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

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.

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.

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.

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.

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.