Trial PaperAnxiety DisordersDepressive DisordersPalliative & End-of-Life DistressSafety & Risk ManagementSet & SettingLSD

Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases

This double-blind cross-over study (n=12) showed that LSD (200 μg, 2 sessions) in combination with psychotherapy was safe to use and trended towards a positive effect on end-of-life anxiety.

Authors

  • Rick Doblin
  • Berra Yazar-Klosinski
  • Peter Gasser

Published

Journal of Nervous and Mental Disease
individual Study

Abstract

A double-blind, randomized, active placebo-controlled pilot study was conducted to examine safety and efficacy of lysergic acid diethylamide (LSD)-assisted psychotherapy in 12 patients with anxiety associated with life-threatening diseases. Treatment included drug-free psychotherapy sessions supplemented by two LSD-assisted psychotherapy sessions 2 to 3 weeks apart. The participants received either 200 μg of LSD (n = 8) or 20 μg of LSD with an open-label crossover to 200 μg of LSD after the initial blinded treatment was unmasked (n = 4). At the 2-month follow-up, positive trends were found via the State-Trait Anxiety Inventory (STAI) in reductions in trait anxiety (p = 0.033) with an effect size of 1.1, and state anxiety was significantly reduced (p = 0.021) with an effect size of 1.2, with no acute or chronic adverse effects persisting beyond 1 day after treatment or treatment-related serious adverse events. STAI reductions were sustained for 12 months. These results indicate that when administered safely in a methodologically rigorous medically supervised psychotherapeutic setting, LSD can reduce anxiety, suggesting that larger controlled studies are warranted.

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Research Summary of 'Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases'

Editorial

βBlossom's Take

This pilot matters because it reintroduced LSD into modern controlled clinical research under a carefully supervised psychotherapy model. Its value is not only the anxiety signal, but the demonstration that an older compound could be studied with active placebo, crossover design and structured preparation without the paper being overwhelmed by safety concerns.

Introduction

Gasser and colleagues situate their work in the context of persistent anxiety, depression and related distress among people with life‑threatening illnesses, noting that many patients fail to obtain satisfactory emotional relief from currently available treatments. Earlier clinical research with lysergic acid diethylamide (LSD) was halted by the early 1970s, leaving uncertainty about its safety and therapeutic potential when combined with psychotherapy under contemporary research standards. The authors identify a gap in the literature for rigorously controlled studies of LSD‑assisted psychotherapy in this patient group. This study set out to evaluate the safety and efficacy of LSD‑assisted psychotherapy for anxiety associated with life‑threatening disease. Using a contemporary randomised, double‑blind, active placebo‑controlled design, the investigators tested a two‑session LSD‑assisted psychotherapy protocol embedded in preparatory and integrative drug‑free psychotherapy, with follow‑up assessments to examine short‑ and longer‑term effects on anxiety and related outcomes.

Methods

The trial is described as a Phase II, double‑blind, active placebo‑controlled, randomised clinical study approved by relevant Swiss and US authorities and conducted in accordance with Good Clinical Practice. Recruitment occurred via media, flyers, hospital and support‑group presentations and physician referral; of about 70 people initially screened, 20 underwent in‑person screening and 12 were enrolled. The extracted text does not clearly report the final analysed group sizes except within results, but it indicates eight participants were randomised to the experimental dose and four to an active placebo, with one placebo participant later excluded from analysis because of a diagnostic correction. Eligibility excluded current alcohol or drug dependence (except caffeine or nicotine), primary psychotic, bipolar I or dissociative disorders, neurocognitive impairment, and pregnancy or nursing. All participants reported scores above 40 on either the state or trait scale of the Spielberger State‑Trait Anxiety Inventory (STAI) at baseline; about half met criteria on the SCID for generalized anxiety disorder, although the investigators note SCID criteria do not clearly distinguish pathology typical of GAD from reactionary anxiety to a life‑threatening illness. The intervention comprised two full‑day experimental sessions scheduled 2–3 weeks apart, embedded within an extended psychotherapeutic process that included two preparatory sessions and three integrative psychotherapy sessions after each experimental day. The experimental sessions took place in a safe, quiet treatment room with a male/female co‑therapist team; participants were encouraged to focus inward with music for approximately two thirds of the session and to have brief conversations for the remainder. The extracted text reports experimental doses as "200 Kg" for the active dose and "20 Kg" for the active placebo; the unit notation in the extraction appears corrupted, and the exact dose units are not clearly reported in the provided text. Participants, therapists, and the independent rater were blind to allocation during the randomised phase. After the 2‑month follow‑up and unmasking, participants assigned to the active placebo could cross over to an open‑label treatment with the higher reported dose. Assessments included physiological monitoring (heart rate, blood pressure) during sessions, adverse event (AE) collection, and documentation of concomitant medications. The STAI (state and trait forms) served as the primary outcome measure. Secondary measures used for exploratory purposes were the EORTC‑QLQ‑C30 (quality of life), the SCL‑90‑R (Global Severity Index), and the Hospital Anxiety and Depression Scale (HADS). Outcomes were collected at baseline, 1 week after experimental sessions, at a 2‑month follow‑up, and at 12 months. A State of Consciousness Questionnaire and daily diaries for medication changes, AEs and pain were also used. For the main analyses, repeated‑measures analysis of variance (ANOVA) assessed change in STAI state and trait scores separately, with an adjusted alpha of 0.025 to account for multiplicity. Effect sizes were estimated using Cohen's d. Because of missing data (two subjects lacked the 1‑week assessment after the second session due to intervening cancer treatments), the investigators dropped that 1‑week post‑second‑session timepoint from the analysis for all participants to avoid reducing sample size. Secondary outcomes were treated as exploratory and were not subjected to formal significance testing to limit multiplicity. One participant randomised to active placebo was excluded post‑hoc when their qualifying diagnosis was corrected and no longer met inclusion criteria.

Results

Participant flow and blinding: Twelve participants entered the study; the extract indicates eight received the experimental dose and four the active placebo, with one placebo participant excluded from analysis after a diagnostic correction, leaving analyses based on eight experimental‑dose and three active‑placebo subjects for some comparisons. Blinding was imperfect: across 24 blinded sessions all participants correctly guessed the dose they had received, and therapists were correct in most sessions and reported high certainty about their judgements, indicating the active placebo dose produced insufficient uncertainty. Primary outcomes (STAI): For trait anxiety, repeated‑measures ANOVA produced a visit × group interaction with p = 0.033 (F = 4.151, df = 2,18), described by the investigators as a trend toward statistical significance given their adjusted alpha. Comparison of baseline with 2‑month follow‑up yielded an effect size of d = 1.1; however, only three of eight experimental‑dose participants dropped below the diagnostic cutoff of 40, while all active‑placebo participants experienced increases in trait anxiety. For state anxiety, the visit × group interaction was significant at p = 0.021 (F = 4.846, df = 2,18) and observed power was 72.7%, meeting the pre‑specified alpha of 0.025. Baseline to 2‑month follow‑up comparison produced an effect size of d = 1.2. Again, only three of eight experimental‑dose participants fell below the diagnostic cutoff after treatment; two active‑placebo participants showed increases. In both STAI outcomes the experimental‑dose group displayed a clear linear decrease over visits, a pattern not seen in the active‑placebo group. Durability: Among participants who ultimately received the higher dose (either in the blind or in crossover), STAI reductions observed at 2 months were sustained at 12 months. The mean differences between 2‑month and 12‑month follow‑ups were small and not statistically significant (trait p = 0.825; state p = 0.531). Secondary measures: Although not formally tested for significance, secondary outcomes were reported to be broadly supportive of the STAI findings. EORTC global health scores rose in the experimental‑dose group from mean (SD) 37.4 (10.0) at baseline to 50.0 (14.9) after two sessions, whereas the active‑placebo group mean decreased from 44.3 (12.7) to 36.0 (12.8). HADS anxiety scores decreased in the experimental‑dose group from 11.7 (3.4) to 8.1 (3.2), compared with a smaller change in the active‑placebo group (11.3 to 10.7); crossover placebo participants who later received the experimental dose showed further decline to 7.0 (2.6). By 12 months all subjects who had received the experimental dose were below the HADS diagnostic cutoff for anxiety (mean 7.6, SD 4.5). SCL‑90‑R Global Severity Index scores also decreased, but exact numerical summaries in the extract are incomplete. Safety and tolerability: No drug‑related severe adverse events were reported; specifically there were no panic reactions, suicidal crises, psychotic states, or medical/psychiatric emergencies requiring hospitalisation. Related AEs comprised common subjective and somatic effects associated with LSD; the experimental‑dose sessions produced more types and a higher frequency/intensity of AEs (18 types) than active placebo (8 types). Most AEs resolved as drug effects subsided; only a small number of mild related AEs (illusions, feeling cold or abnormal, some emotional distress) persisted beyond the acute session in a few reports. Physiological monitoring showed no clinically significant changes in blood pressure or heart rate. Concomitant medications were used by some participants during the study—two experimental‑dose participants received SSRIs (tapered before sessions), three used benzodiazepines as needed, and three received pain medication—one required acetaminophen for a moderate post‑session headache.

Discussion

Gasser and colleagues interpret their findings as evidence that LSD‑assisted psychotherapy, delivered in a carefully prepared and supervised psychotherapeutic setting, can be administered without severe drug‑related adverse events and is associated with reductions in anxiety among people facing life‑threatening illness. They highlight that this trial is the first controlled evaluation of LSD‑assisted psychotherapy in more than 40 years and emphasise methodological improvements over older studies, including randomisation and blinding procedures implemented to contemporary standards. The authors note that reductions in state anxiety reached statistical significance after two sessions, while trait anxiety showed a strong trend toward reduction despite trait measures being less likely to change with short‑term psychotherapy. They suggest that trait changes observed here and in other recent psychedelic‑assisted therapy studies might reflect neurobiological effects of the adjunctive drug combined with psychotherapy, and they report that anxiety reductions persisted at 12 months. Most participants were LSD‑naive and tolerated the reported moderate dose well; the investigators observed that therapeutic gains were most evident after the second LSD session and that several participants expressed a preference for additional sessions. Limitations acknowledged include the small sample size, which limits precision of effect‑size estimates and statistical power, and imperfect blinding: participants and therapists were generally able to identify dose assignment, reducing internal validity. The authors also discuss challenges inherent to treating people with serious somatic illness—disease progression or improvement can independently affect psychological outcomes and contribute to missing data. They note that the chosen quality‑of‑life instrument emphasises physical aspects and may be insufficient to capture long‑term psychological change in this population. The investigators propose that future studies use larger samples, consider different dosing or additional sessions, improve blinding strategies, and select quality‑of‑life measures more focused on psychological wellbeing. Overall, the study team concludes that results are promising but preliminary, and that larger controlled trials are warranted to further assess the safety and therapeutic potential of LSD‑assisted psychotherapy for anxiety associated with life‑threatening illness.

Conclusion

In this pilot randomised, double‑blind, active placebo‑controlled study, the investigators report that LSD‑assisted psychotherapy administered within a supervised psychotherapeutic framework was safe in their sample of participants with anxiety related to life‑threatening disease: no drug‑related severe adverse events occurred across 22 psychotherapy sessions involving the higher reported dose. Group comparisons showed positive trends and an independent significant reduction in state anxiety after two sessions, with effect size estimates in the range reported as 1.1–1.2. Given these findings, historical literature and recent related work with psilocybin, the authors state that further controlled research into LSD‑assisted psychotherapy in this population is warranted.

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SECTION

illnesses often fail to obtain satisfactory emotional relief from currently available treatment options. Anxiety, depression, chronic pain, as well as unresolved family and relationship issues can become serious problems for these individuals. The present LSD study was designed to evaluate previous findings applying current research methodology.

ETHICS

This phase 2 double-blind, active placebo-controlled, randomized clinical trial (Multidisciplinary Association for Psychedelicwas approved by the Ethics Committee of the Canton of Aargau, Swissmedic, the Swiss Federal Office for Public Health (Bundesamt fuer Gesundheit [Swiss Ministry of Health]), and the US Food and Drug Administration (Investigational New Drug no. 101,825) and was conducted in accordance with Good Clinical Practices. After complete description of the study to all participants, written informed consent was obtained.

PARTICIPANTS

The participants were recruited through general information about the study reported in media, by flyers, presentations in hospitals or cancer support groups, or referral from other physicians. Of 70 participants who were evaluated for eligibility by telephone or e-mail, 20 were further screened in person, and 12 were enrolled in this study (Fig.). Eleven of the 12 subjects had no prior experience with LSD. Individuals with current alcohol or drug dependence (except caffeine or nicotine); primary psychotic, bipolar I affective, or dissociative disorders; and neurocognitive impairment and women who were pregnant or nursing were excluded from this study. All participants reported a score of greater than 40 on either the state or the trait scale of the Spielberger State-Trait Anxiety Inventory (STAI;. According to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID), diagnosis, half of the subjects were diagnosed with generalized anxiety disorder (GAD). Neither the SCID's five items about GAD nor criterion E for GAD in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, differentiates between anxiety typically seen with GAD and a reaction to a lifethreatening disease (and its consequences). Therefore, even though the SCID generates a diagnosis of GAD, this does not mean that the subjects had the conventional pattern of psychopathology usually associated with GAD. Recruitment took place from 2007 FIGURE 1. Consolidated standards of reporting trials LSD/anxiety flow diagram.

GASSER ET AL.

The Journal of Nervous and Mental Disease & Volume 202, Number 7, July 2014 to 2011 until all planned participants were enrolled, and study visits were completed from 2008 to 2012. Tablesummarizes participant demographic characteristics.

SET

The psychotherapeutic method used in this study was a continuous process lasting several months. Two preparatory psychotherapy sessions served to discuss the participant's history, social situation, personality, health, mind-set, and emotional situation, also known by the term set. These also served to explain the action of LSD and structure of the setting, answer questions, and build therapeutic alliance.

SETTING

The physical environment within which the experimental sessions took place was a safe, quiet, and pleasant room in a private practice office. The participant was advised to lie on a mattress on the floor or sit comfortably on a chair. Other than going to the bathroom, the participants remained in the treatment room for the entire 8-hour experimental session and overnight with an attendant nearby.

EXPERIMENTAL DRUG

LSD was supplied as free base by Lipomed (Arlesheim, Switzerland). Capsules consisting of 200 Kg (experimental dose) and 20 Kg of LSD (active placebo) were prepared by Bichsel Laboratories (Interlaken, Switzerland). Quality control, randomization, and blinding were performed by R. Brenneisen, PhD, at the Department of Clinical Research, University of Bern, Switzerland. Capsules were of identical size, color, and shape and were bottled in sequentially numbered containers.

EXPERIMENTAL INTERVENTION

The primary intervention consisted of two full-day experimental sessions scheduled 2 to 3 weeks apart with a male/female co-therapist team, embedded within an ongoing process of drug-free psychotherapy sessions for preparatory and integrative purposes. The participants were randomly assigned to the experimental dose groups, receiving either an oral dose of 200 Kg of LSD (n = 8) or an active placebo of 20 Kg of LSD (n = 4). The experimental dose was a moderate amount expected to produce the full spectrum of a typical LSD experience, without fully dissolving normal ego structures. The 20-Kg dose of LSD was chosen as an active placebo to produce shortlived, mild, and detectable LSD effects that would not substantially facilitate a therapeutic process. The participant, the co-therapists, and the independent rater were blinded to condition assignment. The participants were required to taper off of antidepressants and antianxiety medications, to avoid alcohol and recreational drugs for 24 hours before, and to abstain from driving for 24 hours after the experimental sessions. On the morning of the experimental sessions, the participants arrived at the office for a short discussion about their current mood and mental state and a urine drug test (Drug Screen Multi5A: amphetamine, cocaine, morphine, methamphetamine, tetrahydrocannabinole; nal von minden GmbH, Moers/Germany). If the subjects tested positive, the session would have been postponed, but this did not occur. After LSD administration, the participants were instructed to focus their awareness and mindful attention inward to follow their personal process of perception, emotion, and cognition. Lengthy discussions between the participants and the co-therapists were discouraged during the acute effects of the LSD. Approximately two thirds of each LSD-assisted experimental session was focused inward with music played to deepen self-awareness and facilitate emotional processing, and one third contained brief conversations. The therapeutic session ended after 8 hours, when the acute effects had subsided, followed by a brief review of the day's experiences. After each experimental session, three drug-free psychotherapy sessions lasting 60 to 90 minutes took place, during which the participant's experiences were reviewed for integration and deepening the therapeutic process. Two months after the second experimental session, a follow-up evaluation was completed, and the treatment period was finished by breaking the blind for each individual. The participants who received the active placebo could cross over to an identical but open-label treatment with 200 Kg of LSD. A long-term follow-up evaluation was conducted 12 months after the last experimental session with LSD in either the blinded portion of the study or the open-label crossover.

ASSESSMENTS

A nurse collected heart rate and blood pressure measurements during experimental sessions. After two experimental sessions, a follow-up physical examination was performed by the participant's physician. Throughout the study, adverse events (AEs) were collected, and related AEs were recorded during experimental sessions and at the integrative session on the day after. The related AEs contained both AEs that were disturbing for the participant and those that belong to the mode of action of LSD (e.g., visual patterns). Concomitant medications used to treat anxiety, depression, and pain before the study and in between experimental sessions were documented. The subjects tapered off of these types of concomitant medications approximately five half-lives before each experimental session.

PSYCHOMETRIC MEASURES

The independent rater, an experienced clinical psychologist, conducted the SCID to establish psychiatric diagnoses at screening. The STAI Form X, a widely used self-report instrument for assessing state and trait anxiety in adults, served as the primary outcome measure of anxiety symptoms. Secondary outcome measures included the European Cancer Quality of Life Questionnaire 30-item version 1.0 (EORTC-QLQ-30;, the SCL-90-R, and the Hospital Anxiety and Depression Scale (HADS; Herrmann-Lingen et al., 2011). Outcome measures were completed at baseline, 1 week after experimental sessions, 2-month follow-up, and 12-month follow-up. The participants completed a daily dairy on changes in medication, adverse effects of LSD or medications, and pain using the Visual Analog Pain Scale. After each experimental session, the State of Consciousness Questionnaire was completed.

STATISTICAL ANALYSIS

The statistical software Statistical Package for the Social Sciences for Windows, version 18.0 (IBM Corp, New York), was used. FIGURE 2. Study outcomes. State and trait anxiety scores in the LSD and placebo group. Values are mean T SEM of changes from baseline in eight subjects in the LSD group and three subjects in the placebo group. Measures were obtained before the first treatment session (baseline), 1 week after the first treatment (post 1 LSD), 1 week after the second treatment (LSD 2), and at follow-up after 2 months. At 2 months, state anxiety scores were significantly lower in the LSD group compared with the placebo group. The crossover group (n = 3) shows a positive trend of STAI state and trait score reduction. At 12-month follow-up, the state and trait values remain stable compared with the 2-month follow-up. Repeated-measures analysis of variance (ANOVA) was used to test for significant changes in anxiety from baseline to subsequent posttreatment measurements. STAI trait and STAI state were analyzed in separate ANOVAs. To account for multiplicity, the alpha level indicating significance was adjusted to 0.025 (two tailed). Effect sizes were estimated using Cohen's d techniques. Results of the 12-month follow-up were compared with those of the 2-month follow-up with paired t-tests. Secondary outcome measures conducted for exploratory purposes were not used for significance testing to reduce multiplicity. We were unable to obtain results for two subjects (one experimental dose, one active placebo) from the assessment conducted 1 week after the second experimental session because of intervening cancer treatments. To avoid substantially reducing the sample size because of missing data, the assessment 1 week after the second experimental session was dropped for all subjects from analysis of outcomes. One active placebo participant was excluded from analysis after completing all study procedures because of a correction in the diagnosis of the qualifying disease state, which no longer satisfied the inclusion criteria.

CLINICAL RESPONSE

For STAI trait, Mauchly's Test of Sphericity was not significant ( p = 0.824) and sphericity was assumed. No significant difference was found ( p = 0.261) between group mean scores at baseline. The visit  group interaction testing for differences between the groups produced p = 0.033 (F = 4.151, df = 2,18), and observed statistical power was 65.6%, with results trending toward statistical significance. Comparing trait anxiety at baseline with 2-month follow-up yielded an effect size of 1.1. However, only three of eight experimental dose subjects dropped lower than the threshold value of 40 after the intervention. In contrast, all active placebo subjects experienced increases in trait anxiety. Figureshows a clear linear relationship between visit and mean trait anxiety for the experimental dose group, whereas no such relationship exists for the active placebo group. Comparison of 2-month and 12-month follow-up results in the subjects who received 200 Kg of LSD in either the blinded sessions or the open-label crossover indicate that the benefits were sustained over time. The mean difference varied only by 0.667 between these assessments, and no significant difference was found with p = 0.825 (two tailed). For STAI state, Mauchly's Test of Sphericity was not significant ( p = 0.813), and sphericity was assumed. No significant difference was found between the groups at baseline ( p = 0.563). The visit  group interaction testing for differences between the groups produced p = 0.021 (F = 4.846, df = 2,18), and observed statistical power was 72.7%. Even controlling for multiplicity, the reductions in state anxiety were statistically significant 2 months after two experimental sessions of LSD-assisted psychotherapy. Comparing state anxiety at baseline with 2-month follow-up yielded an effect size of 1.2. However, only three of eight experimental dose subjects dropped lower than the diagnostic cutoff of 40 after the intervention. In contrast, two active placebo subjects experienced increases in state anxiety. Figureshows a clear linear relationship between visit and state anxiety for the experimental dose group, whereas no such relationship exists for the active placebo group. Comparison of 2-month and 12-month follow-up results in the subjects who received 200 Kg of LSD in either the blinded sessions or the open-label crossover indicates that the benefits were sustained over time. The mean difference varied only by 1.00 between these assessments, and no significant difference was found with p = 0.531 (two tailed). Changes in secondary outcome measures were not analyzed for statistical significance because of concerns about multiplicity. However, the results obtained from these measures were, overall, quite supportive of the STAI results (Table). Global health scores from the EORTC-QLQ increased from a mean (SD) of 37.4 (10.0) at baseline to 50.0 (14.9) after treatment with two sessions of 200 Kg of LSD, whereas mean scores decreased from 44.3 (12.7) to 36.0 (12.8) in the active placebo group. Scores increased on average in the subjects who received 200 Kg of LSD treatments and continued to 12-month follow-up, indicating that most of the subjects receiving the experimental dose were able to attain and maintain comparable quality of life with the general European population by participating in this study. The SCL-90-R is a widely used measure of overall psychological problems and psychopathology. Global Severity Index (GSI) scores from the SCL-90-R decreased from a mean (SD) T-score of The HADS results were also generally supportive of overall improvements in this subject sample. The experimental dose group mean (SD) anxiety scores decreased from 11.7 (3.4) to 8.1 (3.2) after two sessions, whereas the active placebo group anxiety scores decreased only from 11.3 (2.1) to 10.7 (3.0). The active placebo subjects who continued to the crossover experienced an even greater decline lower than the diagnostic cutoff for anxiety to 7.0 (2.6). All subjects who received the experimental dose were lower than the diagnostic cutoff at the 12-month follow-up, with a mean (SD) of 7.6 (4.5). The depression results also mirrored the anxiety results. Overall, the secondary outcome measures of the study were useful in supporting the results of the primary outcome measure. For all 24 blinded sessions, all participants correctly guessed the dose of LSD that was administered, and both therapists guessed incorrectly in one active placebo session. The therapists were ''very certain'' in 22 sessions, ''certain'' in 1 session, and ''somewhat certain'' in 1 session. The participants were ''very certain'' in 20 sessions, ''certain'' in 1 session, ''somewhat certain'' in 2 sessions, and ''not at all certain'' in one session. This indicates that the 20-Kg dose was too low to achieve successful uncertainty about the dose.

SAFETY

Neither the experimental dose (200 Kg of LSD) nor the active placebo (20 Kg of LSD) produced any drug-related severe adverse events, that is, no panic reaction, no suicidal crisis or psychotic state, and no medical or psychiatric emergencies requiring hospitalization. Related AEs (Table) included both positive and negative effects commonly associated with LSD. The experimental dose subjects experienced more types of AEs (n = 18) than the active placebo subjects (n = 8). In general, AEs were reported more frequently and with increased intensity in the experimental dose sessions. Interestingly, fewer reports of anxiety were received during experimental sessions with 200 Kg (22.7%) than with active placebo (50%), and the mean intensity of anxiety was comparable between the groups. However, the subjects reported experiencing mild-to-moderate emotional distress similarly in experimental dose sessions (36.4%) and active placebo sessions (33.3%). Most AEs resolved when drug effects diminished. Only six reports of mild related AEs (illusions, feeling cold or abnormal, and some emotional distress) persisted

CONCOMITANT MEDICATION

During the study, two participants (both experimental dose) received concomitant selective serotonin reuptake inhibitor (SSRI) treatment for depression and tapered off of these medications five half-lives before each experimental session because SSRIs may attenuate the effects of the serotonergically active experimental drug. Three participants received benzodiazepines (two experimental dose and one active placebo) as needed. Three participants received pain medication during the study, only one of which was required as rescue medication for a treatment-emergent AE. Acetaminophen was required for this participant for a moderate headache the day after an experimental dose session.

PHYSIOLOGICAL MEASURES

Physiological measures were recorded for all participants during experimental sessions. Consistent with the previous findings, LSD did not significantly alter blood pressure or heart rate (Table).

DISCUSSION

All research with LSD-assisted psychotherapy in the 1950s and the 1960s came to a halt by the early 1970s. Our study, the first in more than 40 years to evaluate safety and efficacy of LSD as an adjunct to psychotherapy, was conducted in participants with anxiety after being diagnosed with a life-threatening illness. In contrast to the shortcomings of older studies, we used a controlled, randomized, and blinded study design to meet contemporary research standards. LSD was given in a psychotherapeutic context to facilitate a deep psychedelic state, allowing the participant to encounter his/her own inner realities during an emotionally intensified dream-like ''journey.In our study, using appropriate inclusion/exclusion criteria, detailed participant preparation, and a carefully supervised experience in a supportive psychotherapeutic setting, psychological side effects were mild and limited. There were no AEs often attributed to LSD such as prolonged anxiety (''bad trip'') or lasting psychotic or perceptional disorders (flashbacks). Congruent with studies in the past (Hintzen and Passie, 2010), the few mild somatic effects of LSD such as changes in heart rate and blood pressure were of no clinical significance. The primary outcome variable in this study was of the STAI anxiety measure. Patients with life-threatening illnesses confront an existential threat from shortened life expectancy that often causes periods of suffering, pain, and anxiety. Congruent with earlier studies, the results in the experimental dose group show a significant reduction in state anxiety, as experienced on a daily basis. Furthermore, the more stable personality-inherent feature of anxiety proneness (trait anxiety) showed a strong trend toward reduction. Trait anxiety is not expected to be altered by short-term psychotherapy, but a comparable finding was reported in recent research with psilocybin in cancer patients that reported significant reductions of trait anxiety (although without correction for multiplicity) but not state anxiety. Therefore, this trait change may be supported by neurobiological effects of adjunctive use of LSD, which was originally introduced for deepening and accelerating psychotherapeutic processingand, in some studies, was shown to alter personality traits. In this study, the experimental dose reduced anxiety when administered in either the blinded treatment or the open-label crossover for the active placebo subjects. These results were stable over time as shown by the 12-month follow-up. Eleven of 12 participants treated were LSD-naive. A moderate dose (200 Kg) provided a psychologically manageable first LSD experience. Most of the participants stated a preference for more than two LSD sessions and a longer treatment period. The results demonstrated a decrease in STAI scores most prominently after the second LSD session, suggesting that at least two LSD sessions are needed to demonstrate these effects. A longer treatment period with additional LSD sessions and larger doses may be indicated.

LIMITATIONS OF THE STUDY

As a pilot study, this study had limited sample size, which reduced precision in effect size estimates and significance testing. The sample size selected was sufficient for a study primarily focused on safety and feasibility. The imperfect blinding also limits the validity of the results. The problem of the double blind in studies with pharmacologically active substances is a well-known methodological challenge. LSD is a potent psychoactive drug, and participants and therapists are likely to detect whether an experimental dose or an inactive placebo or active placebo of very low dose of LSD was administered. Although using a slightly higher LSD dose in the comparator group can increase blinding, it can also increase efficacy of the comparator, compromising the estimates of effect size. Given the safety of the moderate experimental dose, results might have been improved with a larger dose of 250 Kg. Other limitations exist in treating participants with grave somatic diseases because the course of the somatic illness (e.g., worsening or improving) may substantially impact psychological parameters independent of the therapeutic intervention and contribute to missing data. The quality of life questionnaire (EORTC-QLQ), which was chosen as a secondary outcome measure, focuses extensively on physical aspects and was insufficient for evaluating long-term psychological changes. Future studies should include a quality of life measure that focuses on psychological well-being more so than physical aspects of quality of life in this population.

CONCLUSIONS

This pilot study in participants with anxiety associated with the diagnosis of a life-threatening illness has demonstrated safety in 22 psychotherapy sessions assisted by 200 Kg of LSD with no drugrelated severe adverse events. Group comparison results support positive trends in reduction of anxiety after two sessions of LSD-assisted LSD-Assisted Psychotherapy psychotherapy, with effect size estimates in the range of 1.1 to 1.2. In view of promising historical studies with adjunctive LSD treatment in this population and a recent promising study using psilocybin, as well as the urgent need for more effective treatments of anxiety in these participants, further study is warranted into the potential of LSD-assisted psychotherapy.

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128 cited
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98 cited
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136 cited
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112 cited
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184 cited
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