Can Psilocybin Help With Pain?

After being expelled from the medical lexicon half a century ago, we now starting to answer the question, “Can psilocybin help with pain?” Psilocybin (be sure to read “What Kind of a Drug is Psilocybin?” to learn more about the substance), the psychoactive compound in so-called “magic mushrooms”, is making a fierce comeback; it seems that this “mystical experience” inducing psychedelic alkaloid is increasingly finding itself on the tip of people’s tongues, figuratively and even literally, at least according to the National Survey on Drug Use and Health. 

All around the world, an ever-growing number of research institutions and psychedelic corporations are conducting clinical trials to investigate psilocybin’s therapeutic efficacy, mostly yielding impressive results.

A study conducted at the turn of the century led by Johns Hopkins University’s esteemed professor of neuroscience and psychiatry, Roland Griffiths, seems to have sparked this flourishing resurgence of psilocybin research. In this study, two-thirds of psychedelically naive participants rated their psychedelic experience as one of the most personally meaningful and spiritually significant experiences of their entire lives. 33% rated it as the single most spiritually significant experience of their entire life. 

Speaking about these results, Griffiths remarked: “I’ve given a lot of drugs to a lot of people, and what you get are drug experiences. What’s unique about the psychedelics is the meaning that comes out of the experience … As a scientific phenomenon, if you can create a condition in which 70% of people will say they have had one of the most meaningful experiences of their entire lives … well, as a scientist, that’s just incredible.” 

Building upon this landmark study, the Johns Hopkins research team, as well as scientists from New York University and Imperial College London, began studying and demonstrating psilocybin’s rapid and enduring antidepressant effects. Unprecedented therapeutic outcomes in these studies prompted the Food and Drug Administration (FDA) to grant Breakthrough Therapy Designation to psilocybin-assisted psychotherapy for treatment-resistant depression and major depressive disorder.

Psilocybin-assisted psychotherapy has since shown promise as a potential treatment for several other psychiatric disorders, including end-of-life anxiety, substance use disorders, and eating disorders. Now, however, perhaps having concluded that the mental health research side of things is sufficiently covered, some psychedelic researchers have turned their attention toward psilocybin’s ability to treat pain.

Psilocybin for Pain: What Does The Research Say? 

A plethora of anecdotal reports professing the analgesic power of psilocybin seems to have catalyzed growing interest among researchers and investors alike. Despite psilocybin’s current classification as a Schedule I substance, studies exploring the generalizability of anecdotal reports are being conducted with increasing frequency.

So far, evidence of psilocybin’s ability to treat pain is scant. However, a recent review by physical medicine and rehabilitation specialist Dr. Joel Castellanos and colleagues has shed some light on past research in the area. Several preliminary studies suggest that psilocybin and lysergic acid diethylamide (LSD) may relieve pain associated with cancer, phantom limb pain, cluster headache, migraine, and fibromyalgia. 

Some of these studies investigated the analgesic properties of LSD only. However, as both LSD and psilocybin exhibit their psychoactive effects in much the same way, and bear much pharmacological and phenomenological resemblance, it is reasonable to infer that the analgesic properties of one may also exist in the other.

So, exactly how much evidence is there? And how reliable is it? 

Cancer pain

In the 1960s, clinician and pain researcher Dr. Eric Kast observed that LSD compromises one’s ability to selectively attend to any one specific sensation for any meaningful length of time. Kast also noted LSD’s tendency to dissolve ego boundaries, temporarily altering or terminating one’s most typically felt sense of self.

Having arrived at these discoveries, he hypothesized that LSD may have the capacity to switch attention away from pain and towards the altogether more interesting and pleasant experience of the LSD-induced psychedelic journey, thus alleviating pain.

Kast and fellow researcher Dr. Vincent Collins published a preliminary report in 1964 in which they investigated this hypothesis by comparing the analgesic action of LSD with two potent opioids used to treat moderate to severe pain; hydromorphone (Dilaudid) and meperidine (Demerol). 

Study participants, all of whom were “gravely ill” patients, and most of whom had a cancer diagnosis, initially received one of the two opioids in a randomized fashion. As soon as the patients started complaining of pain, and at least 6 hours after initial administration, they were given whichever opioid had not already been taken. As soon as participants complained of pain after administration of the second opioid, and at least 6 hours later, they received 100 micrograms of LSD.

LSD rather impressively outperformed both established opioids in terms of analgesic action, bringing about effects that endured for an average of 3 weeks. 

In 1969, minister and physician Walter Pahnke, associated mostly with his central participation in the notorious Harvard Good Friday Experiment of 1962, published a case series of 22 terminally ill cancer patients who received LSD-assisted psychotherapy. Pahnke and his colleagues reported that LSD-assisted psychotherapy improved patients’ pain, in addition to mood, anxiety, and fear of death.

Four years later, famed Czech psychiatrist and founder of transpersonal psychology and holotropic breathing, Stanislav Grof administered LSD-assisted psychotherapy with the help of his colleagues, to 31 patients with terminal metastatic malignancies. The researchers reported significant improvements in pain severity, preoccupation with pain, and physical suffering.

Although LSD was shown to produce profound analgesic effects in these studies, the study designs do not stand up to the rigors of the gold standard of clinical experimentation employed today — the randomized double-blind placebo-controlled trial. As a consequence, results are perhaps most appropriately interpreted as providing pilot data on safety and efficacy and producing testable hypotheses for subsequent studies investigating the analgesic effects of psychedelics.

Phantom limb pain 

Phantom limb pain, a condition in which amputees continue to feel pain from a part of their body no longer physically there, is believed to be caused by a misfiring of communication between the brain and the spinal cord. The brain can misinterpret incoming information from the peripheral nervous system via nerve connections that remain in place after amputation, wrongfully processing incoming signals as pain. 

Approximately 95% of amputees experience phantom limb pain which typically emerges immediately after surgical removal or accidental amputation of the limb in question, however, for some it may not kick in for several weeks. Phantom limb pain is experienced as excruciatingly painful by two-thirds of patients, and, quite sadly, traditional treatments like opioids and anti-convulsant medications provide little to no relief for many sufferers.

There are, however, two case reports in the scientific literature that point toward psychedelic therapy as a potentially effective treatment. 

A case report from 1997 details an experiment conducted in which 7 people experiencing phantom limb pain received “sub-hallucinogenic” oral doses of LSD. The trial lasted 8 weeks in total, with volunteers receiving a placebo the first week, 25 micrograms of LSD every day for the following week, and 50 micrograms of LSD every day for the two weeks after that, before returning to placebo for the final 4 weeks of the study.

Remarkably, 78% of participants reported significant pain improvements despite substantial reductions in their daily use of pain medication. All patients who experienced pain improvements had reduced their use of analgesic medication by at least 50%. 

One of the more promising treatments for phantom limb pain is mirror visual feedback therapy (MVF), a type of therapy that uses vision to trick the brain into thinking that the amputated limb is still there. A 2018 case report documents the story of a 35-year-old patient who, by combining psilocybin and MVF, experienced significant pain improvements compared with MVF alone. 

The patient, who required amputation of the leg after a car accident, had received little to no relief using opioids or anticonvulsants — an all too prevalent story. Marginal relief prompted the patient to seek out alternative options.

He eventually decided to experiment with MVF in conjunction with a single large dose of psilocybin-containing mushrooms, a combination that produced profound, long-lasting pain relief. Psilocybin and MVF appear to have combined to produce powerful synergistic effects, eliminating paroxysms for up to 2 weeks and reducing pain for months on end after just 3 sessions.

Amazingly, the patient was able to dispense with this combination treatment altogether.

The patient had experienced little to no relief from multiple analgesic medications before he tried psilocybin, which suggests legitimate efficacy. Furthermore, the rapidity and extent of MVF-psilocybin-induced relief make it unlikely that the results were merely spontaneous.

Cluster Headaches 

The term “suicide headache” reflects the unbearable intensity of this often neglected neurological disorder.

Although standard abortive treatments for cluster headaches (stopping pain as soon as it starts) and neuromodulator medications can be helpful for some, they have so far proved simply incapable of terminating cluster periods or extending periods of recovery. Surgical treatment options such as implantable occipital nerve stimulators or hypothalamic brain stimulation do exist for non-responders, however, these surgeries are intense, invasive, have undesirable side effects, and are not always effective. 

After being contacted by a man who experienced enduring remission from his episodic cluster headaches through recreational use of LSD and, subsequently, by ingesting psilocybin, Dr. Andrew Sewell and colleagues at Yale school of medicine became intrigued. They found hundreds of people online who reported the use of psilocybin or LSD to treat cluster headaches, and reached out to them to administer a questionnaire. 

Their final analysis produced profoundly positive outcomes. Stand out findings include:

• Psilocybin terminated cluster attacks within 20 minutes in 90% of users. 
• 52% of participants who used psilocybin prophylactically (as prevention) reported that it completely prevented attacks from occurring.
• An additional 41% reported that psilocybin was partially efficacious as a prophylactic, not preventing attacks altogether, but alleviating pain significantly. 
• All but one of 20 participants who ingested psilocybin during a period of remission reported that it extended their remission period.
• Psilocybin brought about a complete termination of cluster attacks in 10 participants.

Interestingly, 43% of all participants reported partial or complete efficacy from sub-hallucinogenic doses of psilocybin or LSD, leading the authors to infer that perhaps the therapeutic efficacy of psychedelics in treating cluster headaches may be via a mechanism entirely unrelated to their psychoactive effects. 

In 2015, members of Clusterbusters, Inc., a non-profit organization dedicated to the education and research of cluster headaches, developed an internet medication use survey to extend understanding of the effects of both conventional and alternative cluster headache treatments.

Almost 70% of survey respondents who used psilocybin as an abortive therapy found it to be at least moderately effective, with over 30% of respondents reporting that it was completely effective.

When used as prophylactics, infrequent use of psilocybin provided over 70% of respondents with at least moderate protection from attacks and provided total protection in roughly 40%. Notably, and perhaps unsurprisingly to some, this rate of protection is greater than that reported for conventional prophylactic medications. 

Of course, there are several limitations to this study that must be considered. That said, given the high reported efficacy of psilocybin for the treatment of what is a well-established treatment-resistant condition, it is difficult, and perhaps even irresponsible, to dismiss what are encouraging findings.

The analgesic potential of non-hallucinogenic psychedelics 

In an attempt to determine whether psychedelic-induced relief of cluster headache has anything to do with the psychedelic experience, researchers at Hannover Medical School in Germany decided to investigate the efficacy of a non-hallucinogenic analog of LSD called 2-bromo-lysergic acid diethylamide, or BOL-148. 

In this study, BOL-148 was administered in the presence of two medical professionals once every five days for a total of three doses. The 4 participants were asked to continue filling out daily headache diaries for at least one month or until they experienced attacks for 3 consecutive days. 

BOL-148 was shown to:

• Successfully terminate cluster periods. 
• Extend remission periods for up to 9 months. 
• Significantly reduce attack frequency. 
• Initiate transition from the chronic form of cluster headache to the episodic form. 
• Reduce pain intensity to the point where acute interventions were no longer required. 

Of particular note, is the fact that regular administration of BOL-148 did not result in cross-tolerance to LSD, suggesting that its’ analgesic effects, at least as they relate to cluster headache, appear to be unrelated to the 5-HT2A receptor responsible for the psychoactive effects of psychedelics. Therefore, psilocybin’s efficacy as a treatment for cluster headaches may have little to do with the psychedelic experience.

Again, due to the unblinded and uncontrolled nature of this case series, results must be regarded as preliminary. However, controlled trials have shown the placebo response for cluster headache to either be very low or non-existent, so it is highly unlikely that the outcomes of this case series are artifactual.  

Treating migraines with psilocybin 

With a prevalence of approximately 15%, migraine is one of the most common headache disorders and is among the top three diseases in the world. Current treatments for migraine have limited efficacy and are associated with a range of unpleasant side effects, which make it difficult for patients to experience long-term relief.

Can psilocybin help with the pain of migraines?

Evidence suggesting that psilocybin may have clinical efficacy as a migraine treatment has existed since the 60s’, albeit preliminary.

In 2017, a group of psychologists from Karlstad University in Sweden analyzed data from the online forums Shroomery.org, Bluelight.org, and Clusterbusters.org, to better understand users’ experiences self-treating migraine with psychedelics who had previously been resistant to other migraine treatments.

Here, psilocybin was reported to reduce both the frequency and intensity of migraine attacks. Psilocybin was also reported to be effective as a prophylactic, and even induced full remission in some users. The average user administered 1 gram of dried psilocybe cubensis occasionally, however, species, dose, and frequency of administration varied between users depending on their sensitivity and desired experience.

As one user put it, “You might have to experiment with the dose a bit because what works for one person does not necessarily work for another.” — a statement that is perhaps true of many things…

Interestingly, a few psilocybin users reported that it initially intensified pain temporarily, before any mitigating or preventative effects set in. Also, the majority of sufferers following a microdose regiment reported great success, which is once again suggestive that psilocybin’s analgesic effects may be unrelated to its psychoactive effects.

The first controlled study investigating the effects of psilocybin in migraine was conducted in 2020. In this study, participants, who had a frequency of migraine attacks of 2 per week or more, reported a significantly greater reduction in migraine than after placebo.

More specifically, 80% of participants experienced a 25% reduction in weekly migraine days, 50% experienced a 50% reduction in migraine days, and 30% experienced a 75% reduction in migraines. The largest reduction in migraine days for placebo was just 20%, with 30% of participants having experienced no pain relief at all after placebo. 

In addition to migraine attacks, psilocybin was more effective than placebo at reducing pain severity, attack-related functional impairment, and weekly migraine abortive days.

Psilocybin and chronic pain 

Considered one of the leading causes of disability worldwide, approximately 20% of the population lives with chronic pain. Chronic pain is defined as any pain that lasts for more than three months and may remain even after the original cause of pain fully heals. Chronic Low Back Pain, Headache, and Fibromyalgia are common examples of chronic pain conditions. 

To inform the design of a fibromyalgia trial they plan to run in the not too distant future, researchers at Imperial College in London conducted what’s called a ‘patient-involvement’ (PI) to gather information from individuals who self-medicate with psychedelics. 11 individuals, who had been living with chronic pain for up to 25 years and had tried up to 14 chronic pain treatments, participated in a semi-structured interview.

All participants reported lasting changes in how they perceived their condition, claiming that psilocybin enabled them to become more accepting and feel more in control of their pain. They reported that increased acceptance of their situation improved their confidence and inspired feelings of hope for the future.

Accounts like the following exemplify how psilocybin-induced psychedelic experiences can provide a somewhat mellowing and uplifting sense of perspective: 

“Every time I’ve done (mushrooms), it’s always reminded me that there’s a light at the end of the tunnel, that (the pain) might suck, but it’s not that bad. It’s totally manageable, I can be happy while all of this is going on.”

Some participants also reported that they had entirely forgotten about their pain for the duration of their psilocybin experience, and as a consequence, the majority experienced complete analgesia. Consistent with the observations of Dr. Kast in the 1960s, this is suggestive of a re-allocation of attention to the psychedelic effects of psilocybin vs the pain. 

Most participants in this study experienced enduring analgesic effects with psilocybin. This is in stark contrast to patients’ experience with existing opioid medications which failed to provide any relief, and, in some cases, even exacerbated symptoms. 

One interviewee made the following comparison between psilocybin and hydromorphone:

“I equate (hydromorphone) to putting your phone on vibrate—it’s still ringing, it doesn’t mean it’s off. But the mushrooms turned the phone off. It’s not masking my pain in any way. It took (the pain) out back and shot it, and I’m good now.”

Interestingly, the two participants for whom psilocybin eradicated pain were also the only two to report experiencing “somatic discharge”, a phenomenon that can loosely be defined as an act of intense physical release. It is believed that somatic discharge, which has shown to be cathartic in individuals with trauma, for example, may also be effective for those suffering from chronic pain. 

In general, participants using both high and low doses of psilocybin reported being surprised by its’ perceived powerful efficacy. Most regained the ability to physically function, and many described feeling more healthy after their psilocybin use.  

The researcher’s analysis indicates that positive reframing of one’s relationship with chronic pain, and an increase in somatic presence, could potentially be responsible for psilocybin’s perceived efficacy as a treatment for chronic pain.

How Does Psilocybin Treat Pain?

Now that the “Can psilocybin help with pain” question has been somewhat answered, it’s time to figure out how it might do it. While the exact mechanism of action responsible for psilocybin’s pain treating capacity is, as yet, unclear, psychedelics may alleviate pain via the actions that initiate psychedelic effects by indirectly affecting an individual’s experience of pain, or, alternatively, via actions within physiological systems that are directly involved in pain processing and modulation.

In any case, the following mechanisms have been proposed.

Psilocybin’s activity at the 5-HT2A receptor 

One mechanism that could be responsible for psilocybin’s antinociceptive effects is its activation of the 5-HT2A serotonin receptor. There are many similarities between the way in which psilocybin activates the 5-HT2A receptor and the pathways involved in modulating nociceptive pain, i.e. any pain caused by stimuli harming the body.  

Activity of the 5-HT2A receptor has been shown to upregulate specific genes associated with neuroplasticity and reduce inflammation produced by a particular cytokine involved in infections and cancers called tumor necrosis factor-alpha (TNF-α).

Psilocybin-assisted treatment also causes downregulation of 5-HT2A receptor binding sites, likely caused by the receptor relocating from the surface of the cell to compartments within the cell. Although studies have yet to investigate whether psilocybin causes 5-HT2A to be redistributed within specific pain-sensing neurons in the spinal cord, this effect could lessen the sensitivity of, or completely desensitize, pain responses in neuropathic pain conditions.

Research also indicates that mood improvements and distraction can have a profound impact on pain perception. Randomized controlled trials conducted by researchers at New York University and Johns Hopkins University have shown that psilocybin-assisted psychotherapy significantly reduces symptoms of anxiety and depression in patients with life-threatening cancer.

In the case of phantom limb pain, psilocybin’s activation of the 5-HT2A receptor may make the brain more receptive to MVF by enhancing communication between the brain regions involved in vision and processing of sensory information, improving its efficacy as a consequence. 

Disruption of neural networks 

It is thought that psilocybin initiates the psychedelic experience, via its action at the 5-HT2A serotonin receptor, by altering neural connectivity. Specifically, psilocybin disrupts an established network of brain regions known as the Default Mode Network (DMN).

The DMN is a network of interacting brain regions that is most active when individuals are at rest or relatively inactive. It is associated with an individual’s internal mental state, and is thought to play a central role in introspection and self-awareness.  

Studies using functional magnetic resonance imaging (fMRI) technology to measure brain activity suggest that this disruption of the DMN is at least partially responsible for psilocybin’s efficacy in treating psychiatric disorders. Of course, supportive psychotherapy delivered as an adjunct to psilocybin administration is integral to positive therapeutic outcomes in psychiatric indications. Perhaps, for the treatment of pain, psilocybin could be delivered in conjunction with body-centered therapies such as Somatic Experiencing. 

Interestingly, evidence suggests that chronic pain impairs activity in DMN, leading to negative cognitive effects and altered perceptions of self. It is, therefore, possible that psilocybin’s inhibition of activity in the DMN may affect brain regions implicated in chronic pain associated with pain disorders.

Psilocybin has also been shown to disintegrate and subsequently enhance communication between distant brain networks that do not ordinarily communicate. Incidentally, these same networks are involved in pain perception, specifically complex, chronic neuropathic pain caused by damaged nerve fibers.

Eventually, this increase in communication solidifies, forming secure functional connections. According to medicinal chemist David Nichols, a well-renowned figure in psychedelic circles, this atypical pattern of neural connectivity may be reinforced by psilocybin’s anti-inflammatory properties, thus allowing more optimal reconnections to occur.

The brain’s ability to grow and reorganize allowing it to function differently is often referred to as neuroplasticity. Considering the mounting evidence indicating an association between chronic pain states and alterations in brain connectivity, psilocybin’s ability to stimulate neural plasticity is perhaps one of the most likely explanations for its apparent pain-treating properties. 

Can Psilocybin Help With Pain?

Findings from case series and preliminary studies complement research in past decades with psilocybin demonstrating enduring therapeutic effects in treating a range of psychiatric disorders, including anxiety, depression, and substance use disorders. Now, recently conducted research, including the first-ever controlled trial investigating psilocybin’s efficacy as a migraine treatment, appears to be answering the question of “Can Psilocybin Help With Pain?”

Findings in studies using non-hallucinogenic compounds and sub-hallucinogenic psychedelic doses suggest that the lasting therapeutic action of psilocybin in pain disorders may be unrelated to the psychedelic experience. This raises the interesting possibility that the widely purported pain-relieving effects of psilocybin may not be dependent on its psychedelic effects.

To verify this promising research, results will need to be replicated in randomized placebo-controlled investigations using larger samples. While the findings to date are exciting, and particularly encouraging for those suffering from pain disorders, additional controlled investigations must be completed in the coming years so that we can better understand psilocybin’s full analgesic power.

Furthermore, clinical investigations that include varying doses and repeated administration will hopefully shine a light on the question of whether or not psilocybin’s analgesic effects are dose-dependent, and help to determine its efficacy as a transitional and/or prophylactic treatment. 

In parallel with clinical trials, mechanistic studies could produce useful information geared towards the development of novel drugs, perhaps modified to strip away unnecessary effects and maximize analgesic properties. 

One thing is for sure: As of now, there is a desperate need for safer, more effective pain treatments that do not necessitate repeated, daily administration, do not exacerbate existing symptoms, and do not cause unpleasant side effects. Whether psilocybin will prove to fill this glaring medical void remains to be seen, but preliminary signs are very encouraging. 

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