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Official websites use. Share sensitive information only on official, secure websites. Box , Maastricht, MD, the Netherlands. Email: j. Lysergic acid diethylamide LSD is an ergot alkaloid derivative with psychedelic properties that has been implicated in the management of persistent pain. Clinical studies in the s and s have demonstrated profound analgesic effects of full doses of LSD in terminally ill patients, but this line of research evaporated after LSD was scheduled worldwide. The present clinical study is the first to revisit the potential of LSD as an analgesic, and at dose levels which are not expected to produce profound mind-altering effects. A Cold Pressor Test was administered at 1. Ratings of dissociation and psychiatric symptoms as well as assessments of vital signs were included to monitor mental status as well as safety during treatments. LSD elevated mean blood pressure within the normal range and slightly increased ratings of dissociation, anxiety and somatization. The present study provides evidence of a protracted analgesic effect of LSD at a dose that is low enough to avoid a psychedelic experience. The present data warrant further research into the analgesic effects of low doses of LSD in patient populations. Lysergic acid diethylamide LSD is a psychedelic compound that was synthesized by the Swiss chemist Albert Hofmann in He was also the first to describe the psychoactive properties of the compound Hofmann, such as psychosensory changes, illusionary changes of perceived objects, synesthesia, enhanced mental imagery, hyperamnesia, mysticism and ego dissolution Grof, ; Katz et al. LSD may also possess therapeutic properties Liechti, ; Vollenweider and Kometer, and has been implicated in the management of pain Whelan and Johnson, Serotonergic agents, such as ergot alkaloids, have traditionally been used for the acute and preventive treatment of cluster headache and other primary headaches Lambru and Matharu, LSD is yet another ergot alkaloid derivative, but most data supporting the use of LSD as analgesic are based on reports of self-medication. Recent surveys Andersson et al. Moreover, cluster headache patients who had used LSD to treat their condition reported cluster period termination and extension of the remission period Sewell et al. Controlled studies on the efficacy of LSD as an analgesic are virtually absent or dated. LSD showed more protracted and more effective action than the other drugs. LSD strongly reduced subjective pain ratings and increased the number of pain-free periods during the day. Apart from the profound analgesic effects, patients also experienced a psychedelic state, which to some was so disturbing that they refused a second administration of LSD. Overall, these studies suggest a role for LSD in pain management but controlled research is warranted to provide further evidence. From a medical point of view, controlled research on the efficacy of LSD in pain management should focus on non-hallucinogenic, low doses of LSD, which are more manageable and thus preferable over treatment with high doses of LSD that produce full-blown psychedelic effects. We measured their subjective response to pain evoked by a Cold Pressor Test CPT as well as their objective pain tolerance. Based on the preliminary evidence described above, it was expected that LSD would reduce pain perception as compared with placebo treatment. In addition, ratings of dissociation and other psychiatric symptoms as well as assessments of vital signs were included to monitor mental status as well as safety during treatments. Treatment orders were randomly assigned to participants according to a balanced block design. LSD doses 0. The mean SD age of participants was All participants had previous experience with psychedelics and their mean SD frequency of use in the year prior to the study was 2. All participants reported the use of alcohol. All participants were fully informed about all procedures, possible adverse reactions, legal rights and responsibilities, expected benefits, and their right for voluntary termination without consequences. Participants were recruited through advertisements at Maastricht University, via social media, and by word of mouth. Candidate participants were screened and examined by a study physician, who checked for general health, conducted a resting ECG, and took blood and urine samples in which hematology, clinical chemistry, urine, and virology analyses were conducted. Exclusion criteria included history of drug abuse or addiction according to DSM-5 criteria; history of psychiatric and neurological disorders, adverse response to psychedelic drugs anxiety or panic attacks , cardiovascular abnormalities, hypertension, psychotic disorder in first-degree relatives, tobacco smoking of more than 20 cigarettes a day, excessive alcohol use i. Prior to the first treatment day, participants were familiarized with tests and study procedures. They were also instructed to not consume caffeinated or alcoholic beverages on treatment days and to arrive well rested at the test facility. On arrival, participants were screened for the presence of drugs THC, opiates, cocaine, amphetamine in urine, and for alcohol in breath. An additional pregnancy test was given if participants were female. If all tests were found to be negative, participants were allowed to proceed. Blood samples were collected 1. Participants resided in a secluded room that contained a bed, table and chairs. The present study also included assessment of mood, cognition, empathy, and creativity that will be reported elsewhere. The CPT was used to induce a painful sensation according to previously validated procedures Smeets et al. Participants were informed that the procedure could be painful and that they could stop the task at any point without consequences. When you cannot take it any longer, you are allowed to remove your hand from the water. Try, however, to hold on as long as possible. Participants were not aware of this time limit. Dependent measures of the CPT included pain tolerance seconds , i. Water temperature at onset and completion of the CPT were assessed as control measure. Summed together, these subscales form a total dissociative score. The CADSS is specifically designed to be a standardized measure of present-state dissociative symptomatology Bremner et al. Component scores above 15 depersonalization , 36 derealization , and 6 amnesia are considered severe. Component scores below 5 depersonalization , 12 derealization , and 2 amnesia indicate that symptoms are absent or mild. The scale has recently been shown to be sensitive to dissociative effects of psychedelics and drugs of abuse Derntl et al. The BSI contains only the three six-item scales somatization, anxiety, and depression Spitzer et al. The scale was recently shown to be sensitive to the effects of psychedelics Uthaug et al. The samples were rigorously mixed and subsequently centrifuged. An LLOQ of 2. Analyses were carried out by means of the SPSS 25 program series to investigate whether the effects of LSD doses differed from those of placebo. Mean contrast LSD dose versus placebo tests were conducted for measuring the significance of individual dose effects, relative to placebo. Canonical correlation analyses were conducted to understand the association between a set of measures of pain i. Mean SE pain tolerance and subjective ratings of painfulness, unpleasantness and stress during the CPT as a function of Treatment and Time after treatment administration are shown in Figure 1. Ratings of stress were not affected by Treatment, Time after treatment or their interaction. Mean SE pain tolerance and subjective ratings of painfulness, unpleasantness, and stress during the Cold Pressor Test CPT as a function of treatment condition and time after treatment administration. Mean symptom severity ranged from not present to mild across all treatment conditions. The association suggested that increments in symptoms of dissociation are associated with increased pain tolerance and a decrease in subjective pain perception. Mean SE heart rate, systolic and diastolic blood pressure as a function of treatment and time after treatment administration are shown in Figure 3. Heartrate was not affected by Treatment, Time after administration or their interaction. The association suggested that increments in blood pressure are associated with increased pain tolerance and a decrease in subjective pain perception. Controlled studies on the therapeutic potential of LSD in pain management are scarce and date back to the s and s, before LSD was placed into the most restrictive drug control schedule in many countries worldwide. The present controlled clinical study is the first to revisit the potential of LSD as an analgesic in a very long time, and at dose levels that are not expected to produce relevant mind-altering effects. The latter is of importance, as this would increase the acceptability of a psychedelic drug in the management of pain. The findings were also statistically robust. These phenomena, however, seem interrelated, as a reduction in subjective pain experience can explain why participants were able to tolerate pain for a longer period of time. These subjective data clearly indicate that even these low doses of LSD produced pharmacological effects that were noticeable to the participants. However, the magnitude of these effects was small. Increments in level of dissociation that were observed in the present study were also much lower than those observed after regular doses of other compounds that have been implicated in pain management such as ketamine and cannabis. LSD also increased mean blood pressure but did not affect heart rate. Overall, however, levels of systolic and diastolic blood pressure throughout all treatment conditions were well within the normal range, suggesting that the impact of LSD on blood pressure is of limited clinical relevance. The present findings are in line with another recent study Bershad et al. Elevations in blood pressure after LSD are well described and have been attributed to the vasoconstrictive properties of LSD Passie et al. Previous studies have shown that full, psychedelic doses of LSD i. Overall, the physiological changes observed after low doses of LSD were mild and safe. At present, it is unclear how LSD may influence pain perception. Explanatory models have focused on pharmacological changes in the processing of nociceptive information or on psychological changes in coping with pain. The latter explanation suggests that LSD does not alter nociception and that reductions in subjective pain perception arise from attentional reorienting from pain sensation to the psychedelic experience of LSD Kast and Collins, Alternatively, LSD may be analgesic by promoting self-transcendence, in much the same way that meditation-induced self-transcendence is Garland and Fredrickson, ; Garland et al. Such analgesic mechanism might be most pronounced in moderate to high-dose LSD sessions, or potentially, in treatments that combine mindfulness meditation interventions with microdoses of LSD. In any of these scenarios one would expect the magnitude of pain relief to be intrinsically related to the intensity of the psychedelic experience. There was some evidence to support this view in the present study, as a significant canonical association was found between reduced levels of pain perception and increasing levels of dissociation across all treatments. But, these data do indicate that attentional reorientation or self-transcendence may contribute to some degree to the analgesic effect of LSD, even with low doses. The pharmacological view stresses the role of serotonin and 5HT 2A receptors in peripheral and centrally mediated pain processes Whelan and Johnson, In vivo electrophysiology studies in rats suggest that LSD has partial agonist actions at 5-HT 2A receptors and full antagonistic action at 5-HT1A in the dorsal raphe, a structure known to be involved in actions of descending pain inhibitory processes De Gregorio et al. However, the relationship between 5-HT and additional neurotransmitter systems implicated in nociception and how their interconnectivity may be affected by LSD needs further research Whelan and Johnson, An additional or alternative explanation for the analgesic effects of LSD could be hypertension-associated hypoalgesia. Previous studies in animals and humans have shown that blood pressure correlates positively with pain tolerance and negatively with the perception of the intensity of the painful stimulus in acute pain models such as the CPT Sacco et al. How alterations in blood pressure and perception of pain are related is poorly understood, but it has been suggested that pain activates the sympathetic nervous system with resulting increase in blood pressure, which, in turn, causes increased stimulation of baroreceptors that consecutively activate the inhibitory descending pathways that originate from the dorsal raphe nucleus and project to the spinal cord to release serotonin and reduce the perception of pain Bruehl et al. The current data suggest that LSD might enhance this mechanism of pain alleviation either by increasing blood pressure or by stimulation of 5HT 1A and 5HT 2 receptors in the inhibitory descending pathways De Gregorio et al. The present study provides compelling evidence of a moderate and protracted analgesic effect of LSD at a dose that is low enough to avoid a psychedelic experience. The study revealed the minimal dose at which analgesic activity of LSD is effective. Yet, an extended dose-finding study is needed to determine the dose at which analgesic effects of LSD are optimal, i. Such a study could potentially explore the trade-off between increments in treatment efficacy and psychedelic symptoms in a low to medium dose range i. Further research is also needed to replicate the current findings in patient populations who suffer from persistent pain, and comorbid neuropsychiatric ailments, and to determine the potential for tolerance development after repeated dosing. The present data suggest that low doses of LSD might constitute a novel pharmacological therapy that can be efficacious in patients and is devoid of problematic sequelae that are associated with current mainstay drugs, such as opioids Kertesz and Gordon, In conclusion, the present study provides evidence for analgesic activity of LSD in healthy volunteers at doses that are low enough to avoid physiological or mental challenges. NH and NM were responsible for data collection. JR wrote the paper with contributions from all co-authors. As a library, NLM provides access to scientific literature. J Psychopharmacol. Find articles by Johannes G Ramaekers. Find articles by Nadia Hutten. Find articles by Natasha L Mason. Find articles by Patrick Dolder. Find articles by Eef L Theunissen. Find articles by Friederike Holze. Find articles by Matthias E Liechti. Find articles by Amanda Feilding. Find articles by Kim PC Kuypers. Issue date Apr. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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