LSD-assisted therapy in patients with anxiety: open-label prospective 12-month follow-up.

BACKGROUND: Anxiety disorders are a major public health burden with limited treatment options. AIMS: We investigated the long-term safety and efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with anxiety with or without life-threatening illness. METHOD: This study was an a priori-planned long-term follow-up of an investigator-initiated, two-centre trial that used a double-blind, placebo-controlled, two-period, random-order, crossover design with two sessions with either oral LSD (200 µg) or placebo per period. Participants (n = 39) were followed up 1 year after the end-of-study visit to assess symptoms of anxiety, depression and long-term effects of psychedelics using Spielberger's State-Trait Anxiety Inventory-Global (STAI-G), the Beck Depression Inventory (BDI), the Persisting Effects Questionnaire and measures of personality traits using the NEO-Five-Factor Inventory. RESULTS: Participants reported a sustained reduction of STAI-G scores compared with baseline (least square means (95% CI) = -21.6 (-32.7, -10.4), d = 1.04, P < 0.001, for those who received LSD in the first period (94 weeks after the last LSD treatment) and -16.5 (-26.2, -6.8), d = 1.02, P < 0.05, for those who received LSD in the second period (68 weeks after the last LSD treatment)). Similar effects were observed for comorbid depression with change from baseline BDI scores of -8.1 (-13.2, -3.1), d = 0.71, P < 0.01, and -8.9 (-12.9, -4.9), d = 1.21, P < 0.01, for the LSD-first and placebo-first groups, respectively. Personality trait neuroticism decreased (P < 0.0001) and trait extraversion increased (P < 0.01) compared with study inclusion. Individuals attributed positive long-term effects to the psychedelic experience. CONCLUSIONS: Patients reported sustained long-term effects of LSD-assisted therapy for anxiety.

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

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.

Guiding Through Challenging Psychedelic Experiences and "Bad Trips".

Psychedelic substances have gained recognition for their therapeutic potential, but they also present challenges, with individuals occasionally experiencing distressing episodes referred to as challenging experiences or, in the recreational setting, "bad trips". Trial therapists and physicians, but also healthcare professionals in emergency rooms, need a comprehensive strategy to effectively manage these cases. Three case reports are presented to underline the problem and propose strategies for handling these situations. Finally, this article outlines a stepwise approach, encompassing helpful interventions, supportive care, and rescue medication, to ensure the well-being of individuals undergoing challenging psychedelic experiences and prevent further complications and long-term harm.

Lysergic Acid Diethylamide-Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study.

BACKGROUND: This study aimed to investigate the efficacy and safety of lysergic acid diethylamide (LSD)-assisted therapy in patients who experienced anxiety with or without association with a life-threatening illness. METHODS: The study is an investigator-initiated 2-center trial that used a double-blind, placebo-controlled, 2-period, random-order, crossover design with 2 sessions with either oral LSD (200 µg) or placebo per period. The primary end point was anxiety symptoms 16 weeks after the last treatment session, assessed by the Spielberger State-Trait Anxiety Inventory-Global score in 42 patients. Further outcome measures included ratings for depression symptoms (Beck Depression Inventory and Hamilton Depression Rating Scale, 21-item version) and ratings for acute subjective drug effects. The outcomes for the first period (between-subjects analysis) are primarily shown due to carryover effects. RESULTS: LSD treatment resulted in significant reductions of State-Trait Anxiety Inventory-Global scores up to 16 weeks after treatment (least-square mean [standard error] change from baseline difference = -16.2 [5.8], 95% CI, -27.8 to -4.5, d = -1.18, p = .007). Similar effects were observed for ratings of comorbid depression on the Hamilton Depression Rating Scale, 21-item version (-7.0 [1.9], 95% CI, -10.8 to -3.2, d = -1.1, p = .0004) and the Beck Depression Inventory (-6.1 [2.6], 95% CI, -11.4 to -0.9, d = -0.72, p = .02). Positive acute subjective drug effects and mystical-type experiences correlated with the long-term reductions in anxiety symptoms. Transient, mild, acute untoward effects of LSD treatment were reported by 8 patients (19%). One treatment-related serious adverse event (acute transient anxiety) occurred (2%). CONCLUSIONS: LSD produced long-lasting and notable reductions in anxiety and comorbid depression symptoms up to 16 weeks.

Psychedelic Group Therapy.

Gatherings in groups are a ubiquitous phenomenon throughout human history. This is true for everyday social tasks as well as for healing and spiritual purposes. In psychotherapy, group treatment started soon after developing psychoanalytic treatment procedures. For psychedelic therapy however, individual treatment guided by one or sometimes even two therapists is the most common and widespread treatment model for clinical research and therapy thus far. Since the foundation of the Swiss Medical Society for Psycholytic Therapy (Schweizerische Ärztegesellschaft für psycholytische Therapie, SÄPT) in 1985 in Switzerland, we however had the opportunity to conduct psychedelic group treatment in specific settings, which the following article describes.

Using a MDMA- and LSD-Group Therapy Model in Clinical Practice in Switzerland and Highlighting the Treatment of Trauma-Related Disorders.

The Swiss Federal Act on Narcotics allows for the restricted medical use of scheduled psychotropic drugs in cases of resistance to standard treatment, and preliminary evidence of efficacy of the scheduled drug for the particular condition. Since 2014, the authors have obtained 50 licenses on a case-by-case basis and developed a psychedelic-assisted group therapy model utilizing MDMA and LSD. The majority of the patients taking part in the psychedelic group therapy suffered from chronic complex post-traumatic stress disorder (c-PTSD), dissociative, and other post-traumatic disorders. Treatment modalities, typical developments and problems encountered during and after the psychedelic experiences are described. Recurrent depression poses a frequent problem, and requires special attention. Symptoms of c-PTSD predominantly addressed by the psychedelic experiences are the regulation of emotions and impulses, negative self-perception, alterations in relationships to others, as well as meaning, recall, and processing of traumatic memories. C-PTSD needs a larger number of psychedelic experiences in contrast to PTSD resulting from single trauma. In this model MDMA was most often used in the first phase to enhance motivation to change, strengthen the therapeutic alliance, allowing it to become more resilient, stress-relieved and less ambivalent. When emotional self-regulation, negative self-perception and structural dissociation had also begun to improve and trauma exposure was better tolerated, LSD was introduced to intensify and deepen the therapeutic process. The majority of participants improved by clinical judgement, and no serious adverse events occurred. A short case vignette describes a typical process. The experiences with this model can serve to further develop the method of psychedelic-assisted psychotherapy (PAP) and to give directions for future research.

Acute subjective effects in LSD- and MDMA-assisted psychotherapy.

BACKGROUND: Lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA) were used in psychotherapy in the 1960s-1980s, and are currently being re-investigated as treatments for several psychiatric disorders. In Switzerland, limited medical use of these substances is possible in patients not responding to other treatments (compassionate use). METHODS: This study aimed to describe patient characteristics, treatment indications and acute alterations of mind in patients receiving LSD (100-200 µg) and/or MDMA (100-175 mg) within the Swiss compassionate use programme from 2014-2018. Acute effects were assessed using the 5 Dimensions of Altered States of Consciousness scale and the Mystical Experience Questionnaire, and compared with those in healthy volunteers administered with LSD or MDMA and patients treated alone with LSD in clinical trials. RESULTS: Eighteen patients (including 12 women and six men, aged 29-77 years) were treated in group settings. Indications mostly included posttraumatic stress disorder and major depression. Generally, a drug-assisted session was conducted every 3.5 months after 3-10 psychotherapy sessions. LSD induced pronounced alterations of consciousness on the 5 Dimensions of Altered States of Consciousness scale, and mystical-type experiences with increases in all scales on the Mystical Experience Questionnaire. Effects were largely comparable between patients in the compassionate use programme and patients or healthy subjects treated alone in a research setting. CONCLUSION: LSD and MDMA are currently used medically in Switzerland mainly in patients with posttraumatic stress disorder and depression in group settings, producing similar acute responses as in research subjects. The data may serve as a basis for further controlled studies of substance-assisted psychotherapy.

Development and Evaluation of a Therapist Training Program for Psilocybin Therapy for Treatment-Resistant Depression in Clinical Research.

Introduction: Psychological support throughout psilocybin therapy is mandated by regulators as an essential part of ensuring participants' physical and psychological safety. There is an increased need for specially trained therapists who can provide high-quality care to participants in clinical studies. This paper describes the development and practical implementation of a therapist training program of psychological support within a current phase IIb international, multicenter, randomized controlled study of psilocybin therapy for people experiencing treatment-resistant depression. Description of Training Program: This new and manualized approach, based on current evidence-based psychotherapeutic approaches, was developed in partnership with different mental health researchers, practitioners, and experts; and has been approved by the FDA. Training consists of four components: an online learning platform; in-person training; applied clinical training; and ongoing individual mentoring and participation in webinars.This paper provides a brief overview of the method of support, the rationale and methodology of the training program, and describes each stage of training. The design and implementation of fidelity procedures are also outlined. Lessons Learned: As part of the phase IIb study of psilocybin therapy for treatment-resistant depression, 65 health care professionals have been fully trained as therapists and assisting therapists, across the US, Canada and Europe. Therapists provided informal feedback on the training program. Feedback indicates that the didactic and experiential interactive learning, delivered through a combination of online and in-person teaching, helped therapists build conceptual understanding and skill development in the therapeutic approach. Clinical training and engagement in participant care, under the guidance of experienced therapists, were considered the most beneficial and challenging aspects of the training. Conclusions: Clinical training for therapists is essential for ensuring consistently high-quality psilocybin therapy. Development of a rigorous, effective and scalable training methodology has been possible through a process of early, active and ongoing collaborations between mental health experts. To maximize impact and meet phase III and post-approval need, enhanced online learning and establishing pathways for clinical training are identified as critical points for quality assurance. This will require close public, academic and industry collaboration.

Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review.

Anxiety and depression are some of the most common psychiatric symptoms of patients suffering with life-threatening diseases, often associated with a low quality of life and a poor overall prognosis. 5-HT2A-receptor agonists (serotonergic hallucinogens, 'psychedelics') like lysergic acid diethylamide (LSD) and psilocybin were first investigated as therapeutic agents in the 1960s. Recently, after a long hiatus period of regulatory obstacles, interest in the clinical use of these substances has resumed. The current article provides a systematic review of studies investigating psychedelics in the treatment of symptoms of existential distress in life-threatening diseases across different periods of research, highlighting how underlying concepts have developed over time. A systematic search for clinical trials from 1960 to 2017 revealed 11 eligible clinical trials involving a total number of N=445 participants, of which 7 trials investigated the use of lysergic acid diethylamide (LSD) (N=323), 3 trials investigated the use of psilocybin (N=92), and one trial investigated the use of dipropyltryptamine (DPT) (N=30). The 4 more recent randomized controlled trials (RCTs) (N=104) showed a significantly higher methodological quality than studies carried out in the 1960s and 1970s. Evidence supports that patients with life threatening diseases associated with symptoms of depression and anxiety benefit from the anxiolytic and antidepressant properties of serotonergic hallucinogens. Some studies anecdotally reported improvements in patients´ quality of life and reduced fear of death. Moreover, low rates of side effects were reported in studies that adhered to safety guidelines. Further studies are needed to determine how these results can be transferred into clinical practice.

LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects.

OBJECTIVE: A recently published study showed the safety and efficacy of LSD-assisted psychotherapy in patients with anxiety associated with life-threatening diseases. Participants of this study were included in a prospective follow-up. METHOD: 12 months after finishing LSD psychotherapy, 10 participants were tested for anxiety (STAI) and participated in a semi-structured interview. A Qualitative Content Analysis (QCA) was carried out on the interviews to elaborate about LSD effects and lasting psychological changes. RESULTS: None of the participants reported lasting adverse reactions. The significant benefits as measured with the STAI were sustained over a 12-month period. In the QCA participants consistently reported insightful, cathartic and interpersonal experiences, accompanied by a reduction in anxiety (77.8%) and a rise in quality of life (66.7%). Evaluations of subjective experiences suggest facilitated access to emotions, confrontation of previously unknown anxieties, worries, resources and intense emotional peak experiences à la Maslow as major psychological working mechanisms. The experiences created led to a restructuring of the person's emotional trust, situational understanding, habits and world view. CONCLUSIONS: LSD administered in a medically supervised psychotherapeutic setting can be safe and generate lasting benefits in patients with a life-threatening disease. Explanatory models for the therapeutic effects of LSD warrant further study.

Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects.

BACKGROUND: After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans. METHODS: In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 µg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects. RESULTS: Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed. CONCLUSIONS: In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.