Are psychedelics the answer to chronic pain: A review of current literature

We aim to provide an evidence‐based overview of the use of psychedelics in chronic pain, specifically LSD and psilocybin.

paracetamol (acetaminophen) or nonsteroidal inflammatory drugs (NSAIDs). Although there is an indication for opioids in acute pain and cancer pain, opioids are controversial when treating chronic pain. Despite clear restrictive guidelines, many chronic pain patients are prescribed strong opioids, contributing to the current opioid epidemic. 5 Therefore, there is an urgent need to provide alternatives to opioids. Currently, the analgesic effects of psychoactive agents like psychedelics (LSD, DMT, psilocybin) and antipsychotics are being explored in chronic pain conditions. This increased interest in the use of psychedelics in the management of chronic pain is also found in the literature. 6,7 Special interest is being paid to the use of "classic hallucinogens," because of their antagonistic action on the serotonin-2A (5-HT 2A ) receptor, which may play an important role in the treatment of chronic pain. Examples of "classic hallucinogens" are lysergic acid diethylamide (LSD), psilocybin, and ayahuasca. For centuries, these substances have been used either recreationally or spiritually by different cultures and have shown potential benefits in psychiatric and chronic pain disorders. 6,8 However, the substances were stigmatized in the 1960 s due to their recreational overuse and were classified as a Schedule 1 drug by the Controlled Substances Act in the USA, making it impossible to conduct further clinical research. 9 Although human studies with psychedelics have been resumed in recent years, barriers and challenges remain.
Currently, a number of large trials are being conducted on the effects of LSD and psilocybin on psychiatric disorders (e.g., therapy resistant depression, anxiety in end-of-life care, and addiction). [10][11][12][13] These provide promising results on overall efficacy and safety and extend our knowledge on the mechanisms of action. However, studies of the analgesic effects of these psychedelics are limited to small sample sizes and are non-randomized. Other psychoactive compounds like ketamine and cannabis have also shown efficacy in chronic pain disorders, but these are not included in this review as they have different mechanisms of action. 14,15 In this article, we review the current evidence on the effectiveness of psychedelics in the management of chronic pain, specifically LSD and psilocybin. This includes their potential therapeutic value in cancer/palliative related pain, phantom limb pain, cluster headache, and migraine, based on the available literature. Conclusions are drawn on potential mechanisms of action, effectiveness and safety in patients with chronic pain conditions. Additionally, we include recommendations for future research.

What are psychedelics?
Psychedelics are powerful psychoactive substances that can alter perception and mood and affect cognitive processes. 9 Classic hallucinogens, also referred to as serotonergic hallucinogens, are defined as one group because they act as agonists of the serotonergic 5-HT 2A receptor. 6 As shown in Figure 1, they are divided in three main classes of alkaloids: (1) The phenethylamines, consisting of substances with a similar chemical structure to norepinephrine, epinephrine and dopamine, with mescaline as the prototypical drug; (2) the tryptamines, with a structure similar to serotonin, with psilocybin and N,N-Dimethyltryptamine (DMT, ayahuasca) being the most well-known; (3) ergolines, tetracyclic ergoline derivatives, with LSD as prototypical member. 6,9 Classic hallucinogens are commonly being used either recreationally or spiritually by different cultures due to the short-term hallucinogenic effects. These commonly exist out of sensory and physical effects, like hallucinations, change in perception of time, intensified feelings and experiences, increased energy.

Lysergic acid diethylamide
In 1938, LSD was synthesized by the Swiss chemist Albert Hofmann, but its psychoactive effects remained undiscovered until 1943. 16 It is a 5-HT receptor agonist, which also acts on dopaminergic and adrenergic receptors. It is the most potent psychedelic substance available, with a threshold dose to initiate a psychedelic effect of between 20 and 30 μg (oral). Recreational doses often range from 50 to 200 μg. Psychological effects occur 30-45 min after ingestion and can persist for 6-9 h. 7 Due to its potency, LSD is mostly taken in a diluted liquid solution or laid onto blotter paper. In theory it can be administered orally, sublingually, or by insufflation or injection.

Psilocybin and psilocin
Hofmann also isolated psilocybin from so-called "magic mushrooms." After oral ingestion, psilocybin is mainly metabolized to the active compound psilocin. This is a full partial agonist of the 5-HT receptor, with a high affinity for 5-HT 2B and 5-HT 2C subtypes and lower affinity for the 5-HT 2A receptor. Psychedelic effects occur with doses between 4 and 10 mg, and recreational doses range from 10 to 50 mg (oral). First effects appear 10-40 min after ingestion and persist for up to 6 h. 7 Psilocybin is commonly administered orally but can also be injected intravenously.

M ET HOD S
For this narrative review, the PubMed database was searched for literature on this topic. A search strategy was made in cooperation with a Liberian of the Radboud University. The initial search was conducted in January 2021 following the created search strategy in Appendix 1. This resulted in a total of 632 articles, which were evaluated.
An additional search was performed on 24 February 2022 to screen for research published in 2021-2022. A total of 62 articles were evaluated.
Evaluation was done by one reviewer and if in doubt a second independent reviewer was asked. Evaluation was done by judging the relevance based on title/abstract. If relevant, full text was read to judge if the article was useful to answer one of the research questions. The searches were exported to "Endnote" and "Rayyan" was used for judging. Quality of the included studies were not systematically assessed.

POT EN T I A L M EC H A N I SM S OF ACT ION I N C H RON IC PA I N
The development of chronic pain and the working mechanisms of psychedelics are complex processes. We provide a review of the mechanisms associated with their potential role in the management of chronic pain.

Pharmacological mechanisms
Psychedelics primarily mediate their effects through activation of the 5-HT 2A receptor. This is supported by research showing that psychedelic effects of LSD are blocked by a 5-HT 2A receptor antagonist like ketanserin. 17 Those of psilocybin can be predicted by the degree of 5-HT 2A occupancy in the human brain, as demonstrated in an imaging study using a 5-HT 2A radioligand tracer 18 showing the cerebral cortex is especially dense in 5-HT 2A receptors, with high regional heterogeneity. These receptors are relatively sparse in the sensorimotor cortex, and dense in the visual association cortices. The 5-HT 2A receptors are localized on the glutamatergic "excitatory" pyramidal cells in layer V of the cortex, and to a lesser extent on the "inhibitory" GABAergic interneurons. 19,20 Activation of the 5-HT 2A receptor produces several neurophysiological responses in the brain, these are discussed later.
It is known that the 5-HT receptors are involved in peripheral and centrally mediated pain processes. They project onto the dorsal horn of the spinal cord, where primary afferent fibers convey nociceptive signals. inhibition of pain and injecting 5-HT directly into the spinal cord has antinociceptive effects. 21 However, the role of 5-HT pathways is bidirectional, and its inhibitory or facilitating influence on pain depends on whether pain is acute or chronic. It is suggested that in chronic pain conditions, the descending 5-HT pathways have an antinociceptive influence, while 5-HT 2A receptors in the periphery promote inflammatory pain. 21 Rat studies suggest that LSD has full antagonistic action at the 5-HT 1A receptor in the dorsal raphe, a structure involved in descending pain inhibitory processes. Via this pathway, LSD could possibly inhibit nociceptive processes in the central nervous system. 7,22 However, the mechanisms of psychedelics in chronic pain are not fully understood, and many hypotheses regarding 5-HT receptors and their role in chronic pain have been described in the literature. It should be noted that this review does not include all of these hypotheses.

Functional connectivity of the brain
The human brain is composed of several anatomically distinct regions, which are functionally connected through an organized network called functional connectivity (FC). The brain network dynamics can be revealed through functional Magnetic Resonance Imaging (fMRI). fMRI studies show how brain regions are connected and how these connections are affected in different physiological and pathological states. The default mode network (DMN) refers to connections between certain brain regions essential for normal, everyday consciousness. The DMN is most active when a person is in resting state in which neural activity decreases, reaching a baseline or "default" level of neural activity. Key areas associated with the DMN are found in the cortex related to emotion and memory rather than the sensorimotor cortex. 23 The DMN is, therefore, hypothesized to be the neurological basis for the "ego" or sense of self. Overactivity of the DMN is associated with several mental health conditions, and evidence suggests that chronic pain also disrupts the DMN's functioning. 24,25 The activation of the 5-HT 2A receptor facilitated by psychedelics increases the excitation of the neurons, resulting in alterations in cortical signaling. The resulting highly disordered state (high entropy) is referred to as the return to the "primary state". 26 Here, the connections of the DMN are broken down and new, unexpected connections between brain networks can be made. 27 As described by Elman et al., 28 current research implicates effects on these brain connections via immediate and prolonged changes in dendritic plasticity. A schematic overview of this activity of psilocybin was provided by Nutt et al. 12 Additional evidence shows that decreased markers for neuronal activity and reduced blood flows in key brain regions are implicated in psychedelic drug actions. 29 This may also contribute to decreased stability between brain networks and an alteration in connectivity. 6 It is hypothesized that the new functional connections may remain through local anti-inflammatory effects, to allow "healthy" reconnections after the drug's effect wears off. 28,30 The psychedelic-induced brain network disruption, followed by healthy reconnections, may provide an explanation of how psychedelics influence certain brain regions involved in chronic pain conditions. Evidence also suggests that psychedelics can inhibit the anterior insula cortices in the brain. When pain becomes a chronic, a shift from the posterior to the anterior insula cortex reflects the transition from nociceptive to emotional responses associated with pain. 7 Inhibiting this emotional response may alter the pain perception in these patients.

Inflammatory response
Studies by Nichols et al. 9,30 suggest the antiinflammatory potential of psychedelics. Activation of 5-HT 2A results in a cascade of signal transduction processes, which result in inhibition of tumor necrosis factor (TNF). 31 TNF is an important mediator in various inflammatory, infectious, and malignant conditions. Neuroinflammation is considered to play a key role in the development of chronic neuropathic pain conditions. Research has shown an association between TNF and neuropathic pain. 32,33 Therefore, the inhibition of TNF may be a contributing factor to the longterm analgesic effects of psychedelics.

Blood pressure-related hypoalgesia
It has been suggested that LSD's vasoconstrictive properties, leading to an elevation in blood pressure, may also play a role in the analgesic effects. Studies have shown that elevations in blood pressure are associated with an increased pain tolerance, reducing the intensity of acute pain stimuli. 34 One study on LSD with 24 healthy volunteers who received several small doses showed that a dose of 20 μg LSD significantly reduced pain perception compared to placebo; this was associated with the slight elevations in blood pressure. 35 Pain may activate the sympathetic nervous system, resulting in an increase in blood pressure, which causes increased stimulation of baroreceptors. In turn, this activates the inhibitory descending pathways originating from the dorsal raphe nucleus, causing the spinal cord to release serotonin and reduce the perception of pain. However, other studies suggest that in chronic pain conditions, elevations in blood pressure can increase pain perception, thus it is unclear whether this could be a potential mechanism. 34

Psychedelic experience and pain
The alterations in perception and mood experienced during the use of psychedelics involve processes that regulate emotion, cognition, memory, and self-awareness. 36 Early research has suggested that the ability of psychedelics to produce unique and overwhelming altered states of consciousness are related to positive and potentially therapeutic after-effects. The so-called "peak experiences" include a strong sense of interconnectedness of all people and things, a sense of timelessness, positive mood, sacredness, encountering ultimate reality, and a feeling that the experience cannot be described in words. The 'psychedelic afterglow' experienced after the psychotropic effects wear off are associated with increased well-being and life satisfaction in healthy subjects. 37 This has mainly been discussed in relation to anxiety, depression, and pain experienced during terminal illness. 38 Although the psychedelic experience could lead to an altered perception of pain, several articles also support the theory that psychotropic effects are not necessary to achieve a therapeutic effect, especially in headache. 39,40

Non analgesic effects
There is a well-known correlation between pain and higher rates of depression and anxiety. 41,42 Some of the first and best-documented therapeutic effects of psychedelics are on cancer-related psychological distress. The first well-designed studies with psychedelic-assisted psychotherapy were performed in these patients and showed remarkable results, with a sustained reduction in anxiety and depression. 10,[43][44][45] This led to the hypothesis that psychedelics could also have beneficial effects in depressed patients without an underlying somatic disease. Subsequently, an open-label study in patients with treatment-resistant depression showed sustained reductions in depressive symptoms. 11 Large RCTs on the effects of psilocybin and treatment-resistant depression and major depressive disorders are ongoing. [46][47][48] Interestingly, a recently published RCT by Carhart et al. 49 showed no significant difference between psilocybin and escitalopram in antidepressant effects. Secondary outcomes did favor psilocybin, but further research is necessary. Several studies also note the efficacy in alcohol use disorder, tobacco dependence, anorexia nervosa, and obsessive-compulsive disorders. 13 The enduring effects in these psychiatric disorders are possibly related to the activation of the 5-HT 2A receptor and neuroplasticity in key circuits relevant to treating psychiatric disorders. 12

E F F ECT I V EN E S S I N C H RON IC PA I N Palliative/cancer-related pain
Cancer is one of the leading causes of morbidity and mortality worldwide. 50 Patients with advanced or terminal cancer often suffer from physical and psychological distress. The intense pain often experienced by these patients can arise from the tumor compressing or infiltrating nearby tissues, or from treatments and immune responses. 51 Articles studying the use of psychedelics to treat cancer patients often use the term 'existential distress,' which includes a feeling of demoralization, hopelessness, loss of purpose, and isolation. Cancer is often associated with several adverse outcomes like anxiety, depression, desire for hastened death, increased pain perception, and decreased quality of life. 38,44 Psychological interventions have been developed to address these patients' existential distress. Pharmacological interventions, often including opioids, aim at reducing this pain. 52 It has been suggested that psychedelics could treat both psychological and physical distress in cancer patients.
The first paper on the analgesic potential of psychedelics by Kast and Collins appeared in the 1960s. They performed a comparative efficacy trial with LSD (100 μg) and two opioids in 50 severely ill patients, of which most had terminal cancer. LSD significantly reduced pain compared to the opioids, and it was hypothesized that the analgesic effects of LSD were related to its ability to alter pain attention and perception. 53 Kast extended the research to 128 pre-terminally ill patients all suffering from metastatic cancer. One dose of LSD (100 μg) diminished pain acutely and the effect could last up to 2 weeks. He also included psychological outcomes and found that the general mood of participants was elevated, that they had less concerns about death, and that their sleep was improved. Patients also experienced some mild visual distortions or mild hallucinations and anxiety. 54 These psychological factors became the primary focus of research involving psychedelic treatment in cancer patients. The studies paid special attention to set, setting and pre-and post-treatment psychotherapy sessions. The first study by Pahnke et al., 55 including 22 case series of terminal metastatic cancer patients with depression, claimed that LSD-assisted psychotherapy improved pain, mood, anxiety and fear of death, with minimal adverse effects. A study by Grof et al. analyzed 31 cancer patients that had received LSD-assisted psychotherapy (200-500 μg) and showed that it resulted in relief from emotional distress (depression, tension, anxiety, insomnia, isolation), relief from pain, and changes in attitude towards death. Analgesic effects were observed for weeks up to several months. 56 Kurland et al. included a detailed description of four cases with advanced cancer receiving LSD-assisted psychotherapy and mention the importance of reaching the "psychedelic peak experience" for optimal therapeutic effects. 57 Research on psychedelic-assisted psychotherapy to treat cancer-related psychological distress resumed in the 21st century, but relief of pain was no longer included as an outcome. Small RCTs including LSD-and psilocybin-assisted psychotherapy strongly suggest a positive effect of these treatments on anxiety, depression, existential distress, and quality of life in cancer patients. 10,43,[58][59][60] Phase 3 trials with psilocybin-assisted psychotherapy are currently proposed in the US and Europe. This may lead to a major break-through for psychedelics as a treatment for cancer patients, with the expected rapid and sustained effect on several psychological factors, with an additional potential for pain management.

Phantom limb pain
Approximately 90% of the patients who undergo amputation experience phantom limb sensation. In a considerable portion (roughly two-thirds), this sensation is extremely painful and is referred to as phantom limb pain (PLP). Several theories about PLP's causes exist, including complex signals from the brain and spinal cord, which are disrupted and reorganized in such a way that pain is experienced. Several medications prescribed for PLP (e.g., antidepressants, opioids) are only effective in a small group of patients. 61 A potential role for psychedelic treatment has been suggested in the literature, although evidence is limited. In a study by Fanciullacci et al., seven patients with PLP received 25 μg of LSD daily for 1 week followed by a daily dose of 50 μg for 2 weeks. In five patients, pain and use of analgesics was reduced. In two out of five, the reduction in pain was so striking that the use of analgesics was no longer needed. A Japanese study by Kuromaru et al. 62 included eight patients with PLP or phantom limb sensation and found a significant and sustained reduction in phantom limb sensation in seven out of eight patients and pain relief in five of the six patients. An older review on the phantom limb phenomenon also suggests a potential therapeutic role of psychedelics in PLP treatment. Fischer 63 hypothesized that psychedelics could disturb the body image (sensory-cerebral space-time) as well as interfere with re-adaption.
Recently, mirror visual-feedback (MVF), where the intact limb is placed in front of a mirror so that the reflection is optically on the felt position of the phantom, has been described as an effective treatment. This appears to restore the visual-motor loop and alleviate the pain. This was combined with psilocybin treatment in a case report. When psilocybin was used alone, the patients experienced a striking relief of pain during psychoactive effects of the drug. When combined with MVF, the patient experienced a reduction in pain that persisted for several weeks. 64 The activation of the 5-HT 2A receptor might make the brain more receptive to MVF by enhancing communication between the visual and somatosensory cortex. Increased functional connections are made and neuroplasticity is influenced, which may result in long-lasting pain relief. 64,65 Although evidence is limited, this suggests a promising mechanism for the relief of PLP in patients.

Cluster headache
The prevalence of cluster headache (CH) is estimated at 0.1% of the population worldwide; it is considered one of the most painful medical conditions. The term "suicide headache" reflects the intense pain experienced during attacks. The "attack" usually consists of severe, unilateral pain around the eye, which can occur multiple times daily, at predictable times. A "cluster" is the period in which attacks occur regularly, ranging from weeks to years, also occurring at predictable times. During "remission periods," there is a prolonged attack-free interval. 66 About 15%-20% of CH patients suffer from chronic CH, with only brief or no remission periods. 67 Therapies for these patients often range from refractory to conventional. Abortive treatment options consist of highflow oxygen inhalation and subcutaneous sumatriptan administration (Figure 2). High doses of verapamil, corticosteroids, or other neuromodulators are used as prophylactic treatments and often induce side-effects. 68 Given the extremely painful and disabling nature of CH, there is an urgent need for effective treatments. Several studies on the effects of psychedelics on headaches and specifically CH have been published.
The first therapeutic effects of psychedelics on headache were reported in the 19th century. Experiments were conducted with peyote, a mescaline containing cactus, and beneficial results were found for 'nervous headaches'. Remarkably, the use of mescaline was later reported to cause headache, and research was discontinued. 69 Later, when LSD was researched in the 1950 s for its therapeutic effects, an effect on headaches, particularly migraine, was found. Complete remission of the headaches lasting 9 months to 2 years in four of six patients was reported. 70 The first-time psychedelics were specifically mentioned for the treatment of cluster headaches was in 1963 by Dr. Sicuteri. 71 However, the exact phenomena of what we now call 'cluster headache' was only defined in the 1980 s, it is arguable whether research from before this date is reliable.
The interest in psychedelics as a potential treatment for CH returned in 2001 when a CH patient created an online forum (clust erbus ter.org) and shared his discovery that the use of LSD led to complete remission of his CH. Subsequently, a small study based on 53 similar self-medicating CH patients was published. People selfmedicating with psilocybin reported that it could lead to acute abortion of their attacks. Additionally, selfmedicating with either LSD or psilocybin could lead to a termination of cluster periods and an extension of the remission periods. This was the first time a substance was reported to terminate cluster periods. Additionally, they reported that a single dose of LSD could be sufficient to induce a remission, unlike other ergot-based medication that must be taken daily. Finally, sub-hallucinogenic doses were reported to be effective, suggesting that psychoactive experiences were not necessary to treat CH. 72 A study by Karst et al. followed, researching the effect of the non-hallucinogenic LSD derivative, 2-bromo-LSD (BOL-148). This experimental substance was assumed to be a safe and legal alternative for other illicit psychedelic substances. 73 This study included five cases of seriously affected CH sufferers who did not respond to verapamil. Results showed that three single doses of BOL-148 (30 μg/kg/body weight) within 10 days could break a CH cycle or considerably improve the frequency and intensity of attacks in four out of five patients. In one patient this resulted in a shift from the chronic to the episodic form, with a remission period extended for many months. The compound showed no serious side-effects. 73 Reviews aiming at unconventional treatments for CH report that BOL-148 is a potentially promising substance for the treatment of CH. 74,75 Lysergic acid amide (LSA) containing seeds are also mentioned as a potential treatment option (Figure 2). LSA is easier to obtain, but the ingestion is often accompanied with gastro-intestinal side-effects making it an unpleasant experience. It is less likely to induce hallucinogenic side-effects and is listed as a Schedule 3 drug, which makes it easier to perform research. 69,75 However, the large variation in seeds makes it difficult to draw conclusions from people selfmedicating with the substance. 69 More recently, as the number of CH patients using unconventional treatments such as psychedelics increased, studies suggested that CH patients were more prone to illicit drug use. 76,77 However, an Italian survey in 54 CH patients reported that psychedelics were not commonly used for recreational purposes (the experience of psychotropic effects) but for their effectiveness in terms of CH treatment. A patient's choice to divert to using psychedelics was often driven by their dissatisfaction with conventional treatments. Additionally, they reported that the prophylactic effects of psychedelics were sustained F I G U R E 2 Chemical structures of lysergic acid derivatives used for the treatment of cluster headaches and migraine disorders. even when only consumed a few times a year and at subhallucinogenic doses. 39 In 2015, Schindler et al. conducted a larger survey with 496 participants from clust erbus ter.org and other headache forums or clinics. They considered both conventional and unconventional treatment options and included a variety of demographics. They found that psilocybin was often tried as an abortive treatment in one-third of the participants, with two-third of these participants finding it at least moderately effective, and one-third finding it completely effective. As a prophylactic treatment, psilocybin and LSD provided at least moderate protection from attacks in 70% of the participants. In 40%, complete remission was reported, higher than in any other conventional treatment. LSA was reported to have a slightly smaller effect. Ten participants used BOL-148, reporting that this provided at least moderate protection from attacks in 60% of cases. Participants described relatively infrequent use of psychedelics compared to other prophylactic treatment options. A single dose of psilocybin or LSD was able to prevent attacks, shorten/abort clusters, or induce remission, although the number is small and includes uncontrolled variables. Sub-hallucinogenic doses were used by several participants, again suggesting that psychoactive effects are not necessary for a therapeutic effect. 40 Andersson et al. conducted a qualitative study to improve insights in the use of psychedelics in CH and migraines. They concluded that patients are often desperate for an effective treatment and use psychedelics as a last resort. These patients are often not interested in the psychoactive effects and would rather avoid them by using sub-hallucinogenic doses. Psilocybin and LSD were most often reported, with significant reduction of frequency and intensity of attacks and full remission in several cases, making them effective as both acute and prophylactic treatments, with minimal adverse effects. LSA, DMT and mescalin were also mentioned, but only in small numbers. Participants often limited their use of psychedelics to a few times a year to maintain their symptoms. This was often done using a busting regimen, with moderate to high doses, following the predictable cycles of CH. Microdosing was sometimes preferred as it interfered less with daily responsibilities and could have beneficial effects on people's mood and creativity. 78 This concept of microdosing was extensively researched by Fadiman et al. who offered protocols to people willing to perform their own microdose self-study. People reported having fewer headaches or even total remission of their migraine or other headache conditions. Although the paper suggests that microdosing has no observable effect in chronic pain, it suggested a role in neuropathic pain. 79 Currently, an open-label interventional study in Denmark is investigating the prophylactic effects of psilocybin in CH. Using fMRI, it aims to identify the possible brain mechanisms underlying CH and treatment response. 80 Additionally, two RCTs investigating psilocybin or LSD will further determine these substance's safety and efficacy in CH. 81,82 Migraine Migraine is one of the most common headache disorders, with a prevalence estimated at 15%. It is rated one of the world's most disabling disorders and, despite improved efficacy and tolerability of recent drug classes, additional treatments can still add value. Drugs produced for the treatment of migraine are chemically and pharmacologically similar to LSD and psilocybin ( Figure 2). Methysergide, the first prophylactic drug for migraine, was developed by Dr. Sicuteri. 69 He was the first to discover the importance of serotonin in headaches and he selected several lysergic acid derivatives for tests on 390 headache patients. Although methysergide showed promising results and has been used as a prophylactic treatment for several decades, it was ultimately removed from the market due to unpredictable sideeffects. Another 5-HT 2A agonist, dihydroergotamine, is still used for the treatment of migraine.
Research on psychedelics was only recently recontinued when Schindler et al. performed an exploratory, double-blind, placebo-controlled, cross-over study with psilocybin in 10 migraine patients dissatisfied with their current treatment. They reported promising results, showing a significant reduction in migraine measures (e.g., frequency, pain severity, impairment) in the 2 weeks after a single dose of psilocybin (0.143 mg/kg). The subhallucinogenic dose suggests that the effects in migraine are independent of psychotropic effects, as has also been noted for CH. Additionally, they hypothesize that the immunomodulatory and anti-inflammatory effects of psychedelics play a key role in migraine. 83 Similar to CH, migraine sufferers have also selfmedicated with psychedelics to manage their condition. This was reported by Andersson et al., who found that both psilocybin and LSD were used to cure or alleviate migraine, with prophylactic and acute efficacy. Results discussed for CH patients are also applicable to patients with migraine. 78 The microdose self-study by Fadiman et al. 79 also noted beneficial effects of small doses of psychedelics to treat migraine.

Side effects
Although psychedelics have been portrayed as dangerous drugs, they appear to have a generally favorable safety profile, especially when compared to other analgesic agents like opioids. The physiological toxicity of LSD and psilocybin is low, and several studies confirm that they do not cause organ damage or neurotoxicity. 8,9 Some physiological symptoms noted include dizziness, nausea, blurred vision, and a moderately increased heartrate and blood pressure. As stated in the introduction, the doses for recreational use and for the threshold of effect differ. Based on the founded literature, low doses rarely cause side effects, as recreational doses do. Further research is necessary to establish appropriate treatment doses. Psychedelics may interfere with daily activities when used often, but do not cause physiological dependence, addiction or withdrawal symptoms. 8 Although rare, ergotamine-derived dugs have been associated with retroperitoneal fibrosis due to the endogenous serotonin levels that may lead to fibrotic reactions. 84,85 Some case studies have also shown possible association with valvular heart disease. 86,87 However, these associations have never been proven in LSD or psilocybin.
Generally, safety concerns are mainly focused on the psychological side effects. The acute psychological effects, referred to as 'bad trips," include panic attacks and feelings of anxiety or paranoia. People experiencing a bad trip can pose a danger to themselves or others, although this is rare, especially in controlled settings. 88 Cases of prolonged psychosis after the use of psychedelics have been reported, mainly in people with preexisting mental illness or with a family history of mental illness. 8 Another uncommon risk is the development of hallucinogen persisting perception disorder (HPPD), which is the re-occurrence of hallucinations after the effects of the drug have worn off. 89

Tolerance
Opioids are renowned for the development of tolerance and addiction. In contrast to opioids, psychedelics are not addictive and, therefore, considered to have a low abuse potential. However, LSD and psilocybin have both been associated with tachyphylaxis, that is, drug tolerance takes place very rapidly. LSD dosage should, therefore, be taken once in 3 days. For psilocybin, the effect was similar to baseline after 7 days in absence of further consumption. Both LSD and psilocybin are known for cross-tolerance with other psychedelics, that is, their effect is reduced if taken with other psychedelics.

Other considerations
Johnson et al., have developed a guideline for the safe administration of psychedelics in humans, which includes several factors for consideration when performing research. Several exclusion criteria have to be considered when selecting participants. These include pregnancy, personal or family history of mental illness (schizophrenia, psychosis, bipolar disorders), significant cardiovascular medical history, and the use of other psychoactive medication (e.g., antidepressants, antipsychotics). 8 It is likely that many patients with chronic pain use antidepressants, so special attention should be paid when recruiting these as participants. Medication may have to be discontinued or patients may have to be excluded if this is not feasible.
Additionally, patients may be more vulnerable in this population. Those patients with cancer-related pain can be extremely ill, which may increase the risk of adverse effects. However, recent studies on psychedelics and cancer-related psychological disorders have not shown any significant adverse events. 10,58 Patients may also have several psychological complaints like depression and anxiety. To prevent participants from experiencing a bad trip, researchers should be well trained and able to guide the participant through the psychedelic experience. This may be less of a concern when sub-hallucinogenic doses are used. Selection of the environment is very important; participants should feel comfortable and safe, with minimal outside distractions. It is also important to appropriately prepare the participants and monitor them during and after the treatment session. Psychotherapy may be useful to guide the patient, especially if higher doses are used. 8

CONC LUSION
Chronic pain is a complex problem with many theories underlying its etiology. Psychedelics may have a potential role in the management of chronic pain, through activation of the 5-HT receptors. It has also been suggested that local anti-inflammatory processes play a role in establishing new connections in the default mode network by neuroplastic effects, with possible influences on brain regions involved in chronic pain. The exact mechanism remains unknown, but we can learn more from studies combining psychedelic treatment with brain imaging. Although the evidence on the efficacy of psychedelics in chronic pain is yet limited and of low quality, there are indications of their analgesic properties.
Sufficient evidence is available to perform phase 3 trials in cancer patients with existential distress. Should these studies confirm the effectiveness and safety of psychedelics in cancer patients, the boundaries currently faced in research could be reconsidered. This may make conducting research with psychedelic drugs more feasible. Subsequently, studies could be initiated to analyze the analgesic effects of psychedelics in cancer patients to confirm this therapeutic effect.
For phantom limb pain, evidence is limited and currently insufficient to draw any conclusions. More case reports of patients using psychedelics to relieve their phantom pain are needed. It has been suggested that the increased connections and neuroplasticity enhanced by psychedelics could make the brain more receptive to treatments like MVF. Small exploratory studies comparing the effect of MVF and MVF with psilocybin are necessary to confirm this.
The importance of serotonin in several headache disorders is well-established. Patients suffering from cluster headache or severe migraine are often in desperate need of an effective treatment, as they are refractory to conventional treatments. Current RCTs may confirm the efficacy and safety of LSD and psilocybin in cluster headache. Subsequently, phase 3 trials should be performed to make legal prescription of psychedelics for severe headache disorders possible. Studies to confirm appropriate dosing regimens are needed, as sub-hallucinogenic doses may be effective and easier to prescribe.
It is important to consider that these substances have a powerful psychoactive potential, and special attention should be paid to the selection of research participants and personnel. Yet, psychedelics have a generally favorable safety profile, especially when compared to opioids. Since patients with chronic pain are in urgent need of effective treatment, and given the current state of the opioid epidemic, it is important to consider psychedelics as an alternative treatment. Further research will improve our knowledge on the mechanisms and efficacy of these drugs and provide hope for chronic pain patients left with no other options.

F U N DI NG I N FOR M AT ION
No funding was received for this manuscript.

CON F L IC T OF I N T E R E ST
There was no conflict of interest for this manuscript.

DATA AVA I L A BI L I T Y STAT E M E N T
Data sharing is not applicable to this article as no datasets were generated or analyzed.