health put into law that women must be included in all clinical trials.

Given this history and the large fraction of women who suffer from chronic pain, developing relevant treatments is an urgent women’s health priority.

Psychedelics for pain relief

A blossoming area of today’s research in chronic pain therapeutics is psychedelic drugs. When people think of psychedelics, what often comes to mind are people illegally “tripping” as their world appears magically transformed by sensory hallucinations, swirling into fractal rainbow delirium at one moment, perhaps encountering singing trees the next.

What might psychedelics have to do with anything medical? In fact, there is an expanding body of evidence suggesting psychedelics have great potential as therapeutics across a range of clinical realms, including analgesia (i.e., pain relief).

Of particular interest is how women might physiologically react differently to these compounds than men and the implications this has on psychedelics’ effectiveness in treating pain in women. But we will get to this a bit later.

Fig. 1 depicts the number of studies conducted on psychedelic treatments for a variety of medical conditions. Most ongoing and completed studies on psychedelics are for mental health applications. Among the most studied psychedelic compounds are lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), psilocybin, and ibogaine, which are considered “classic” due to their mechanism of action. Non-classic psychedelics include ketamine and 3,4-methylenedioxymethamphetamine (MDMA), which have different mechanisms of action but mimic aspects of classic psychedelics via their effects on altered perception.

Fig. 1 Conditions of study for clinical trials (including trials that are marked Completed; Not Yet Recruiting; Recruiting; Active, Not Recruiting; Enrolling by Invitation) for psychedelic compounds (LSD, DMT, Psilocybin, Ketamine, MDMA) as of April 10, 2023. Note: some clinical trials with divergent research focuses from the topic of this article (i.e., pharmacokinetics) were excluded from this count.

Classic psychedelics stimulate the brain’s serotonin receptors, most notably the 5-HT2A receptor, which mediates both excitatory and inhibitory neurotransmission. Such receptor activity triggered by psychedelic compounds results in a range of dose-dependent behavioural and neurobiological effects. These effects include anti-addictive and anti-depressant effects, which are being exploited to treat a variety of psychiatric disorders, from PTSD to OCD.

Current psychedelic studies for mental health focus on their use as short-term treatments with heavier hallucinogenic dosages. Interestingly, the effects of these compounds often last beyond their presence in the body’s blood plasma, underscoring their potential long-term benefits.

Evidence suggests that psychedelics induce neuroplasticity—the brain’s ability to form new or alter existing neural connections—even after just a single dose. While psychedelics have an extremely low chance of lethal overdose, they are not for everyone. Anecdotal reports show that these compounds may pose serious a risk of psychotic or manic episodes for people who have a personal or family history of schizophrenia and bipolar disorder.

A growing number of medical studies are focusing on the potential analgesic capabilities of psychedelics. With the addiction and overdose risks that are concomitant with the use of opioids to treat chronic pain, psychedelics may offer an attractive alternative given their significantly more favorable safety profile.

Preclinical evidence in mice and individual case reports suggest that psychedelics help attenuate pain for conditions for which conventional medicines do not offer sufficient relief, such as cluster headaches and phantom limb pain. In a 1964 study, a single dose of LSD given to terminally ill patients with ‘severe intolerable pain’ showed protracted and more effective pain relief compared to single-dose opioids.

More recently, a single, sub-hallucinogenic dose of psilocybin (the psychoactive compound in “magic mushrooms”) was found to significantly decrease the number of migraines participants experienced over a two-week study period.

There is not yet a definitive neurobiological answer as to how these compounds act against pain, particularly how their effects last beyond their acute pharmacologic presence in the body. Nevertheless, a handful of plausible hypotheses exist. The 5-HT2A receptor is integral to the central pain response, so it is possible that psychedelics directly act on neural pain pathways.

Furthermore, brain imaging studies suggest the resetting of neural circuits that function abnormally in chronic pain patients. Studies in mice have also shown that some psychedelics have stronger anti-inflammatory properties than steroids, thereby dampening inflammation associated with chronic pain. Inflammation is a key pathology in autoimmune conditions like rheumatoid arthritis, another chronic disorder that overwhelmingly affects women, and psychedelics might be an avenue toward improved symptomatic relief.

Considering sex hormones in psychedelic pain research

There is a gap in current research as to how psychedelics may uniquely impact female biology, given their historical exclusion in these studies. A factor as to why sex bias is present in research is that women’s reproductive capacity is framed to pose greater health and legal risks in clinical studies. Hormonal fluctuations due to the menstrual cycle have also been considered confounding factors, complicating data analysis.

Yet, it is precisely these distinct biological differences between sexes that make women’s inclusion in clinical studies imperative, as results pulled from a male participant pool might not be generalisable to female populations.

In fact, estrogen, a primary female sex hormone, has been found to have interactions with the 5-HT2A receptor. Estrogen levels can be up to 40 times greater in healthy pre-menopausal women compared to men.

One preclinical study found that estrogen increases the density of 5-HT2A receptors in areas of the brain responsible for mood and cognition. It is thus possible that estrogen could act synergistically with psychedelics to cause different reactions in women as compared to men. For one, women who took MDMA (i.e., “ecstasy”) have reported more intense experiences, as well as greater adverse effects, which researchers attribute to female preponderance of 5-HT2A. This means sex might be another important variable to include when calculating optimal dosages, in addition to standard weight considerations.

Additionally, the fluctuation of a woman’s hormones through the month, as well as through their lifetime (e.g., menarche to menopause), means that differences in psychedelic effects might also vary with age and the course of one’s menstrual cycle. Research at the intersection of psychedelics and women’s health is being pioneered by Imperial College London’s Centre for Psychedelic Research and Johns Hopkins Center for Psychedelic & Consciousness Research, the latter of which has conducted a cross-sectional survey to study the effectiveness of psychedelics in reducing fibromyalgia pain symptoms.

Ideas and hurdles for implementation, with materials science

In treating chronic pain conditions like fibromyalgia, how frequently must psychedelics be administered? While long-term pain relief (>1 month) after a single psychedelic dosing is uncommon, in the case of psilocybin, repeated sub-hallucinogenic dosages were found to produce increased pain relief. These findings support the potential therapeutic use of micro-dosing—a low dosage of psychedelics that does not cause perceptual change nor impair functioning.

Turning to materials science-based solutions for micro-dosing could lead to improved health outcomes. Psychedelics could be integrated into “controlled-release platforms”. Such a platform can be thought of as a tea bag, with the tea leaves being medicinal agents that slowly release from an encapsulating polymer, or the tea bag filter.

The rate with which the internal agents are released can be controlled by tailoring the “filter” properties, such as porosity (i.e., the measure of void space in a material), degradation rate, and hydrophilicity (i.e., attraction to water). Importantly, these platforms can be implanted into the body to offer major benefits, including localising drug delivery and reducing administration frequency for weeks to months.

Targeted delivery minimises systemic toxicity by allowing the use of lower drug concentrations while still achieving therapeutic effects. These platforms can be biodegradable and often take the form of injectable hydrogels (i.e., a gel made from hydrated polymers) or surgical implants. Loading such platforms with anti-inflammatory psychedelics could provide long-term release at sub-hallucinogenic dosages.

Controlled drug release platforms, compared to faster-acting oral pills and quick-diffusing injections, have already revolutionised many pharmaceutical treatments, such as contraceptive IUDs and anti-psychotic injections for schizophrenia.

Polymeric implantable platforms have also been developed for patients with endometriosis to sustain drug release for up to 30 days from the peritoneum (i.e., a membrane that lines the abdominal cavity) to the uterus. As of 2021, out of the 41 FDA-approved formulation-based long-acting injectable products, six were for pain/anesthesia and two for inflammation.

While there are a growing number of clinical studies on the use of psychedelics in these specific areas, there is expansive terrain for medical exploration of controlled-release psychedelics.

While media reports often tout micro-dosing as a compelling solution for many ills, robust clinical trials have not yet been conducted to establish its efficacy and safety, particularly for daily administration. A 2020 study found that administering 20ug or less of LSD to healthy older volunteers every four days (for 24 days) was well tolerated.

Yet, positive outcomes from four-day administration increments do not mean this holds true for more frequent dosing. Daily dosages would likely be the case if using standard controlled release platforms, as loaded compounds are released continuously rather than intermittently, as done in the 2020 study. In addition to safety concerns, frequent dosing may reduce effectiveness, depending on how quickly the patient’s body builds tolerance to psychedelics.

As an alternative to micro-dosing, researchers are investigating mitigating additives as a means to prevent the hallucinogenic effects of psychedelics while retaining their non-psychoactive properties.

For instance, 5-HT2A receptor antagonists, such as risperidone, have been shown to block psilocybin’s hallucinogenic effects. Some researchers are also attempting to synthesize non-hallucinogenic derivatives by making minor molecular modifications to psychedelics, though to date, these attempts frequently do not eliminate hallucinogenic properties.

A successful example of a modification is 2-bromo LSD, which does not cause subjective psychoactive effects and was shown to provide significant therapeutic benefits in five patients with cluster headaches. Contrastingly, in the case of mental health disorders such as depression and substance use disorders, the psychoactive effects (in conjunction with psychotherapy) appear to be key in producing persisting psychiatric improvements. Perhaps these psychoactive effects might also be necessary for resetting the pain circuits that single-dose pain alleviation has been hypothesized to rely on.

Some shamans and plant medicine healers from communities where psychedelic usage originated consider the removal of hallucinatory effects as sacrilegious. While the Western clinical model tends to treat symptoms of a pathology, plant medicine aims to heal one’s spirit holistically.

As psychedelic research moves forward, it is important to talk to those from the indigenous communities to truly understand the context, efficacy, and usage of these powerful compounds and give credit where credit is due.

While psychedelics offer immense potential in assuaging chronic pain disorders that debilitate millions of women, psychedelics are not a panacea. Chronic pain disorders are complex, as they are not just physiological but also exacerbated by a variety of psychological modulators, such as commonly concurrent depression that can intensify an individual’s experience of pain.

Still, psychedelics offer promise as one piece in holistic pain treatment, and this is driving a growing number of research projects on its analgesic properties. The women’s health implications of psychedelics also extend beyond chronic pain: they help in the healing of sexual trauma, eating disorders, and premenstrual dysphoric disorder.

With the re-emergence of psychedelic research, the field is in a particularly flexible state of creative inquiry, with much that remains to be discovered. There is a real chance that embracing unconventional approaches through synergies between psychedelics, women’s health, and materials science might offer a world where far fewer women suffer from chronic pain—a world where far fewer women temporarily disappear without explanation.