Chronic Pain in Women — and the Potential of Psychedelic Relief

Pain keeps you safe when it’s warning you that you are putting too much weight on a bone, or that you need to allow your finger to heal after hurting yourself while grating cheese.

But what happens when pain persists without a clear cause? How can pain be understood and treated when the bone which hurts seems fine on a scan, or the patch of skin which feels like burning looks healthy?

Such chronic pain affects ~20% of people worldwide and, to add insult to injury, usual treatments—including pain medication, antidepressants, physiotherapy or surgery—are often inefficient, leaving pain sufferers feeling hopeless. 

What is pain?

That pain simply follows injury is an outdated view.

Instead, the latest biopsychosocial model describes pain as a result of the complex interaction between biological factors, mental state, and the wider social context. When these three aspects converge in an unfortunate way, pain that initially feels like an injury caused by external forces can become a learnt response to emotional triggers.

In this sense, pain is seen as an experience produced by the brain in response to perceived danger. If this pain lasts for several months or longer, it becomes chronic.

While some conditions like cluster headaches are more common in men, most chronic pain disorders—such as migraines, arthritis, fibromyalgia, and irritable bowel syndrome (IBS)—disproportionately affect women. In addition, women can develop syndromes specific to female biology—such as pelvic pain caused by a pathological growth of uterine tissue, vulvar pain, or vaginismus.

Even though more women are in pain than men, their needs have been overlooked. A recent House of Commons report reveals that women’s pain is often dismissed, research into women-specific conditions remains underfunded, and women have been historically excluded from clinical trials—highlighting how now, more than ever, it is crucial to consider the unique needs of women in the search for novel chronic pain treatments.

Female Biology Holds Important Clues to Why Chronic Pain is More Common in Women

1) Serotonin

Over 35 years of research in both rodents and humans shows differences in pain processing between sexes. Some of these concern serotonin—the main place of action for psychedelics—raising the question: Could psychedelics produce different analgesic effects in women and men?

Serotonin is known to affect pain processing, but whether it increases or reduces pain depends on the amount of serotonin released, where it acts in the nervous system, the types of serotonin receptors involved, and whether pain is acute or chronic—with much still left to be understood. Crucially, serotonin production and breakdown rates differ between sexes. In women the recovery of serotonin levels after a high-stress situation is slower. This is thought to explain why women have a higher prevalence of serotonin imbalance conditions, such as mood disorders and chronic pain.

Serotonin receptor types, their distribution, and other molecules involved in serotonin signaling also differ between sexes. Of particular note, women’s brains were found to have elevated levels of the serotonin receptor 5-HT2C. In a rodent model of chronic pain, 5-HT2C expression is increased in the amygdala, a key brain region involved in processing the emotional dimensions of pain. In another striking example, women with a genetic variant of the serotonin receptor 5-HT2A required more painkillers after major abdominal surgery.

Psychedelics interact with a broad range of serotonin receptors, including 5-HT2A and 5-HT2C—though their binding affinity varies by type—and show great promise for pain relief. Given the well-documented sex differences in these receptors, identifying the most effective psychedelic type and dosage for women or women-specific conditions is essential.

2) Hormones

Sex hormones clearly influence pain perception, as shown by the rise in pain conditions following puberty in girls and after hormonal treatment administration in transgender women. Sex hormones can influence pain in several ways, including by interacting with the serotonin system. Estrogens, especially, affect most aspects of serotonin signaling and metabolism—synthesis, degradation, transport, and receptor activity. Overall, estrogens enhance serotonin activity in the nervous system, but their effects on pain can vary depending on hormonal state and whether the pain is acute or chronic. 

Given the substantial impact of estrogens on serotonin, it is reasonable to believe pain in women changes throughout the menstrual cycle. However, evidence to support this is inconclusive. Intriguingly, this seems to be the case in women with chronic pain, where perhaps the interaction is brought to light by imbalances in the two systems. 

In addition to estrogens, hormones released by the hypothalamus and pituitary gland during stress shape the pain experience. A recent study found that two of these brain-derived hormones have a sex-specific effect: prolactin increases activity in pain-sensing neurons in females, while orexin does so in males. This marks the first documented sex-based difference in human sensory neurons and reinforces the critical need for sex-specific approaches in treatment.

Psychedelics interact with hormones, a topic previously introduced on Hystelica’s blog and discussed at length in the newly-published pioneering article by Hystelica’s Dr. Zahira Cohen and Dr. Grace Blest-Hopley. In addition, LSD and psilocybin have been reported to increase prolactin levels and—by acting on the hypothalamic-pituitary-adrenal (HPA) axis—other stress hormones such as cortisol. This may be worrying, since prolactin and stress are conducive to pain in women. However, counter to its pain-promoting role at the periphery, prolactin release in the brain can inhibit the HPA axis and provide resilience under chronic stress.

The complex interactions between stress, hormones and serotonin make finding the right treatment for pain a challenging task. Yet, given their unique properties as master-modulators, the right psychedelics under the right conditions may be able to shift the balance towards pain resolution with unmatched efficiency. Therefore, psychedelics may be perfectly suited to treat pain conditions characterised by a serotonin imbalance with a higher prevalence in women, such as fibromyalgia, migraines and IBS. However, when investigating the role of psychedelics in chronic pain, a woman’s hormonal state—such as reproductive life stage, time point in the menstrual cycle, or the use of hormone-based treatments—must be taken into account.

3) Inflammation

Inflammation is widely recognised to play a role in the onset and maintenance of chronic pain. Perhaps the most striking difference between sexes reported so far is the involvement of two different populations of immune cells in chronic pain. Overlooking the need for a sex-specific treatment strategy may explain why clinical trials conducted on both men and women, but based on male-only data, have failed—argues a commentary on the original article. This raises the question: Which other clinical trials would show a different outcome when sex is taken into account?

The understanding that a one-size-fits-all approach won’t do is both key and timely, given the rise of psychedelics as unique anti-inflammatory agents. Broad-spectrum immunosuppressants, such as corticosteroids, suppress the immune response to levels below its normal baseline, increasing the body’s susceptibility to infections. Instead, psychedelics such as the synthetic compound (R)-DOI reduce subsets of proinflammatory molecules only back to baseline—re-establishing homeostasis through yet unknown mechanisms. These compounds act as both anti-inflammatory agents and analgesics, showing great promise in treating painful inflammatory conditions such as arthritis, which mostly affects women.

Excitingly, these compounds were shown to be highly effective at microdoses. The absence of noticeable behavioral effects at such low doses may reassure those hesitant about psychedelics, potentially enhancing their appeal as therapeutic options.

The biological sex differences outlined here make one thing clear: chronic pain works differently in women. In line with women-specific needs often being overlooked, currently available treatments are inefficient or even dangerous. For example, women with severe IBS can be prescribed alosetron—an inhibitor of the serotonin receptor 5-HT3 and the only FDA-approved women-specific drug—despite its small but known risk of serious complications of colitis. With the opioid crisis still unfolding, the demand for safe,  alternative pain relief is urgent. Psychedelics might just be the ideal treatment for such a complex condition like chronic pain—acting on molecular pathways involved in processing pain while also, as we’ll explore in Part 2, disrupting rigid mental patterns that sustain the pain experience.