Action of lysergic acid diethylamide (LSD) and LSD analogs to aid in psychotherapy for generalized anxiety disorder or other anxiety unrelated to life threatening diseases

Abstract

To provide a method for treating anxiety disorder which is not particularly related to a life-threatening serious physical disease.SOLUTION: A method of treating anxiety disorders not particularly associated with a cause such as a life-threatening serious medical condition by administering a hallucinogenic agent to a person and treating anxiety, in particular producing a reduction in a rating scale score measure of anxiety (STAI global or condition or characteristic anxiety), and / or a measure of depression (HDRS or BDI score), and / or a measure of general psychological distress (SCL-90 rating) in the patient over several weeks beyond administration of the hallucinogenic agent. A method of treating anxiety by administering a hallucinogenic substance, preferably a LSD, to an individual having anxiety that is not associated with a cause, such as a life-threatening serious medical condition, and inducing a positive acute drug effect and a positive long-term therapeutic effect in the individual.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Background of the Invention 1.Technical Field The present invention relates to the use of LSD and LSD analogues or derivatives to induce a psychedelic state and to assist in psychotherapy for generalized anxiety disorder. [Background technology]

[0002] 2. Background technology Hallucinogens, such as lysergic acid diethylamide (LSD), are substances that can induce distinctive subjective effects, including altered consciousness, positive emotions, enhanced self-observation, perception of the environment, body, and self, and the experience of loss of self-consciousness (Carhart-Harris et al., 2016b; Dolder et al., 2016;Holze et al., 2021;Liechti, 2017;Passie et al., 2008;Schmid et al. al., 2015).

[0003] All serotonergic hallucinogens, such as LSD, psilocybin, DMT, and mescaline, are agonists at the 5-HT2A receptor (Rickli et al., 2016), and therefore Furthermore, hallucinogens, as shown in particular in clinical trials of LSD, can produce very similar physical effects. 2A It exerts its acute effects in humans via receptor activation ( Holze et al., 2021 ; Preller et al., 2017 ).

[0004] Acute effects of hallucinogens that may contribute to their therapeutic benefits include increased openness, trust, feelings of connectedness or empathy with people, insight into psychological issues, and an improved therapeutic relationship due to stimulation of neuroregenerative processes, which are detailed elsewhere (Vollenweider et al., 2020).

[0005] Hallucinogens are being investigated as potential treatments for medical conditions. Clinical trials have examined the use of LSD in patients with addiction (Krebs et al., 2012), anxiety specifically associated with life-threatening illnesses (Gasser et al., 2014; Gasser et al., 2015), as well as in patients with major depression (Carhart-Harris et al., 2016a; Davis et al., 2021; Griffiths et al., 2016; Roseman et al., 2017; Ross et al., 2016), anxiety associated with terminal illness (Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2016), and different forms of addiction (Bogenschutz, 2013;Bogenschutz et al., 2015;Garcia-Romeu et al., 2019;Garcia-Romeu et al., 2015;Johnson et al. Beneficial effects of psilocybin use have been described in psychotropic ...

[0006] Several studies have included patients with anxiety in trials with hallucinogens. Several earlier studies were conducted in the 1950s and 1970s using hallucinogens in patients with existential anxiety associated with advanced cancer and / or dying (Grof et al., 1973; Kast, 1966; Kast et al., 1964; Pahnke et al., 1969).

[0007] Grob et al. conducted the first modern double-blind, placebo (niacin)-controlled trial of psilocybin in 12 patients with advanced cancer and anxiety (Grob et al., 2011). The study primarily examines the feasibility of administering moderate doses of psilocybin to patients with cancer and anxiety. and safety were established. Part of the data revealed a positive trend toward improvement in mood and anxiety. Specifically, there was a trend toward a psilocybin effect on mood at 1 day and 2 weeks after drug administration, but no significant improvement in anxiety was observed (Figure 1). This result supports the need for further research. Psilocybin acutely induced a psychedelic state as assessed by the 5-dimensional altered states of consciousness scale (5D-ASC; Figure 2), which is also used in the present invention (Grob et al., 2011). Anxiety diagnoses varied in this study. The conditions included acute stress disorder, generalized anxiety disorder, cancer-related anxiety disorder or adjustment disorder with anxiety, but importantly, all patients had advanced stage cancer.

[0008] Griffiths et al. compared depression and anxiety in 51 patients with life-threatening cancer. A randomized, placebo-controlled, double-blind study was conducted in patients with psilocybin. Depressed mood was defined as meeting criteria for major depressive disorder, dysthymic disorder, or adjustment disorder with anxiety and depressed mood. Anxiety was defined as meeting criteria for generalized anxiety disorder, adjustment disorder with chronic anxiety, or adjustment disorder with anxiety and depressed mood. All 51 participants had a diagnosis of potentially life-threatening cancer, and 65% had recurrent metastatic disease. The study used a crossover design with high-dose psilocybin 22 mg or 30 mg / 70 kg versus very low (placebo-like) doses of psilocybin 1 mg or 3 mg / 70 kg, with follow-up observations at 5 weeks and 6 months between sessions. The high-dose psilocybin resulted in significant reductions in depressed mood and anxiety, along with improved quality of life and reduced death anxiety (Figures 3A-3C). At 6-month follow-up, these changes were maintained (Figures 3A-3C), with approximately 80% of participants continuing to demonstrate clinically significant reductions in depressed mood and anxiety. Participants attributed improvements in attitudes toward life / self, mood, relationships, and spirituality to the high-dose experience, with over 80% perceiving a moderate or large increase in happiness / life satisfaction (Griffiths et al., 2016). Higher acute Mystical Experiences Questionnaire (MEQ) scores in response to psilocybin were positively associated with lower anxiety and depression 5 weeks after psilocybin administration (Figures 4A-4B), indicating that more positive acute psilocybin effects are associated with better long-term therapeutic benefits (Griffiths et al., 2016).

[0009] Ross et al. conducted a randomized controlled trial of psilocybin treatment for anxiety and depression in 29 patients with life-threatening cancer (Ross et al., 2016). 62% of patients reported symptoms of psilocybin-induced depression. All patients had advanced stage III or IV cancer. Twenty-six patients had adjustment disorder, and only three patients had generalized anxiety disorder. Patients were randomly assigned to receive a single dose of psilocybin (0.3 mg / kg) or niacin placebo. The primary outcomes were anxiety and depression assessed between groups at week 7 before crossover. Psilocybin improved anxiety and depression and improved quality of life (Figures 5A-5C and 6A-6C). Again, higher mystical-type experiences were associated with better long-term treatment outcomes.

[0010] Carhart-Harris et al. conducted an open-label feasibility study of psilocybin (10 mg and 25 mg, 7 days apart) with psychological support for the treatment of treatment-resistant depression in 12 patients (Carhart-Harris et al., 2016a). There was no control group. Psilocybin was well tolerated by all patients. Notable side effects were transient anxiety during drug initiation (all patients), transient confusion or thought disorder (9 patients), mild and transient nausea (4 patients), and transient headache (4 patients). Relative to baseline, depressive symptoms were significantly reduced 1 week (p = 0.002) and 3 months (p = 0.003) after high-dose treatment (Figure 7). Significant and sustained improvements in anxiety and sexual anhedonia were also noted. This study provided preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression ( Carhart-Harris et al., 2016a ).

[0011] Davis et al. administered two psilocybin sessions (Session 1: 20 mg / 70 kg; Session 2: 1 week later, waiting list for 30 mg / 70 kg or delayed treatment A randomized trial was conducted in 27 patients with major depression randomized to either a 2-week or 4-week treatment group (Davis et al., 2021). The primary outcome was depression severity (Hamilton Depression Rating Scale, HAMD) 1 and 4 weeks after Session 2. Twenty-four patients completed the intervention. The mean (SD) HAMD scores at 1 and 4 weeks in the immediate treatment group (8.0 [7.1] and 8.5 [5.7], respectively) were statistically significantly lower than the scores at the equivalent time points of 5 and 8 weeks in the delayed treatment group (23.8 [5.4] and 23.5 [6.0], respectively) (Figure 8). The effect size was 0.05 at week 5 (Cohen's d = 2.2; 95% CI, 1.4-3.0; P < 0.001). and at 8 weeks (Cohen's d = 2.6; 95% CI, 1.7 to 3.6; P < 0.001). The findings suggest that psilocybin in therapy is effective in treating depression, thus extending the results of previous studies of this intervention in patients with cancer and depression, as well as non-randomized studies in patients with treatment-resistant depression (Davis et al., 2021).

[0012] Gasser et al. conducted the first modern study of LSD in patients with life-threatening illnesses and associated anxiety (Gasseret et al., 2014). Treatment included a drug-free psychotherapy session and two LSD sessions spaced 2–3 weeks apart. Twelve patients were included: eight received two doses of 200 μg LSD (orally administered as a capsule) over two LSD sessions spaced 2–3 weeks apart, and three patients received a placebo (low dose of 20 μg LSD). All patients had elevated levels of anxiety (>40 points) on either the state or trait scale of the State-Trait Anxiety Scale (STAI), and half were diagnosed with generalized anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV. This study demonstrated a significant decrease in STAI anxiety 2 months after the two LSD sessions compared with baseline anxiety scores (Figures 9A–9B). In contrast, STAI scores did not decrease after the placebo session. However, the placebo control group was too small to allow statistical comparison with the treatment group. This study also demonstrated sustained anxiety reduction up to 12 months after LSD treatment, but not in the placebo group (Gasser et al., 2015). There were no significant drug-related serious adverse effects, panic reactions, or There were no other medical or psychiatric complications. The authors of this study concluded that LSD can be used safely in patients with anxiety disorders, but that larger controlled trials are warranted to confirm efficacy (Gasser et al., 2014). A 12-month follow-up study The study also demonstrated no adverse effects up to 12 months, providing qualitative evidence of the beneficial effects of LSD in this study (Gasser et al., 2015).

[0013] LSD was also used in several smaller, older studies in depressed patients without physical illness (Savage, 1952). LSD was also used experimentally and episodically in patients with affective disorders (depression, anxiety, obsessive-compulsive disorder) in Switzerland from 1988 to 1993, in the absence of supporting research data and outside of clinical trials (Gasser, 1996). LSD was similarly used outside of placebo-controlled clinical trials in the 1960s and 1970s (Pahnke, 1999). However, the effectiveness of LSD in patients with anxiety without physical illness has not been established. Even with other psychedelics, such as psilocybin, there is only data on anxiety and depression associated with cancer, but not on anxiety disorders unrelated to physical illness (Griffiths et al., 2016; Ross et al., 2016) or depression (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016a; Davis et al., 2021).

[0014] Schmid et al. described the controlled therapeutic use of LSD in Swiss psychiatric patients. From this observational study, 11 patients were described who were treated with LSD in addition to psychotherapy. The patients suffered from post-traumatic stress disorder (4), major depression (2), anxious personality disorder (1), narcissistic personality disorder (1), obsessive-compulsive disorder (1), and dissociative disorder (2). LSD was comparable to that assessed in healthy subjects and compared with other studies using psilocybin in patients with cancer-related anxiety or depression (Grob et al., 2011; Roseman et al., 2017) or using LSD to treat cancer-related anxiety. These results are similar to those reported in studies using the MRI technique (Gasser et al., 2014; Liechti et al., 2017). These results indicated acute effects on the 5D-ASC scale and MEQ (Figures 10 and 11).

[0015] After a lack of formal human studies in the past 40 years, LSD is now being investigated in healthy subjects. Carhart-Harris and colleagues conducted an experimental, single-blind, within-subject, placebo-controlled pilot study in 10 healthy volunteers using 40–80 μg of LSD administered intravenously (Carhart-Harris et al., 2015; Kaelen et al., 2015). LSD produces subjective effects such as "clouding of thoughts," "feeling wonderful," and "feeling warm inside" (Kaelen et al., 2015). LSD slightly increases blood pressure and heart rate. LSD has been shown to increase suggestibility (Carhart-Harris et al., 2015), enhance emotional responses to music (Kaelen et al., 2015), and induce synesthetic-like experiences. The same group then conducted another larger, placebo-controlled crossover study in 20 subjects using a 75 μg dose of LSD (equivalent to approximately 100 μg of intravenous, oral LSD) and included a functional magnetic resonance imaging (fMRI) scan session (Carhart-Harris et al., 2016b; Carhart-Harris et al., 2016c; Kaelen et al., 2016; Lebedev et al., 2016; Roseman et al., 2016; Speth et al., 2016; Tagliazucchi et al., 2016). All participants had at least one prior experience with a classic hallucinogen and had used LSD an average of 14 times (Carhart-Harris et al., 2016b). LSD produced elevated mood, euphoric states, and acute psychotic-like symptoms, including thought disorder, delusional thinking, and paranoia. There was a very small increase in anxiety, significantly smaller than the euphoric experiences. Overall, there was a bias toward positive affect. As previously described for psilocybin (Griffiths et al., 2008; MacLean et al., 2011), LSD produced lasting effects (Carhart-Harris et al., 2016b). LSD increased optimism and trait openness at two weeks compared to placebo. There was no effect on delusional thinking at two weeks, and there was a trend toward less distress and fewer preoccupations with delusional thinking (Carhart-Harris et al., 2016b). Data indicate that in healthy subjects, hallucinogens increased openness and psychological well-being in the medium to long term (Carhart-Harris et al., 2016b; Griffiths et al., 2008; MacLean et al., 2011).Consistently, follow-up data from placebo-controlled studies ( Carhart-Harris et al., 2016b ; Studerus et al., 2011 ) or epidemiological data ( Johansen et al., 2015 ; Krebs et al., 2013b ) have shown no association of psychological or psychiatric problems with the use of hallucinogens by healthy subjects. There was no evidence.

[0016] Several double-blind, placebo-controlled, randomized sequence crossover Phase I trials have been conducted in healthy subjects in Switzerland. The first study characterized the psychological, physiological, endocrine, and pharmacokinetic effects of LSD in 16 subjects (8 men, 8 women) using a 200 μg oral dose of LSD (Dolder et al., 2015b; Schmid et al., 2015; Trajhar et al., 2016). 2016). Administration of LSD produced a significant change in wakefulness that lasted for 12 hours. The main effects induced by D included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. LSD increased subjective well-being, happiness, closeness to others, openness, and trust. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and adrenaline. LSD-induced adverse effects subsided completely within 72 hours. No severe acute adverse effects were observed (Schmid et al., 2015; Strajhar et al., 2016). Maximum LSD concentrations were reached 1.5 hours after administration. Concentrations then declined according to first-order kinetics with half-lives ranging from 3.6 to 12 hours and slower subsequent elimination. No gender differences were observed in the pharmacokinetic profile of LSD. Acute subjective and sympathomimetic responses to LSD closely correlated with plasma concentrations over time, indicating no acute tolerance (Dolder et al., 2015b).

[0017] The second study examined the effects of a 100 μg LSD dose in 24 healthy subjects (12 men, 12 women) (Dolder et al., 2016). The second study examined the effects of a 100 μg LSD dose in 16 healthy subjects (12 men, 12 women). One study tested the effects of doses of 25, 50, 100, and 200 μg, as well as a placebo, in 100 subjects (Holze et al., 2021). Another study compared the effects of MDMA and d-amphetamine with those of 100 μg of LSD (Holze et al., 2020b).

[0018] In an fMRI study, LSD was found to reduce amygdala reactivity to fearful stimuli. This finding is consistent with findings obtained after psilocybin administration, which has been reported to attenuate the perception of negative facial expressions (Kometer et al., 2012; Schmidt et al., 2013) and reduce amygdala BOLD responses to fearful faces (Kraehenmann et al., 2015). Furthermore, amygdala deactivation by LSD was accompanied by its acute subjective psychedelic effects. Thus, reduction of amygdala reactivity using hallucinogens may reflect potential therapeutic effects, reducing perceptions of negative emotions and facilitating the therapeutic alliance.

[0019] LSD also positively impacts the processing of emotional information by reducing the recognition of fearful and sad faces and, similar to MDMA, increasing affective empathy and prosociality (Dolder et al., 2016). These effects of LSD in healthy participants may have translational relevance for LSD-assisted psychotherapy in patients, where they may be expected to reduce perceptions of negative emotions and facilitate the therapeutic alliance.

[0020] LSD has been investigated in patients with life-threatening illnesses such as cancer. The above-mentioned studies did not include patients with generalized anxiety disorder without physical illness, so it is unknown and has not been investigated whether patients with anxiety in the absence of physical illness would benefit from psychedelic-assisted therapy. Although there is evidence that psilocybin and LSD improve anxiety, depression, and quality of life in patients with cancer-related anxiety, it cannot be assumed that patients with generalized anxiety or social anxiety disorder will also benefit.

[0021] Other types of anxiety disorders, such as generalized anxiety disorder and social anxiety disorder, are highly prevalent, represent quantitatively larger health problems, and impose higher costs on society than adjustment disorders to cancer and other life-threatening diseases. Furthermore, pharmacological treatment options, such as chronic administration of drugs such as serotonin transporter inhibitors (citalopram, paroxetine), quetiapine, or pregabalin, are limited. These medications have substantial adverse drug effects and are limited in effectiveness. Psychotherapy can be used effectively. However, additional and complementary treatment options are needed. Summary of the Invention [Problem to be solved by the invention]

[0022] Therefore, there remains a need for effective treatments for generalized anxiety disorder. [Means for solving the problem]

[0023] Summary of the Invention The present invention provides a method for treating anxiety disorders not specifically associated with a cause such as a life-threatening serious physical illness by administering a hallucinogen to an individual and treating anxiety, specifically by causing a reduction in the patient's anxiety rating scale score measures (STAI global or state or trait anxiety), and / or depression measures (HDRS or BDI scores), and / or general psychological distress measures (SCL-90 scores) over several weeks following administration of the hallucinogen.

[0024] The present invention involves administering a hallucinogen (preferably LSD) to an individual experiencing anxiety that is not associated with a cause such as a life-threatening serious physical illness, and producing positive acute drug effects and To provide a method for treating anxiety by inducing positive long-term therapeutic effects.

[0025] Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0026] DESCRIPTION OF THE DRAWINGS [Figure 1A] 1 is a graph of the effect of psilocybin on depression in patients with advanced stage cancer and anxiety in the prior art, showing BDI scores. [Figure 1B] FIG. 1 is a graph of the effect of psilocybin on depression in patients with advanced stage cancer and anxiety in the prior art, showing STAI state anxiety scores. [Figure 2A] 1 is a graph showing the acute changes in mind produced by psilocybin in a patient with advanced stage cancer and anxiety, according to the prior art, showing the 5D-ASC dimension. [Figure 2B] 1 is a graph showing the acute changes in mind produced by psilocybin in a patient with advanced stage cancer and anxiety, according to the prior art, showing further changes. [Figure 3A] 1 is a graph showing reduction in depression in cancer patients treated with psilocybin in the prior art. [Figure 3B] 1 is a graph showing the reduction in anxiety in cancer patients treated with psilocybin in the prior art. [Figure 3C] 1 is a graph showing improved quality of life in cancer patients treated with psilocybin in the prior art. [Figure 4A]1 is a graph showing the relationship between changes in anxiety and acute psilocybin-induced mystical experiences 5 weeks after psilocybin administration in patients with cancer before crossover in the prior art. [Figure 4B] 1 is a graph showing the relationship between change in depression and acute psilocybin-induced mystical experiences 5 weeks after psilocybin administration in patients with cancer before crossover in the prior art. [Figure 5A] 1 is a graph showing the reduction in depression following a single dose of psilocybin and compared to a niacin placebo in patients with cancer in the prior art. [Figure 5B] 1 is a graph showing reduction in state anxiety following a single dose of psilocybin and compared to a niacin placebo in patients with cancer in the prior art. [Figure 5C] 1 is a graph showing the reduction in trait anxiety following a single dose of psilocybin and compared to a niacin placebo in patients with cancer in the prior art. [Figure 6A] 1 is a graph showing reduction in depression after a single dose of psilocybin compared to a niacin placebo in patients with cancer after crossover in the prior art. [Figure 6B] 1 is a graph showing reduction in state anxiety after a single dose of psilocybin compared to niacin placebo in patients with cancer after crossover in the prior art. [Figure 6C] 1 is a graph showing reduction in trait anxiety after a single dose of psilocybin compared to niacin placebo in patients with cancer after crossover in the prior art. [Figure 7] 1 shows the effect of a single dose of psilocybin in patients with treatment-resistant depression on depression scores one week and three months after administration in an open-label, prior art study without a control group. [Figure 8] 1 shows the effect of two doses of psilocybin in patients with major depression compared to patients awaiting later treatment in the prior art on depression scores and. [Figure 9A]FIG. 1 is a graph showing the effect of two LSD sessions on state anxiety scores in the LSD (n=8) and placebo (n=3) groups, two months after drug administration, in patients with a life-threatening disease, placebo-treated and then crossover-treated, according to the prior art; data is shown for all remaining patients from both groups (n=9) after two and 12 months. [Figure 9B] FIG. 1 is a graph showing the effect of two LSD sessions on trait anxiety scores in the LSD (n=8) and placebo (n=3) groups, two months after drug administration, in patients with a life-threatening illness, placebo-treated and then crossover-treated, according to the prior art; data is shown for all remaining patients from both groups (n=9) after two and 12 months. [Figure 10] 1 is a graph showing acute changes in the mind induced by LSD in psychiatric patients and healthy subjects according to the prior art. [Figure 11] Prior art studies have demonstrated mystical-type experiences in psychiatric patients and healthy subjects. [Figure 12] 1 is a diagram of the patient enrollment plan for an example study of the present invention. [Figure 13] 1 is a diagram of the study visit plan including outcome measures. [Figure 14] 1 is a table showing patient characteristics for patients with anxiety disorders treated in the example study. [Figure 15A] FIG. 1 is a graph of the effects of LSD and placebo on anxiety, depression, and psychological distress in patients with anxiety disorders across subjects (n=9-10 / group), showing the STAI-S. [Figure 15B] FIG. 1 is a graph of the effects of LSD and placebo on anxiety, depression, and psychological distress in patients with anxiety disorders across subjects (n=9-10 / group), showing the STAI-T. [Figure 15C] FIG. 1 is a graph of the effects of LSD and placebo on anxiety, depression, and psychological distress in patients with anxiety disorders across subjects (n=9-10 / group), showing the STAI-G. [Figure 15D] FIG. 1 is a graph of the effects of LSD and placebo on anxiety, depression, and psychological distress in patients with anxiety disorders across subjects (n=9-10 / group), showing the HDRS. [Figure 15E] FIG. 1 is a graph of the effects of LSD and placebo on anxiety, depression, and psychological distress in patients with anxiety disorders across subjects (n=9-10 / group), showing the BDI. [Figure 15F] FIG. 1 is a graph of the effects of LSD and placebo on anxiety, depression, and psychological distress in patients with anxiety disorders across subjects (n=9-10 / group), showing SCL-90 global. [Figure 16A] FIG. 1 is a graph of the effect of LSD on anxiety, depression and psychological distress in patients with anxiety disorders within subjects (n=19 / group), showing the STAI-S. [Figure 16B] FIG. 1 is a graph of the effect of LSD on anxiety, depression, and psychological distress in patients with anxiety disorders within subjects (n=19 / group), showing TAI-T. [Figure 16C] FIG. 1 is a graph of the effect of LSD on anxiety, depression and psychological distress in patients with anxiety disorders within subjects (n=19 / group), showing the STAI-G. [Figure 16D] FIG. 1 is a graph of the effect of LSD on anxiety, depression and psychological distress in patients with anxiety disorders within subjects (n=19 / group), showing HDRS. [Figure 16E] FIG. 1 is a graph of the effect of LSD on anxiety, depression, and psychological distress in patients with anxiety disorders within subjects (n=19 / group), showing the BDI. [Figure 16F] FIG. 1 is a graph of the effect of LSD on anxiety, depression and psychological distress in patients with anxiety disorders within subjects (n=19 / group), showing SCL-90 global. [Figure 17] 1 is a graph showing acute changes in the mind induced by LSD or placebo. [Figure 18] 1 is a graph showing acute mystical-type effects induced by LSD or placebo. [Figure 19] 1 is a table showing the correlation coefficient between the acute effect of LSD and the therapeutic effect of LSD at 2 weeks after the second administration. [Figure 20] A list of adverse events is presented as the total number of reports across all visits. DETAILED DESCRIPTION OF THE INVENTION

[0027] Detailed Description of the Invention The present invention provides a method of treating anxiety not associated with a life-threatening physical illness, such as generalized anxiety disorder, by administering a hallucinogen (preferably LSD) to an individual and treating the anxiety, preferably specifically causing a reduction in the individual's rating scale score measures of anxiety (STAI global or state or trait anxiety), and / or depression (HDRS or BDI score), and / or general psychological distress (SCL-90 score) over several weeks beyond administration of the hallucinogen.

[0028] As used herein, "generalized anxiety disorder" refers to a condition characterized by persistent and excessive worry. Generalized anxiety disorder is characterized by an individual's difficulty controlling their worries for at least six months or more, and by at least three defined symptoms: feelings of tension, irritability or restlessness, a sense of imminent danger, feelings of panic or hopelessness, increased heart rate, rapid breathing (hyperventilation), sweating and / or trembling, weakness or fatigue, difficulty concentrating, sleep disturbances, and gastrointestinal (GI) problems. Generalized anxiety disorder differs from anxiety caused by a specific stressor, such as an illness.

[0029] Individuals treated herein may suffer from anxiety disorders such as generalized anxiety disorder and social anxiety disorder (which causes social phobia, anxiety about everyday interactions, fear, self-consciousness, and embarrassment), panic disorder (sudden, overwhelming fear for no apparent reason and rapid heartbeat, difficulty breathing, and sweating) or other phobias, adjustment disorder, or post-traumatic stress disorder. This method may also treat low mood associated with or coexisting with depression or anxiety.

[0030] The present invention preferably uses LSD, its salts, its tartrates, its analogs, its homologs, or any ergotamine as a hallucinogen.Other hallucinogens, such as, but not limited to, psilocybin, mescaline, dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), its salts, its tartrates, its analogs, or its homologs, can be used in the methods of the present invention, which are tryptamines or phenethylamines and induce the same or similar acute effects on the 5D-ASC scale as LSD.

[0031] LSD is preferably administered at a dose of 200 μg, although a range of 25-400 μg may also be used. Preferably, two doses of LSD are administered. A second dose, usually 200 μg (25-400 μg), may be administered 3-5 weeks after the first dose. The effects of LSD may last 8-12 hours after administration, and the individual is preferably monitored by a medical professional, such as a psychiatrist, during this period. Other hallucinogens may be administered by those skilled in the art.

[0032] LSD is preferably administered orally, although intranasal, transdermal, subcutaneous, intravenous and intramuscular formulations may also be suitable.

[0033] A single dose can also be administered and an effect can be achieved. Using the present invention, and in patients with anxiety disorders, additional non-drug sessions after the LSD session can be beneficial if performed by the same therapist and in the same setting, or if a placebo or low dose of LSD is used because there is a conditioned effect from the initial LSD administration.

[0034] Based on the Phase 1 and dose-finding studies described above, as well as pilot studies in patients, a higher dose of 200 μg was selected for use in the present invention (Gasser et al., 2014; Gasser et al., 2015). However, during the dose-finding process and with the increased pharmacokinetic data available, previous studies have shown that the reported dose of 200 μg is significantly lower than the dose of 200 μg previously reported. It should be noted that the study revealed that 140 μg of LSD was used instead of the previously reported 200 μg (Holze et al., 2020a; Holze et al., 2021). Indeed, another advantage of the present invention is that, whereas previous studies used undefined doses, this is the first time a pharmaceutically defined dose of LSD has been used in patients, meaning that the LSD content and content uniformity in the dose was unclear; even later studies demonstrated an LSD content approximately 30% lower (Holze et al., 2019) than that reported in the original publications (Gasser et al., 2014; Gasser et al., 2015). Importantly, in contrast to the dose used in the present invention, older studies in healthy subjects also used pharmaceutically undefined doses of LSD (Dolder et al., 2015b; Dolder et al., 2016; Schmid et al., 2015).

[0035] As mentioned above, hallucinogens such as LSD, psilocybin, and the DMT-containing plant ayahuasca have been used to treat individuals with depression associated with life-threatening illnesses. However, there have been no studies examining the use of LSD in patients with generalized anxiety disorder or other anxiety disorders not associated with life-threatening illnesses and therefore not adjustment-type anxiety. In fact, patients with anxiety or affective disorders within the year prior to the onset of cancer have typically been excluded from previous studies evaluating the effects of hallucinogens in patients with cancer and associated anxiety (Grob, 2011 #1910; Gasser, 2015 #3955).

[0036] Cancer and other life-threatening illnesses can cause adjustment disorder-type anxiety. This type of anxiety is not present in patients before the physical illness and develops as a result of fear of actual life-threatening danger caused by cancer or a life-threatening illness. Psychedelic therapy aims to reduce cancer-related anxiety, is designed to promote existential crisis, and often aims to reduce the fear of death (Grob, 2011 #1910; Gasser, 2015 #3955). In contrast, in forms of anxiety without a physical cause, such as generalized anxiety disorder, social anxiety disorder (social phobia), panic disorder, and / or agoraphobia, there is no apparent external cause of the illness. Patients are troubled by "things for no apparent reason," and in the absence of a cause for the illness, their functioning can be severely impaired. This type of anxiety has also been called endogenous, arising from within the mind, as opposed to exogenous anxiety, which arises from other sources outside the mind.

[0037] In Example 1, in a study of human patients with generalized anxiety disorder, the present innovation was compared for the first time with placebo in a double-blind, placebo-controlled, randomized trial involving patients with generalized anxiety disorder in the absence of severe physical illness. The study in the example demonstrated significant beneficial effects on mood and psychological distress, as well as a trend toward improvement in anxiety ratings. LSD significantly reduced State-Trait Anxiety Scale (STAI)-S, STAI-T, and STAI-G ratings after the second administration. STAI-S and STAI-G ratings were significantly reduced already after the first administration. LSD significantly reduced scores on the HDRS, BDI, and SCL-90 Global after the second administration. LSD induced significant and noticeable changes in all scales of the 5D-ASC questionnaire. LSD significantly and significantly increased ratings of type experiences on the MEQ30 questionnaire. The favorable drug effect of LSD predicts favorable treatment outcomes two weeks after treatment.

[0038] This method may also reduce psychological distress and / or improve quality of life in an individual. This method may also enhance the psychotherapy an individual receives (e.g., administered on separate days before and after the hallucinogen administration). This method may be used when an individual has an inadequate therapeutic response or adverse effects after the use of other hallucinogens and may be used as a second-line treatment. This method may also be used when an individual has a need for a qualitatively different psychedelic response after the use of other hallucinogens.

[0039] In this invention, LSD is used to induce a psychedelic state and to aid in psychotherapy. This provides the first data supporting the use of LSD in generalized anxiety disorder to improve mood, symptoms of psychological distress and / or quality of life, providing medical benefit to these patients and society.

[0040] The compounds of the present invention are administered and administered in accordance with good medical practice, taking into consideration the clinical condition of the individual patient, the site and method of administration, the administration schedule, the patient's age, sex, weight, and other factors known to physicians. Thus, for purposes herein, a pharmaceutically "effective amount" is determined by such considerations, as known in the art. The amount should be an amount effective to achieve an improvement, such as, but not limited to, improved survival or more rapid recovery, or improvement or elimination of symptoms, and other indicators selected as appropriate criteria by those skilled in the art.

[0041] In the method of the present invention, the compounds of the present invention can be administered in various ways. It should be noted that they can be administered as a compound, and can be administered as an active ingredient alone or in combination with pharmaceutically acceptable carriers, diluents, adjuvants and excipients. The compounds can be administered parenterally, such as orally, subcutaneously, or intravenously, intramuscularly and intranasally. The patient to be treated is a warm-blooded animal, particularly a mammal such as a human. Pharmaceutically acceptable carriers, diluents, adjuvants and excipients, as well as implant carriers, generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating materials that do not react with the active ingredients of the present invention.

[0042] The administration may be single or multiple or continuous over several hours.

[0043] When the compound of the present invention is administered parenterally, it is generally prepared in an injectable unit dosage form (solution, suspension, emulsion).The pharmaceutical preparation suitable for injection includes sterile aqueous solution or dispersion and sterile powder that can be reconstituted into injectable sterile solution or dispersion.The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), its suitable mixture, and vegetable oil.

[0044] Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. Non-aqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil, and esters, such as isopropyl myristate, can also be used as solvent systems for the formulation compositions. Additionally, various additives that enhance the stability, sterility, and isotonicity of the composition, such as antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It is often desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms can be achieved by the use of agents that delay absorption, such as aluminum monostearate and gelatin. However, any vehicle, diluent, or additive used in accordance with the present invention must be compatible with the compound.

[0045] Sterile injectable solutions can be prepared by incorporating the compounds used in practicing the present invention in the required amount of the appropriate solvent with various other ingredients, as desired.

[0046] The pharmaceutical formulations of the present invention can be administered to patients in injectable formulations containing any compatible carrier, such as various excipients, adjuvants, additives, and diluents; or the compounds used in the present invention can be administered to patients parenterally in the form of sustained-release subcutaneous implants or targeted delivery systems, such as monoclonal antibodies, vector delivery, iontophoresis, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include: 25,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0047] The present invention also provides a method for treating anxiety by administering a hallucinogen to an individual with anxiety not associated with a cause such as a life-threatening serious physical illness, thereby inducing positive acute drug effects and positive long-term therapeutic effects in the individual. As shown in Example 1, LSD induced significant and noticeable changes in all scales of the 5D-ASC questionnaire, and LSD significantly and significantly increased ratings of mystical-type experiences on the MEQ30 questionnaire (indicating an acute effect). These acute effects of LSD on the 5D-ASC and MEQ30 questionnaires were associated with the therapeutic effects of LSD two weeks after the second administration (indicating a long-term therapeutic effect).

[0048] The present invention is further described in detail with reference to the following experimental test examples. The examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise specified. Therefore, the present invention should in no way be construed as limited to the examples, but should be construed to encompass any and all variations that become evident as a result of the teachings provided herein. [Example]

[0049] Example 1 A randomized, double-blind, placebo-controlled phase II study was conducted using LSD treatment in patients with psychiatric anxiety disorders or anxiety symptoms associated with serious physical illness.

[0050] The study included both physically ill and non-physically ill patients. Data from non-physically ill patients are presented to illustrate the use of the present invention in generalized anxiety disorder, and therefore in anxiety conditions not related to fear of cancer or death.

[0051] Specifically, patients with generalized anxiety disorder were given LSD or a placebo in a double-blind manner in two sessions, six weeks apart, with anxiety, depression, and psychological distress assessed between sessions at 2, 8, and 16 weeks after the second session. Patients who received LSD then crossed over to the placebo, and vice versa.

[0052] Thus, the study evaluated the effect of LSD versus placebo between subjects in the first period (parallel design) and the effect of LSD within subjects versus placebo over the entire study period (crossover design).

[0053] LSD had beneficial effects on anxiety, depression and quality of life in these patients with generalized anxiety disorder, which are detailed below.

[0054] Research Introduction Lysergic acid diethylamide (LSD) is the prototypical classical hallucinogen (Nichols, 2004; Passie et al., 2008). LSD was first synthesized by Albert Hofmann, a chemist at Sandoz who also discovered its psychoactive properties (Hofmann, 1979). 1950s From the 1950s to the 1970s, LSD was initially used as an experimental tool (a "psychotometic drug") to model psychotic-like states and psychoses (Bercel et al., 1956; Koelle, 1958). and as an adjunct in "psychotic manifestation (substance-assisted) psychotherapy."

[0055] LSD has been shown to be associated with alcoholism (Krebs et al., 2012), addiction (Savage et al., 1973), and group headache (Sewell et al., 2006) and anxiety associated with terminal illness (Gasser et al., 2014; Grof e LSD has been studied for the treatment of psychosis (Hintzen et al., 2010; Nichols, 2010). 2004; Nichols, 2016; Passie et al., 2008).

[0056] Today, LSD is used illegally for recreational (personal or psychoactive) purposes. It is estimated that 38 million people in the United States, or 15% of those over the age of 12, have ingested a hallucinogenic substance at some point in their lifetime (Johnston et al., 2016; Krebs et al., 2013a). In Europe, the lifetime prevalence of LSD use among adults is estimated to be in the 6-8% range. Thus, a significant proportion of Western society is familiar with the effects of this substance.

[0057] LSD is not associated with compulsive drug-seeking (addiction) and is relatively free of medical emergencies and adverse effects (Nichols, 2016). LSD or psilocybin use has been shown to have no significant adverse effects on mental health. are not associated with health problems and may even be protective (Johansen et al., 2015; Krebs et al., Despite the widespread recreational use of LSD, clinical research with LSD was halted in the 1970s due to political and cultural pressures and legal restrictions.

[0058] Recently, the medical value of hallucinogenic substances has been investigated again in several clinical trials (Baumeister et al., 2014; Bogenschutz et al., 2015; Davenport, 2016; Gasser et al., 2014; Gasser et al., 2015; Grob et al., 2011; Johnson et al., 2014; Kupferschmidt, 2014; Nichols, 2016). Specifically, both LSD and psilocybin , which have been shown to reduce anxiety associated with life-threatening illnesses (Gasser et al., 2014; Gasser et al., 2015; Grob et al., 2011). Based on these preliminary data, the Federal Ministry of the Interior A small number of patients are treated with LSD in Switzerland by specialized psychiatrists in compassionate use situations with special case-by-case authorization from the Provincial Health Office (BAG).

[0059] Currently available pilot study data are insufficient in quantity and quality and need to be confirmed in larger, placebo-controlled studies. Therefore, the study embodiments of the present invention aim to evaluate the effect of LSD compared to placebo on anxiety and depression in patients with anxiety disorders (new use) or / and increased anxiety associated with life-threatening illness (past use, confirmatory data).

[0060] This study was conducted in collaboration with psychiatrist P. Gasser, MD, who conducted a Phase II-type pilot study on the safety and efficacy of LSD-assisted psychotherapy in patients (Gasser et al., 2014; Gasser et al., 2015).

[0061] This study was financially supported by the Swiss Medical Society for Psycholytic Therapy (Schweizerische Arztegesellschaft fur Psycholytische Therapie, SAEPT) and the University Hospital Basel.

[0062] Purpose of the Example Test The goals of this innovation were to explore 1) reduction in anxiety (STAI), 2) reduction in depression (HDRS and BDI), and 3) improvement in global psychopathology (SCL-90) and to demonstrate safety.

[0063] Test Method Test Design The example study used a double-blind crossover design with two treatment sequences, each lasting 24 weeks (LSD vs. placebo-assisted psychotherapy), separated by a 2-week period between sequences. The sequences were counterbalanced and randomized. Each participant completed the entire 52-week study period. The treatment effects were also compared between subjects during the first 24-week study period before crossover.

[0064] Exam period The study will run from January 1, 2017, to December 31, 2021 (until December 31, 2020, for patients with generalized anxiety disorder); duration for each participant: 52 weeks, including screening, and follow-up at 102 weeks.

[0065] Clinical trial facilities 1) Outpatient Clinical Trials Center, University Hospital Basel, 2) Private psychiatric practice Dr. Gasser (Solothurn).

[0066] Investigators / Staff LSD / placebo sessions and study visits are conducted by the investigator / psychiatrist. Generally, one physician will conduct the session or visit, and the same physician will treat the same patient throughout the study.

[0067] Clinical trial population Anxiety with or without a life-threatening illness The goal was to include patients with anxiety disorders with or without a life-threatening illness. Study patients had to meet DSM diagnostic criteria for an anxiety disorder or report a score of greater than 40 on the State or Trait STAI (Spielberger et al., 1983). Patients without a life-threatening illness always had to meet the DSM-V diagnosis of an anxiety disorder (high STAI anxiety alone was not sufficient to include these patients). The goal was to include approximately equal-sized subgroups of patients with anxiety, with or without a life-threatening illness.

[0068] Recruitment Patients were recruited largely from the patients of the participating trial psychiatrist (Dr. Gasser, in private practice). 40 participants were enrolled in the trial. Dropouts during the trial were replaced to reach a final trial sample of at least 30 subjects who completed the trial (12 months). Approximately 10 participants were recruited per year, with a recruitment period of 4 years and a total duration of 5 years (Figure 12).

[0069] Inclusion criteria 1. Age > 25 years old 2. Meet DSM-IV criteria for an anxiety disorder as indicated by the SCID-IV or have a score of at least 40 on the state or trait STAI scale at study entry. 3. 40% or more of participants have a diagnosis of advanced, potentially fatal disease (cancer without autoimmune, neurological, or CNS involvement). Patients are outpatients, are not terminal, and may have an approximate life expectancy of greater than 12 months. 4. Patients without advanced, potentially fatal disease must meet DSM-IV criteria for an anxiety disorder (high STAI scores are not sufficient for inclusion). 5. Thorough understanding of clinical trial procedures and associated risks. 6. Participants must be willing to comply with study procedures and sign the consent form. 7. Participants willingly refrain from taking psychiatric medications during the experimental sessions. If participants are being treated with antidepressants or taking anti-anxiety medications on a fixed daily schedule, they must discontinue such medications for a sufficiently long period (the interval will be at least 5 half-lives of the particular drug [usually 3-7 days]) before the LSD / placebo treatment session to avoid potential drug-drug interactions. 8. If ongoing psychological therapy, participants recruited for the study may continue to see an outside therapist, provided that the investigator signs a waiver to communicate directly with the therapist. Participants should not change therapists, increase or decrease the frequency of therapy, or start a new type of therapy during the study (not including follow-up). 9. Participants must refrain from use of any psychotropic medications within 24 hours of each LSD / placebo treatment session, with the exception of long-term pain medications or caffeine or nicotine. Participants must agree to abstain from nicotine use for at least 2 hours before and 6 hours after each dose of LSD. Participants must agree to abstain from alcohol-containing beverages for at least 1 day before each LSD treatment session. Non-routine medications to treat uncontrollable pain taken within 24 hours prior to an LSD treatment session may result in the treatment session being rescheduled for another day, as determined at the investigator's discretion after discussion with the participant. 10. Participants must be willing not to drive a vehicle or operate machinery within 24 hours after LSD / placebo administration.

[0070] Exclusion criteria 1. Women who are pregnant, breastfeeding, or of childbearing potential and women who are not using effective contraception (double-barrier contraception, i.e., pill / intrauterine device and prophylactic / contraceptive diaphragm). 2. Past or current diagnosis of a primary psychiatric disorder. Subjects with first-degree relatives with a psychiatric disorder will also be excluded. 3. Past or current bipolar disorder (DSM-IV). 4. Current substance use disorder (within the past 2 months, DSM-V, excluding nicotine). 5. Physical illness, including cancer, severe cardiovascular disease, untreated hypertension, CNS complications of severe liver disease (elevated liver enzymes above upper limit or 5 times normal) or severe renal impairment (estimated creatinine clearance <30 ml / min), or other illnesses that, in the investigator's judgment, pose too high a potential for adverse effects. 6.Weight less than 45kg. 7. Risk of suicide or need for psychiatric hospitalization during the course of the study. 8. Requires ongoing concomitant therapy with psychotropic medications (other than anxiolytics and pain management medications, if necessary) and is unable or unwilling to adhere to drug-free periods.

[0071] Event Schedule The participant's schedule of events is shown in Figure 13. Over the course of 52 weeks, participants participated in a 2-hour screening visit, four 11-13 hour LSD / placebo treatment sessions, ten 1-hour study visits, and a 1-hour end-of-study visit. Follow-up visits (not part of the clinical trial period) were also conducted using questionnaires sent by mail.

[0072] Screening Procedure Informed consent Subjects were informed of the study procedures and associated risks verbally and through an approved written consent form, which both the investigator and subject personally signed and dated as confirmation of consent.

[0073] physical health Subjects were examined by the investigator including medical history, physical examination, vital signs and blood chemistry. Weight and height were also measured.

[0074] mental health Subjects were screened using the SCID for DSM-IV (Wittchen et al., 1997). A detailed examination was conducted by a study psychiatrist who also determined whether subjects met the psychiatric inclusion criteria. A psychiatric interview was also conducted. The psychiatric interview began with the SCID, which provided a DSM-IV diagnosis of anxiety disorder and excluded exclusive Axis I diagnoses (i.e., current substance use disorder, psychotic disorder, bipolar disorder). The HDRS, BDI, STAI, and SCL-90 were then completed.

[0075] Substance use history and urine drug screen Substance history was recorded during the screening, as in a previous similar trial (Gasser et al., 2014). It was expected that most participants would have no prior experience with hallucinogenic drugs. Similarly, psilocybin has generally been used in subjects with little to no prior experience (Griffiths et al., 2008; Griffiths et al., 2011; Griffiths et al., 2006; Johnson et al., 2014; MacLean et al., 2011). Past substance use disorder (not within the past 2 months) was not an exclusion criterion if no serious side effects were caused by the hallucinogenic substance. Subjects were asked to abstain from illicit drug use during the study and were drug screened prior to the testing session. If a urine drug screen was positive (with the exception of tetrahydrocannabinol (Northcote) or opioids when used for pain management), they were excluded from the study. The study session was postponed because THC consumption can be detected in urine for up to several weeks, and the number of days of use prior to the study day is unlikely to affect the results. Based on pilot study data (Gasser et al., 2014), we believe that a positive urine drug screen will not affect the outcome. Subjects were asked to refrain from excessive alcohol consumption (<10 drinks / week) and to abstain the day before the test session.

[0076] Screening Clinical Tests Routine clinical blood tests were performed with screening tests such as creatinine and ALAT.

[0077] personality Personality traits are known to influence subjective responses to psychoactive substances (Studerus et al., 2012; White et al., 2006). The NEO-Five Factor Personality Inventory (NEO-FFI) The Freiburg Personality Inventory (FPI) and the Freiburg Personality Inventory (FPI) were administered during screening to assess personality traits and their potential modulating effects on the response to LSD in this trial. The same instruments have been used in experimental studies in healthy subjects. We explore whether personality traits modify the effects of LSD or whether personality traits are altered by LSD (Carhart-Harris et al., 2016b;Griffiths et al., 2008;MacLean et al., 2011).

[0078] LSD / placebo session Each of the four LSD / placebo sessions lasted 12 hours, from 8:00 AM to 8:00 PM. Sessions took place at the Outpatient Research Center at the University Hospital of Basel or at Dr. P. Gasser's private practice (Solothurn Center). At the beginning of each session, current mood and mental status were discussed, a urine drug screen was performed, and AEs from the last visit were recorded. The investigator addressed open-ended questions or concerns. Participants were encouraged to lie in bed or sit comfortably in a chair. Except for trips to the bathroom, participants remained in the treatment room for the entire 12-hour experimental session and were constantly monitored for up to 8–12 hours after LSD / placebo administration, depending on the participant's response and as needed. The subjective effects of LSD at the doses used in this study were expected to last 8–12 hours (Gasser et al., 2014; Holze et al., 2021; Schmid et al., 2015). The doses are relatively high and have been shown to produce the full spectrum of typical LSD experiences without complete disintegration of normal ego structures (Gasser et al., 2014; Gasser et al., 2015; Holze et al., 2021; Schmid et al., 2015). During the LSD / placebo effect, participants focused their attention inward. Subjects were instructed to wear eye shades (or dim the lights) for the first hour. Participants were encouraged to listen to music and refrain from extensive discussions / conversations with investigators. Subjects remained largely unaffected by brief physical contact every 2 hours, during which their heart rate and blood pressure were measured. At the end of the session, 10-12 hours after LSD / placebo administration, participants retrospectively rated their acute subjective peak effects using the 5D-ASC, SCQ, AMRS, and VAS, and discussed their experiences. 10-12 hours after LSD / placebo administration, participants returned home accompanied and monitored by a partner, relative, or friend. If monitoring was unavailable or effects persisted, participants spent the night at the investigational site.

[0079] Clinical trial visit The 60-90 minute pre-trial visits were used to discuss the participant's history (life story), personality, health status, current social and emotional situation (meaning-centered), and concerns, as well as to explain the effects of LSD, answer questions, and prepare for the LSD / placebo support session (intentions, expectations (Johnson et al., 2008)). Further important purposes of the meetings included establishing a sufficient level of rapport and trust between the patient and the investigator. The patient's anxieties and personal conditions (physical illness-related or non-physical) were explored, and potential issues during the experimental sessions were discussed. One pre-trial visit was scheduled two weeks before the first LSD / placebo session, and there was a six-week gap between the two LSD / placebo sessions. The post-substance support session visit served to discuss and summarize the patient's experiences during the session. There were no formal guidelines for these sessions (elements of psychotomimetic expression therapy, reuse of music played during the sessions, and mutual meaning-making; (Breitbart et al., 2008)). (e.g., Johnson et al., 2008; Leuner, 1969). Patients were encouraged to write about their experiences and then discussed their reports during the sessions. Three meetings were scheduled 2, 8, and 16 weeks after the LSD / placebo session and included outcome assessments. This schedule of 10 study visits represented the minimum number of non-substance meetings. Additional meetings were scheduled as needed but were not mandatory and only occurred if therapeutically necessary. The number of meetings was similar in both treatment periods. Therefore, if an additional meeting occurred during the first treatment period of the study, an additional meeting was scheduled at the corresponding time in the second treatment period. If an additional meeting occurred only during the second treatment period, the number of meetings and the reason for the additional meetings should be recorded on the case report form (CRF). The time points (weeks) at which sessions occurred according to the treatment schedule were to be adhered to as closely as possible (+ / - 1 to 3 weeks), but deviations were not considered protocol violations. The actual dates of all meetings were recorded on the CRF. The number and overall content of sessions were largely standardized in this study, and the same investigator cared for patients throughout the study. Differences in investigator and patient-investigator interactions were reduced by the crossover design of the study, which also included a within-subject comparison of the effects of LSD and placebo.

[0080] Concurrent drug use and other therapies Numerous interactions between acute administration of LSD and chronic medications have been studied (Hintzen et al., 2010; Passie et al., 2008). Concurrent medications were administered at screening and at each visit / study session. Patients were recorded before the LSD / placebo session. Regular medications (hypertension medications, aspirin, statins, painkillers) were generally continued throughout the study, but antidepressants had to be discontinued before the LSD / placebo session. Literature and clinical pharmacological judgment were used to determine whether chronic medications needed to be further discontinued for the situations described in the protocol: Antidepressants: Selective serotonin reuptake inhibitors (SSRIs) can attenuate the response to LSD (Bonson et al., 1996a; Bonson et al., 1996b; Strassman, 1992). Lithium or tricyclic antidepressants Participants using either of these drugs as chronic medication were required to taper off their antidepressant and anxiolytic medications at least five half-lives before each LSD / placebo session. Generally, this resulted in a 1-week break. In a pilot study (Gasser et al., 2014), 2 of 12 patients This approach was used in clinical trials with psilocybin, where medications for depression and anxiety were discontinued for two weeks prior to psilocybin administration and subsequently not reinstated due to the significant therapeutic response (Carhart-Harris et al., 2016b; Griffiths, 2016). Subjects requiring ongoing treatment with antidepressants were excluded from the study. Anxiolytics: Any anxiolytic treatment with benzodiazepines was continued as needed during the study. Anxiolytic use was not permitted on study days and during LSD / placebo sessions, but was allowed in cases of anxiety that could not be treated with verbal support. Analgesics: Chronic analgesic medication was continued as needed during the study, including LSD / placebo sessions. Other ongoing psychotherapy could be continued, but the number of sessions was not increased or decreased. No new psychological treatments were initiated during the study period.

[0081] Ratings and Scales Psychometric evaluation State-Trait Anxiety Scale (STAI) The STAI is a widely used self-report instrument for assessing anxiety in adults. It includes separate measures of state and trait anxiety (Spielberger et al., 1983). The STAI assesses the essential emotional qualities of anxiety, tension, nervousness, and worry. The STAI distinguishes between the momentary state of state anxiety and the more generalized and long-term quality of trait anxiety. The STAI state anxiety subscale asks subjects how they feel at the time they complete the questionnaire, while the STAI trait anxiety subscale asks subjects to indicate how they generally view themselves. For both subscales, a score of 20–39 represents mild anxiety, a score of 40–59 indicates moderate anxiety, and a score of 60–80 indicates severe anxiety. Both the state and trait STAI are commonly used as outcome measures in patients with anxiety disorders (Fisher et al., 1999; Laakmann et al., 1998). An overall STAI score can be derived by summing the state and trait anxiety scale scores (range: 40–160 points). As in the pilot study, both STAI scale scores were used to determine study inclusion at screening (Gasser et al., 2014; Gasser et al. al., 2015). Furthermore, similar to the pilot study and a similar study using psilocybin (Grob et al., 2011), the STAI was then the primary outcome measure in this trial. A pilot study showed within-subject reductions in STAI state and trait anxiety at 2 months after LSD-assisted psychotherapy sessions in patients with life-threatening illnesses, with comparable responses on both scales (Gasser et al., 2014; Gasser et al., 2015). However, no adequately sized placebo group was included. Reductions in STAI trait scales over time at 4 and 12 weeks were seen in a pilot study of psilocybin treatment of anxiety in patients with advanced cancer (Grob et al., 2011). Psilocybin significantly reduced anxiety compared with placebo administration. LSD did not significantly reduce state and trait STAI scores after 2 weeks compared with placebo (Grobet al., 2011). However, this study included 12 subjects and a placebo condition for only 2 weeks. In the present study, both STAI scales were administered at screening, 2 weeks before LSD and placebo administration, and at 2, 8, and 16 weeks after LSD and placebo administration and at follow-up. Ratings were performed according to (Spielberger et al., 1983) and were also performed at screening and in the clinical database (SecuTrial) used in this study.

[0082] Hamilton Depression Rating Scale (HDRS) The study psychiatrists assessed the severity of patients' depression using the HDRS (Hamilton, 1960; Hamilton, 1980). This rating scale consists of 21 items (3- to 5-point scales) that address depression-related symptoms, such as low mood, suicidality, irritability, tension, loss of appetite, insomnia, loss of interest, and somatic symptoms. Summary scores were calculated as described (Hamilton, 1960) and included in the clinical database. This data was provided to SecuTrial.

[0083] Beck Depression Inventory (BDI) The BDI consists of 21 questions developed to measure the severity of depression (Beck et al., 1961). The German BDI-II version (Hautzinger et al., 2006; Kuhner et al., 2007) was used for self-assessment. The BDI has previously been used to measure the severity of depression in patients with advanced cancer. Improvement in mood was evident after 6 months of psilocybin-assisted psychotherapy for anxiety (Grob et al., 2011). Summary scores were calculated as described (Hamilton, 1960) and compared with clinical data. The data were provided to the SecuTrial database.

[0084] Symptom Checklist-90-R (SCL-90-R) The SCL-90-R is a widely used psychological symptom questionnaire for assessing overall psychological distress (Derogatis et al., 1976; Schmitz et al., 2000). We used the German version (Schmitz et al., 2000). The outcome measures were the Global Severity Index, the Positive Symptom Distress Index, and the Total Positive Symptoms. Reductions in these SCL-90 scores were observed after LSD-assisted psychotherapy in patients with life-threatening illnesses (Gasser et al., 2014). SCL-90 scores were calculated according to (Franke, 2002).

[0085] Altered states of consciousness (5D-ASC) The 5 Dimensions of Altered States of Consciousness (5D-ASC) scale is a 94-item visual analog scale (Dittrich, 1998; Studerus et al., 2010). The instrument consists of five scales: It consists of a questionnaire that allows for the assessment of mood, anxiety, derealization, depersonalization, perceptual changes, auditory changes, and decreased arousal. The scale has been well validated (Studerus et al., 2010). , healthy subjects ( Schmid et al., 2015 ) and patients ( Gasser et al., 2014 ; Gasser et al., It has been used to characterize the acute subjective effects of LSD in experimental studies (2015). The 5D-ASC scale was administered once at the end of each session, with subjects instructed to retrospectively rate their peak change during the study session. Each item on the scale was scored on a 0-100 mm VAS. The attribution of individual items to the 5D-ASC subscales followed (Dittrich, 1998; Studerus et al., 2010), and new subscales were developed. , defined as published (Dittrich, 1998; Studerus et al., 2010). Links of items to the scale were provided in a clinical database (SecuTrial). The association between acute peak responses to psilocybin and its long-term therapeutic effects has been repeatedly documented (Carhart-Harris et al., 2016a; Griffiths, 2016). The experience is hypothesized to contribute crucially to the therapeutic potential of LSD and psilocybin (Griffiths, 2016). Aspects of this (mystical) peak experience include the experience of unity (internal, external, perceptual) These include feelings of ineffability (perceived by the individual), transcendence of time / space (eternity / infinity), beauty, sacredness / awe, deeply felt positive mood, ineffability (impossibility to describe in words), and paradox (dead, yet never felt so alive at the same time) (Barrett et al., 2015; Griffiths et al., 2008; MacLean et al., 2011; MacLean et al., 2012). Meanwhile, LSD alters emotional processing in ways that may also contribute to its potential therapeutic effects (Dolder et al., 2016).

[0086] Consciousness State Questionnaire (SCQ) This 100-item questionnaire is rated on a 6-point scale (Griffiths et al., 2011; Griffiths et al., 2006) and has been used with psilocybin (Griffiths et al., 2006) and LSD (Gasser et al., 2014). The SCQ has been used to assess mystical experiences in previous studies (Griffiths et al., 2011; Griffiths et al., 2006) and to explore the relationship between such experiences and the positive long-term effects of psilocybin. The SCQ is administered once at the end of each session, and subjects are instructed to retrospectively rate their peak changes during the test session. Similarly, the criterion for a "complete" mystical experience was a score of at least 60% on each of the following six scales: external or internal unity, sense of the sacred, intellectual quality, timelessness, positive mood, and indescribability. Data on each domain scale were expressed as a percentage of the maximum possible score. Links of items to subscales were provided in a clinical database (SecuTrial).

[0087] Adjective Mood Rating Scale (AMRS) The AMRS or EWL60S is a 60-item Likert scale that allows repeated assessment of mood in six dimensions: active, inactive, well-being, anxious / depressed mood, extraversion and introversion, and emotional excitability. The German version of the EWL60S is used (Janke et al., 1978). The AMRS is administered once at the end of each session, and subjects are instructed to retrospectively rate the peak change during the test session. Scoring of the subscales was performed according to (Janke et al., 1978) and is provided in a clinical database (SecuTrial). It was.

[0088] Visual Analogue Scale (VAS) At the end of the session, the effects of LSD / placebo across the entire session were rated (referenced to peak effects) using a set of VAS, including previously used ratings of "any drug effect," "good drug effect," "bad drug effect," "anxiety," "happy," and "relief" (Schmid et al., 2015).

[0089] Adverse effects Subjects were asked to report any adverse events (AEs) during the session or between the study session at the next session / visit and the study session at the end of study (EOS) visit. Investigators rated hallucinogen-specific AEs occurring during the session using a checklist-adapted form (Gasser et al., 2014; Griffiths et al., 2006; Schmid et al., 2015). Peak effects were rated as "not reported," "mild," "moderate," or "severe" for headache, dizziness, dry mouth, nausea, anxiety, paranoid thinking, emotional distress, emotional lability, blurred vision, chills / chills, and imbalance at the end of the session based on the patient's description and investigator observation. Heart rate and blood pressure were measured at 2-hour intervals (Grob et al., 2011).

[0090] End of study (EOS) visit At the end of the study, the investigators performed physical examinations and blood chemistries. Adverse events were recorded.

[0091] Long-term follow-up Follow-up (not part of the clinical trial) will be conducted by email 52 weeks after completion of the trial, as was also done in the pilot study (Gasseretpal et al., 2015). Participants will be asked to report any ongoing beneficial or harmful effects. The STAI, BDI, and SCL-90 will be repeated. Additionally, personality questionnaires used during screening (NEO-FFI and FPI) will be repeated to assess potential changes in personality (Carhart-Harris et al., 2016b; MacLean et al., 2011). Additionally, the 143-item Johns Hopkins University Sustained Effects Questionnaire will be used to explore information about changes in attitude, mood, behavior, and psychological experience (Griffiths et al., 2011; Griffiths et al., 2006). The 140 items are rated on a 6-point scale and include attitudes about life (13 positive and 13 negative items), attitudes about self (11 positive and 11 negative items), mood changes (9 positive and 9 negative items), behavior changes (1 positive and 1 negative item), and spirituality (22 positive and 21 negative items). Three further questions are included: 1. How personally meaningful was the experience? 2. What impact did the experience have on you? To what extent was it meaningful psychologically? 3. Do you think the experience and reflection on it has changed the current meaning of your personal well-being or life satisfaction?

[0092] investigational drug Recreational Use of LSD: LSD is used for recreational (personal or spiritual) purposes. It is estimated that 38 million Americans, or 15% of those over the age of 12, have taken a hallucinogenic substance at some point in their lifetime (Krebs et al., 2013a). LSD is the most widely used hallucinogenic substance. It is a drug; 24 million Americans have used LSD at least once in their lifetime (Johnston et al., 2016; Krebs et al., 2013a). Thus, a significant proportion of Western society is familiar with the effects of this substance.

[0093] Pharmacology of LSD: LSD is a partial 5-HT 2A The receptor agonist LSD (Nichols, 2016; Rickli et al., 2015; Rickli et al., 2016) is a neurotransmitter that acts on the 5-HT1 receptor. body, adrenaline α1 receptors and dopamine D 1-3 receptors (Rickli et al., 2015). However, these receptor interactions are not related to the psychoactive effects of LSD. The subjective effects of hallucinogenic substances are generally thought to be 5- HT 2A It is thought to be primarily mediated by receptor activation ( Nichols, 2016 ; Vollenweider et al., 1998 ).

[0094] Dose selection for this clinical trial: In this study, a dose of 200 μg of LSD hydrate (ethanol solution, oral) was used, similar to the pilot study (Gasser et al., 2014; Gasser et al., 2015). This dose corresponds to a mid- to high-dose in humans (Passie et al., 2008). The same doses have been used clinically in healthy subjects (Dolder et al., 2015a; Dolder et al., 2015b; Holze et al., 2021; Schmid et al., 2015).

[0095] Clinical pharmacology of LSD: The effects of LSD (200 μg) peak 2 hours after administration and persist for up to 12 hours after administration (Dolder et al., 2015b; Holze et al., 2021; Schmid et al., The plasma elimination half-life of LSD is 3 to 3.6 hours (Aghajanian et al., 1964; Dolder et al., 2015b; Holze et al., 2019; Holze et al., 2020a; Holze et al., 2021).

[0096] Adverse effects of LSD in controlled studies: Perceptual changes after LSD administration include optical illusions, pseudohallucinations, increased color vision, morphological changes of objects and faces, kaleidoscopic or scenic visual imagery, synesthesia, and altered thought and time experience (Holze et al., 2021; Passie et al., 2008; Schmid et al., 2015). Altered body perception, including altered body image, abnormal internal perception of bodily processes, and morphological changes of body shape (Holze et al., 2021; Passie et al., 2008). ; Schmid et al., 2015). At the doses of LSD used in the present study, subjects In contrast to psychotic patients, subjects are expected to maintain control of their thoughts and remain aware of the transient state of the drug-induced experience. Studies using 200 μg of LSD did not confirm a complete loss of thought and bodily control (Holze et al., 2021; Schmid et al., 2015). The subjective effects of LSD are not known in controlled clinical settings. Although the overall positive effects were similar in healthy subjects and patients (Gasser et al., 2014; Gasser et al., 2015; Holze et al., 2021; Passie et al., 2008; Schmid et al., 2015; Schmid et al., 2021), they may include transient dysphoria, anxiety, or mood swings. In pilot studies in patients, neither LSD nor placebo caused any drug-related serious adverse events, i.e., no panic reactions, suicide-related crises, or psychotic states, and no medical or psychiatric emergencies requiring hospitalization. AEs included moderate anxiety (in 23% of LSD sessions and 50% of placebo sessions), mild-to-moderate emotional distress (in 36% of LSD sessions and 33% of placebo sessions), mild emotional lability (in 14% of LSD sessions and 10% of placebo sessions), and nausea (in 10% of LSD sessions and 10% of placebo sessions). Symptoms included mild irritability (in 0% of LSD sessions), mild chills (in 45% of LSD sessions and 0% of placebo sessions), and mild gait disturbance (in 32% of LSD sessions and 0% of placebo sessions). In some cases, some emotional distress persisted into the next day (Gasser et al., 2014). Mild irritability (in 1 or 2 days of daily use) for 1 or 2 days after the LSD session was also reported. Some participants reported negative effects (not interfering with performance) (Gasser et al., 2015). No flashbacks were observed. At a 12-month follow-up (Gasser et al., 2015), none of the participants reported any persistent negative effects from the LSD sessions. Beyond temporary difficulties reported by some participants in dealing with the initial effects of LSD (e.g., intense emotions, changes in self-control), no AEs were noted, consistent with previous findings (Cohen, 1960; Gasser, 1996). Acute AEs of LSD (200 μg) in healthy subjects in a controlled trial included difficulty concentrating (n = 16 participants: 10 after LSD and 1 after placebo), headache (n = 9 after LSD and 3 after placebo), dizziness (n = 7 after LSD and 0 after placebo), nausea (n = 4 after LSD and 1 after placebo), and moderate, transient anxiety (n = 4 after LSD and 0 after placebo) (Schmid et al., 2015). Other investigators have similarly reported initial nausea, decreased appetite, and mild dizziness. They have reported headaches, dizziness, and tremors ( Holze et al., 2021 ; Passie et al., 2008 ). LSD caused mild sympathomimetic stimulation, including pupil dilation (Passie et al., 2008; Schmid et al., 2015). There were no SAEs. The safety profile was confirmed in other studies in over 50 healthy subjects at the Basel center (Dolder et al., 2016; Holze et al., 2021; Holze et al., 2020b). In clinical trials with hallucinogenic substances, mild or moderate anticipatory anxiety is common at the beginning of the drug's effects (Griffiths et al., 2016). Dysphoria, anxiety, and mild transient ideation / paranoia of reference may also occur in some subjects and can be easily managed with reassurance (Griffiths et al., 2006; Schmid et al., 2015). Negative experiences (bad trips) and flashbacks may also occur. The phenomenon of 'lock' can occur under uncontrolled conditions (Strassman, 1984). Under controlled conditions, LSD exposure reportedly had lasting positive effects (Carhart-Harris et al., 2016b). Similarly, psilocybin had lasting positive effects on attitude, mood, and behavior (Griffiths et al., 2011; MacLean et al., 2011; Studerus et al., 2011) without lasting neurocognitive impairment (Halpern et al., 1999). Epidemiological studies have found no increase in psychiatric disorders in hallucinogenic substance users (Johansen et al., 2015; Krebs et al., 2013b). LSD does not produce neurotoxic effects, even at very high doses.

[0097] Material production and quality control: Analytical pure LSD was obtained from Lipomed AG, Arlesheim, Switzerland. The same material was used in a pilot study (Gasser et al., 2014) and was used in the base (Dolder et al., 2015b;Holze et al., 2020a;Holze et al., 2021;Holze et al., 2020b;Schmid et al., 2015;Strajhar et al., 2016), Zurich (Kraehenmann et Previous studies have been conducted in healthy subjects in the UK (Washington, D.C., 2017a; Kraehenmann et al., 2017b; Preller et al., 2017; Preller et al., 2019) and in London (Carhart-Harris et al., 2016b; Carhart-Harris et al., 2015; Kaelen et al., 2015). In contrast to the first previous study, LSD was formulated as a drinking solution in dark glass vials (water / alcohol) and not in capsules. This facilitated regular analytical quality control of the formulation, demonstrating content uniformity and stability of the formulation throughout the study period and for the first time in a clinical trial in patients with LSD (Holze et al., 2019). The clinical drug and placebo (LSD-free solution in the same vial) were prepared in a Swiss Agency-approved Good Manufacturing Practice (GMP) facility (Dr. Apotheke C. Hysek) with randomized individual packaging, labeling, and quality control (QC). The manufacture of the investigational medicinal product (IMP) was approved by the Swiss Agency for Medical Products, and the use of LSD was approved by the BAG.

[0098] Randomization and blinding Each subject received two treatments. Subjects and investigators were blinded to the treatment sequence. Randomization was performed by a GMP facility. Treatment sequence was counterbalanced. The treatment sequence was assigned to each subject number (code list) and maintained by the GMP facility.

[0099] Data analysis Sample size estimation Powder analysis was performed on PASS® (Kaysville, Utah). The pre-determined primary endpoint was STAI anxiety. Data from pilot studies were used to estimate sample size (Gasser et al., 2014; Gasser et al., 2015). In the pilot study, LSD reduced STAI state anxiety scores (mean ± SD, [range]) within subjects from 53.1 ± 13.5 (27-71) to 41.5 ± 9.7 (26-58), an 11.6 ± 9.5-point reduction (raw data available for PI). Trait anxiety scores reduced from 53.3 ± 11.3 (31-70) to 45.3 ± 10.3 (32-62), an 8.0 ± 7.7-point reduction (Gasser et al., 2014; Gasser et al., 2015). While state or trait scale scores were above 40 in all subjects at screening, some subjects had scores below 40 at baseline before receiving LSD or placebo. Based on known pilot study data, a sample size of 6 achieves 80% confidence intervals, and with a known SD of 9.5 and a significance level (α) of 0.05 using a two-tailed one-sample t-test, this difference in STAI state anxiety of 11.6 is detected. However, these data do not include an appropriate placebo control and show change over time, which does not account for substantial placebo / psychotherapy-assisted responses (De Candia et al., 2009; Fisher et al., 1999; Laakmann et al., 1998; Lopresti et al., 2014). Although small, yet clinically relevant (Fisher et al., 1999; Laakmann et al., 1998), the change in LSD compared with placebo was 10% with a 15% SD. Assuming a reduction in anxiety scores of 18, a sample size of 18 would be required to achieve a significance level of 0.05 using within-subject comparisons. Additionally, the inventors analyzed additional secondary outcomes. Therefore, the study was planned to enroll 40 subjects, allowing for a maximum of 10 withdrawals without replacement. In the pilot study, 70 subjects expressed interest in participating. When briefly assessed by phone / email, 50 were ineligible or declined, 20 were fully screened, and 12 were enrolled in the trial (Gasser et al., 2014; Gasser et al., 2015). Based on this pilot data, it is expected that of the 240 people who expressed interest, 80 subjects will be fully screened, 40 will be enrolled in the trial, and at least 30 will be enrolled in the final data analysis.

[0100] Analyzing the results Data were collected on paper via study questionnaires and incorporated into the CRF. Thus, the CRF contains the source data. The data were then entered into a GCP-compatible database. Within the database, the STAI and other questionnaire scores were then calculated using the respective manuals for the study materials. Treatment outcomes were analyzed between subjects in the first treatment period and within subjects treated with LSD versus placebo. In the first analysis presented here, only patients with generalized anxiety disorder were analyzed because this group was terminated, while the group of patients with life-threatening illnesses and anxiety was analyzed later. Ten patients initially received LSD and 11 patients initially received placebo, and these two groups were compared with each other. The two groups were initially compared to demonstrate their similarity in terms of age, gender distribution, illness, and illness severity. All results were then compared between LSD and placebo as changes from baseline, separately for each session in which treatment effect was assessed (between session visits and at 2, 8, and 16 weeks after the second treatment session). The contrast between LSD and placebo was analyzed for differences from baseline using t-tests for each time point and each session and would be consistent with the analysis using baseline as a covariate. LSD and placebo effects were then compared within subjects. First, differences from baseline before each treatment were calculated for each treatment, criterion, and time point. Then, for each outcome, These effects were compared between LSD and placebo at each time point. This analysis assessed the effects of LSD compared with placebo in both within-subject and overall crossover designs. Data were analyzed only for the 19 subjects who completed both treatments; data were not analyzed for two subjects who were included in between-subject comparisons because they only completed the first treatment period. The use of baseline differences accounted for differences in disease severity between and within subjects and reduced carryover effects from the first treatment period. For all these analyses, no correction for multiple testing was applied. This was a subgroup analysis of patients with anxiety only, not an end-of-trial analysis of all patients. Statistical analyses will be performed using Statistica® (StatSoft Version 12). Mixed effects Supplementary analyses using the model or analyses on baseline unexplained scores yielded very similar results overall but are not shown here.

[0101] Protection of Human Subjects See LSD-specific toxicity and safety monitoring.

[0102] Risks to Participation Physical Risks: LSD use is not associated with any known physical risks, but it can lead to psychiatric complications, as described below.

[0103] Potential acute adverse effects: dysphoria, anxiety, mood swings, sleepwalking, transient depersonalization and derealization, mild and transient paranoid thoughts, negative experiences (anxiety, dysphoria, bad trips), tremors, restlessness, acute perceptual changes, acute psychomotor dysfunction, mild tachycardia, mild hypertension, nausea, headache, dizziness, tremors, loss of appetite (Johnson et al., 2012; Passie et al., 2008; Schmid et al., 2015; Studerus et al., 2011). Severe or serious adverse effects are not considered. It was unexpected.

[0104] Possible lasting adverse effects: Flashback phenomena (see below), psychotic reactions.

[0105] Venipuncture (screening and EOS): There was a risk of pain, bruising and thrombophlebitis.

[0106] Risks to subject privacy: Potential risks of data collection include breach of confidentiality. Clinical data are linked to personal data by code lists maintained by the investigator.

[0107] Financial Risk: There was no financial risk to subjects, except for travel costs to the study site (which were not reimbursed). Insurance coverage was provided.

[0108] Considerations of LSD-specific toxicity The primary safety issue in hallucinogen research is psychological rather than physiological in nature. Reactions to hallucinogens involving violent or self-destructive behavior are rare, even under unsupervised and unprepared conditions, making it important not to create unrealistic justifications for the dangers of hallucinogens (Johnson et al., 2008). Nevertheless, even if reports of such dangers are rare, the inventors needed to take such risks seriously and take steps to prevent their occurrence.

[0109] Psychological effects: Transient anxiety and depressive reactions were anticipated in some subjects (Passie et al., 2008; Schmid et al., 2015). In clinical studies with LSD and other psychoactive substances, mild or moderate anticipatory anxiety is common at the beginning of drug effects (Griffiths et al., 2006; Liechti et al., 2001; Schmid et al., 2015). These reactions These are expected to be resolved concurrently with supportive care by investigators (Griffiths et al., 2011; Griffiths et al., 2006; Schmid et al., 2015). At the SD dose, subjects were expected to maintain much of their thought control, and in contrast to psychotic patients, subjects remained aware of the transient nature of drug-induced experiences. More pronounced anxiety, panic attacks, or agitation events could be treated with benzodiazepine administration as needed. A study psychiatrist was present during the session and available for contact afterward. Negative experiences (bad trips) and flashbacks can generally occur under uncontrolled conditions (Strassman, 1984). In the case of psychiatric complications after the study session Participants also had access to a study psychiatrist beyond the study day to provide further assistance if they wished to discuss negative experiences related to the study. Self-harming behavior: People taking LSD may engage in reckless behavior, such as driving while intoxicated. This risk was significantly reduced by continued supervision by the study investigators until the effects of the psychoactive substance had fully subsided. Persistent psychiatric symptoms and / or psychosis after LSD use is a rare reaction unlikely to occur in the cohort of non-psychotic subjects enrolled in this study. LSD or psilocybin may trigger episodes in people already prone to psychosis, rather than directly causing them. Subjects enrolled in this study were non-psychotic and at least 25 years of age.

[0110] Reproductive and Developmental Risks: LSD is not mutagenic or teratogenic, and its chronic use is not associated with birth defects. Pregnant women were excluded from this study; effective contraception was required for female participants; pregnancy tests were administered before each study session.

[0111] Abuse liability: In Switzerland, LSD is scheduled as an anaesthetic. LSD has little, if any, abuse liability. Hallucinogenic substances are not self-administered by animals, and there is no human LSD dependence syndrome (Passie et al., 2008). Currently, people who use the substance Although subjects with a history of substance use disorder were not included in the study, a history of substance use disorder was not an exclusion criterion. Drugs have been used and studied in several substance use disorders, including alcoholism (e.g., alcoholism, alcohol use disorder (e.g., alcoholism, alcoholism, alcoholism), and nicotine dependence (e.g., alcoholism, alcoholism, alcoholism) (Liester, 2014; Ludwig et al., 1969; Mangini, 1998; Pahnke et al., 1970) and nicotine dependence (Johnson et al., 2014). Illicit drug use was monitored throughout the study using repeated urine drug screens.

[0112] Neurotoxicity: LSD is not neurotoxic (Nichols, 2016; Passie et al., 2014; Passie et al., 2008).

[0113] Flashbacks: Flashbacks can be defined as episodic and brief (seconds or minutes) recurrences of elements of a previous substance-related experience (Holland et al., 2011; Passie et al., 2014). These experiences can be positive or negative. Such phenomena are common in many substances. Clinically significant flashbacks have been reported after substance use and are prevalent even in non-substance users (Holland et al., 2011). Clinically significant flashbacks, also defined as hallucinogenic substance persistent perceptual disorder, are considered rare but can occur in patients with anxiety disorders, and they typically have a limited course of several months to a year (Halpern et al., 1999; Holland et al., 2011; Passie et al., 2014).

[0114] Safety Monitoring Guidelines for Hallucinogenic Substance Research: The procedures described herein are based on guidelines for high-dose hallucinogenic substance research (Fischman et al., 1998; Gouzoulis-Mayfrank et al., 1998; Johnson et al., 2008) and experience in conducting research on psychoactive substances. The procedures are intended to support the safe administration of psychoactive substances while minimizing potential side effects. .

[0115] Age of participants: LSD and psilocybin have been studied in recent controlled trials in subjects aged 22–62 (Carhart-Harris et al., 2016b) and 20–64 (Bogenschutz et al., 2015; Griffiths et al., 2006), respectively. Younger age has been associated with negative reactions to psilocybin and increased anxiety (Studerus et al., 2012). Therefore, subjects under the age of 25 are excluded (Studerus et al., 2012). Older subjects were reported to be less likely to experience loss of control in response to psilocybin (Studerus et al., 2012). There is no upper age limit, but physical illness and organ dysfunction are exclusion criteria. Subjects taking medications that may negatively interfere with the test or the substances used will be excluded. Drugs known to alter the effects of hallucinogens include: tricyclic antidepressants, lithium, serotonin uptake inhibitors, antipsychotics, and monoamine oxidase inhibitors (Johnson et al., 2008).

[0116] Other psychiatric disorders: Psychiatric screening criteria were important to minimize the already low possibility of inducing a long-term psychotic reaction to LSD. Subjects with a current or past history of schizophrenia or other psychotic disorders (due to a medical condition) or bipolar disorder meeting DSM-IV criteria were excluded. These are the most important exclusion criteria to ensure safety. Subjects with first-degree relatives with these disorders were also excluded. In addition to anxiety, other psychiatric disorders such as comorbid depression, obsessive-compulsive disorder, or previous substance use disorders were not excluded because hallucinogenic substances have been used in patients with these disorders or specifically to treat these disorders (Gasser et al., 2015; Grob et al., 2011; Krebs et al., 2012; Moreno et al., 2006; Ross, 2012).

[0117] Predictors of response: Significant predictors of more pleasant and mystical-type experiences following administration of hallucinogens in a controlled testing environment are: a high score on the personality trait of absorption (openness to new experiences) and having experienced few psychological problems in the past few weeks prior to the testing session (Studerus et al., 2012). Factors associated with response include: younger age, emotional instability, and the setting involving the brain scan (Johnson et al., 2008; Studerus et al., 2012). Subjects who are more open to new experiences, including the use of hallucinogens, are more likely to be interested in participating in the trial, and this self-selection bias increases the safety of such trials (Johnson et al., 2008; Studerus et al., 2011). Investigators asked participants before each session whether they had recently experienced any psychological problems that might have had a negative impact on their experience, and if so, the session could be postponed or canceled.

[0118] Drug experience: Previous experience with psychoactive drugs can influence the response to psychoactive substances. In a controlled study with psilocybin, drug use and prior experience with hallucinogens only moderately influenced the psilocybin response (Studerus et al., 2012). Participants who smoked cannabis occasionally (multiple times per month) tended to report stronger psilocybin effects overall (Studerus et al., 2012). Participants who smoked cannabis occasionally (multiple times per month) also reported infrequent THC use. subjects tended to experience more pleasant effects and less anxiety compared with subjects who did not (Studerus et al., 2012). Healthy participants with prior experience of hallucinogenic substance use and those with no hallucinogenic substance use were compared. No differences in response to LSD were found between active and passive subjects (Schmid et al., 2015). Of note, subjects with chronic drug use were not included in the study (Studerus et al., 2012). The present study is consistent with previous studies using LSD (Gasser et al., 2014; Gasser et al., 2015; Schmid et al., 2015) and psilocybin The study was conducted in patients with no or limited prior drug exposure, similar to studies conducted by others (Griffiths et al., 2011; Griffiths et al., 2006; Studerus et al., 2011). This included mainly patients with rheumatoid arthritis.

[0119] Study personnel: Interpersonal atmosphere is important for responses to hallucinogenic substances (Johnson et al., 2008). Research personnel present with volunteers during sessions had to be familiar with potential medical and psychological side effects of substances (Johnson et al., 2008). Personnel should also possess interpersonal skills and be familiar with assessing hallucinogenic substance-induced altered states of consciousness (Johnson et al., 2008). Clinical sensitivity (e.g., empathy, respect) is considered more important than formal degrees when considering personnel qualifications (Johnson et al., 2008). In the present study, investigators had experience caring for study subjects after psychoactive substance treatment and were present during substance effects (up to 12 hours). Volunteers were never left alone during acute substance effects (Johnson et al., 2008). The investigators knew the volunteers from screening and preliminary visits. The investigator, who was present during the session, also conducted a screening session with the volunteer to establish good interpersonal rapport.

[0120] Safety procedures during the session During the session, subjects were under constant supervision. One person was always present in the session room with the participant. If the participant needed to use the toilet, they were escorted there. The door was unlocked (staff had the key). Staff ensured that participants could not leave the investigational site during substance effects. In the event of an emergency (fire alarm or other), one person remained with the subject at all times.

[0121] Adverse cardiovascular effects: Only mild cardiac stimulant effects were expected. Cardiovascular effects (blood pressure and heart rate) were measured repeatedly. Close monitoring was performed if blood pressure values ​​exceeded 180 / 120 mmHg or if systolic blood pressure fell below 90 mmHg. Hypertensive reactions (P sysTreatment for hypotension (>220 mmHg) would have included lorazepam and troglycerin. Treatment for hypotension would have included Trendelenburg positioning. Cardiac arrest would have triggered immediate cardiopulmonary resuscitation and a call for an ambulance.

[0122] Headache: LSD can cause transient headaches (Schmid et al., 2015). In the study, one participant required acetaminophen for a moderate headache the day after the LSD session. Conversely, LSD has reportedly reduced cluster headache and migraine episodes (Davenport, 2016; Karst et al., 2010; Sewell et al., 2006). In a pilot study, LSD significantly reduced the number of migraine attacks in two migraine patients.

[0123] Pain: Some patients may require pain medication during the session due to their physical ailments. In the pilot study, three patients took their regular pain medication during the session.

[0124] Adverse psychological reactions: Despite its overall positive mood effects, LSD was expected to produce transient dysphoric reactions and controllable anxiety / concerns. Side effects ("bad trips") were expected to be minimized by the controlled setting, participant selection criteria, participant preparation described above, and interpersonal support provided by the study staff. Subjects were constantly and carefully monitored by the investigators for signs of psychological distress. Unexpected severe anxiety was treated first with psychological support from the study psychiatrist, followed by administration of benzodiazepines. Personal support and reassurance are the most appropriate and important response to adverse psychological reactions. When necessary, subjects were reassured by touching the arm / shoulder and verbally reminded that they were participating in the research study, had taken a psychoactive substance, and would return to normal consciousness within a few hours. Subjects were generally advised to accept abnormal feelings and to let go or distract themselves from their experiences rather than attempting to talk themselves down (Johnson et al., 2008). These technologies are This was considered sufficient in almost all cases and has been used successfully by research teams. While medication is unlikely to be required for panic control in healthy subjects (Hasler et al., 2004; Johnson et al., 2008; Schmid et al., 2015), this was expected in some of the anxiety disorder patients in this study, as well as in pilot studies of patients with anxiety disorders (Gasser et al., 2014; Gasser et al., 2015). In the pilot study, three patients took benzodiazepines during the trial, but not during the actual LSD sessions (Gasser et al., 2014).

[0125] Dizziness / Gait Control: Except during peak drug effects, subjects were able to walk around without difficulty (Schmid et al., 2015). However, the sensory and behavioral effects of LSD / psilocybin were not significant. and proprioceptive effects make walking difficult and guidance may be helpful.

[0126] Other AEs. All other side effects were treated as appropriate by the investigator based on clinical judgment. Nausea or headache during the session ideally would not be treated with medication until its effect was fully determined to avoid drug-drug interactions. Paracetamol could be used to treat headaches after the session, if necessary.

[0127] Inter-session AEs: These effects were assessed as AEs at the beginning of the next session or at EOS.

[0128] Duration of session monitoring: Subjects were closely monitored until all subjective effects had ceased, which was considered to be within 12 hours for LSD. In previous studies using 200 μg of LSD, the effects lasted up to 12 hours (Holze et al., 2021; Schmid et al., 2015). Beyond this time, no close monitoring was required, and subjects were able to stay at home. Thus, 12 hours after LSD / placebo administration, participants were allowed to return home, but only if accompanied and supervised by a partner, relative, or friend. After the test session, subjects were only allowed to leave if the subjective effects, as assessed by the investigator, had ceased. If supervision was not available or if the effects persisted, they had to spend the night at the investigational site. In this case, the investigator was present at the investigational site but in a separate room, as indicated by safety guidelines (Johnson et al., 2008).

[0129] Post-session safety procedures: Based on previous research experience (Gasser et al., 2014; Gasser et al., 2015; Schmid et al., 2015), no formal follow-up support was required. AEs during the session were reported at the next study visit and at the EOS visit. If necessary, an earlier meeting was scheduled. Subjects were prohibited from driving or operating machinery within 24 hours of substance administration.

[0130] Toxicity monitoring Definition of Safety Adverse Events (AE): An untoward medical occurrence in a clinical trial subject administered an IMP and not necessarily causally related to this treatment. Thus, an AE can be any untoward and unintended sign (abnormal clinical condition), symptom, or disease temporarily associated with the use of an (IMP), whether or not considered related to the IMP.

[0131] Side effects (AR): All adverse and unintended reactions to an IMP that are judged by the investigator / sponsor to have a legitimate causal relationship to the IMP. The term legitimate causal relationship generally conveys that there is evidence or arguments suggesting a causal relationship.

[0132] Unanticipated Adverse Reactions (UAR): The adverse reaction, its nature, or severity is inconsistent with the applicable product information (e.g., an investigator's brochure or the officially approved Summary of Product Characteristics (SmPC) for an unapproved investigational product). If the adverse reaction outcome is inconsistent with the applicable product information, the adverse reaction should be considered unexpected. An adverse reaction described in the IB or SmPC that occurs with more severity than expected is also considered unexpected.

[0133] Serious Adverse Events (SAEs) or Serious Side Effects: An untoward medical event or effect at any dose is fatal, life-threatening, requires hospitalization or extension of an existing hospitalization, results in persistent or significant impairment or disability, or results in a congenital abnormality or birth defect. In this context, the term life-threatening means an event in which the trial participant is at immediate risk of death at the time of the event; it does not mean an event that, if more severe, could have caused death.

[0134] Suspected Unexpected Serious Adverse Reaction (SUSAR) The suspected side effects were related to IMP, which was unexpected and severe.

[0135] Causation: Most adverse events and side effects that occurred in this study, whether serious or not, were expected to be treatment-related toxicities caused by the drugs used in this study. Causality assignment was made by the investigators using the definitions in Table 1 below.

[0136] [Table 1]

[0137] Adverse Event (AE) Documentation AEs were noted and recorded on the subject's CRF, regardless of severity or relevance to the IMP. AEs were scored for severity and correlated with the study intervention by the investigator according to standard criteria. Potential relevance to the study was assessed. Subjects with AEs were treated appropriately. Abnormal laboratory values ​​not explained by the patient's illness had to be repeated until normal or until the abnormality could be explained and no longer posed a risk to the subject's integrity.

[0138] legal authorization LSD is a scheduled substance in Switzerland (Anhangd der BetmV-Swissmedic). The Investigational Pharmacopoeia has granted BAG permission to use this substance.

[0139] Clinical trial documentation and record keeping The investigator maintained appropriate records to allow for a complete documentation of the conduct of the trial. Copies of the protocol, identification code, CRFs, original study result reports, dispensing logs, correspondence, informed consent records, and other documents related to the conduct of the trial will be kept on file in the archives of the University Hospital Basel for 10 years. All forms must be typed or completed with blue or black ballpoint pen and must be legible. Errors will be crossed out but not erased, corrections will be inserted, and the changes will be signed and dated by the investigator or an authorized person. For each enrolled subject, a CRF will be completed and signed by the investigator. This also applies to subjects who are unable to complete the trial.

[0140] Quality Control and Quality Assurance Staff training and SOPs Study personnel completed GCP training. The study was conducted in accordance with ICH GCP E6 and in accordance with the QMS of the CTU at the University Hospital Basel.

[0141] monitoring The trial was monitored by CTU Basel.

[0142] Patients with anxiety disorders without physical illness Only data from patients with anxiety disorders without physical illness are presented here. Twenty-one patients initiated treatment and completed the first study period by week 24. Two patients dropped out, and 19 patients completed the entire study.

[0143] Patient characteristics are shown in Figure 14. Twenty-one patients with anxiety disorders without severe physical illness were enrolled in the trial (11 men and 10 women). The mean age was 46 years. Two patients dropped out after the first trial period. Therefore, a total of 21 patients were available for parallel group comparisons, and 19 patients could be enrolled in the within-subject comparison of LSD and placebo.

[0144] All patients had a diagnosis of anxiety disorder and a minimum STAI-S or STAI-T score of 40 at screening. Among the 21 patients, 18 had primary anxiety disorder, 15 had generalized anxiety disorder, 9 had social phobia, and 7 had panic disorder as primary diagnoses. Three patients had a diagnosis of major depression. Nine of the 21 patients were receiving antidepressant medication (one was receiving lithium), and in all cases, the antidepressant was tapered at least two weeks before administration of LSD or placebo. Five patients were receiving anxiolytic medication (benzodiazepines). Illness scores were comparable at study entry (Figure 14) and baseline treatment.

[0145] Patient characteristics were similar in the group initially receiving LSD compared with the group initially receiving placebo, allowing for valid parallel group comparisons of LSD- and placebo-treated patients during the first treatment period (parallel design, between-subject comparisons).

[0146] Figures 15A-15F show the effects of LSD and placebo on anxiety, depression, and psychological distress scores. Figure 15 shows data as mean and SEM values ​​for patients treated first with placebo and then with LSD (placebo first, number of patients = 11) or first with LSD and then with placebo (LSD first, number of patients = 10). LSD or placebo was administered at weeks 3 and 8 in the first study period and again at weeks 29 and 33 in the second study period. LSD significantly reduced STAI-S (Figure 15A), STAI-T (Figure 15B), and STAI-G (Figure 15C) scores at week 10 (2 weeks after the second dose) compared to placebo ( ** p-values ​​= 0.008, 0.001, and 0.002, respectively). STAI-S and STAI-G scores were significantly reduced already after the first session ( *p-values ​​= 0.03 and 0.04, respectively (Figures 15A and 15C). STAI-S, STAI-T, and STAI-G scores continued to decrease after LSD at 16 and 24 weeks (8 and 16 weeks after the second dose) compared to placebo (Figures 15A-C), but did not reach statistical significance. Similarly, LSD significantly reduced scores on the HDRS (Figure 15D), BDI (Figure 15E), and SCL-90 Global (Figure 15F) at 10 weeks (2 weeks after the second dose) compared to placebo (p-values ​​were 0.002, 0.02, and 0.004, respectively). For the HDRS, LSD reduced scores already after the first session (Figure 15C). * p=0.04) (Figure 15D). The effects of LSD on STAI and SCL-90 global remained reduced at 16 and 24 weeks after the second dose and compared to placebo (Figures 15A-C and 15F), but did not reach statistical significance.

[0147] Treatment effects were then evaluated within subjects using the crossover design of the trial, with 19 patients receiving both treatments (one patient received placebo only and one patient received LSD only during the first treatment period). Data from one or two subjects were missing for some measurements and time points. As illustrated in Figures 15A-15F, carryover effects were present because the treatment effects of LSD in the first treatment phase continued into the second treatment phase. To account for shifts in baseline values, data were analyzed as differences from baseline (week 0 or week 26). LSD significantly reduced symptom scores for all measures (STAI-S, STAI-T, STAI-G, HDRS, BDI, and SCL-90 Global) compared to placebo at 2 weeks after the second treatment compared to placebo (p values ​​= 0.01, 0.003, 0.003, 0.03, 0.002, and 0.004, respectively) (Figures 16A-16F).

[0148] Figures 15A-15F also provide important information about the effects of LSD during the first treatment period compared to its effects during the second treatment period. Effects were clearly present after the first and second administrations during the first treatment period. Effects were also present during the second treatment period. However, placebo generally had similar effects to LSD during the second treatment period in subjects who had already received LSD during the first treatment period. Given that participants met with the same therapist and in the same setting during the first session with LSD, this can be explained by a conditioned response. This would imply that, using the present invention and in patients with anxiety disorders, additional non-drug sessions may be beneficial if conducted with the same therapist and in the same setting, or if a placebo or low dose of LSD is used due to the presence of a conditioned effect from the first LSD administration.

[0149] In 19 patients, data for the LSD condition were finally evaluated over time without placebo. Again, at 2 weeks after the second treatment, LSD reduced scores on all outcome measures for the STAI-S, STAI-T, STAI-G, HDRS, BDI, and SCL-90 global scores in within-subject comparisons with baseline measurements (p-values ​​= 0.006, 0.01, 0.03, 0.02, and 0.03, respectively).

[0150] Acute changes in the mind induced by LSD and placebo are shown in Figure 17. LSD induced significant and significant changes in all scales of the 5D-ASC questionnaire (all p<0.001 vs. placebo). Acute LSD effects were comparable in sessions 1 and 2. The acute effects of LSD were generally higher than those observed in healthy subjects treated with the same LSD dose of 200 μg in a clinical setting (Holze et al., 2021). Specifically, the positive effects of LSD (nominal OB scores) were higher in anxious patients compared to healthy subjects, while negative effects such as impaired control and cognition and disembodiment, as well as perceptual VR effects, were similar. Thus, the present invention demonstrates an overall positive acute effect of LSD in anxious patients, with an overall positive acute effect profile comparable to or superior to the negative acute effect profile in patients compared to healthy subjects.

[0151] The acute mystical-type effects of LSD and placebo are shown in Figure 18. LSD significantly and strongly increased the mystical-type experience rating on the MEQ30 questionnaire. The effects were similar in the first and second sessions. The effects tended to be higher in anxiety patients compared to healthy subjects treated with LSD (Garcia-Romeu et al., 2015; Griffiths et al., 2016). In the present study, LSD apparently produced mystical-type effects known to be associated with positive therapeutic outcomes for psilocybin in other therapeutic studies and patient populations (Garcia-Romeu et al., 2015; Griffiths et al., 2016).

[0152] Association of Acute Effects with Long-Term Therapeutic Benefits: The acute effects of LSD on the 5D-ASC and MEQ30 questionnaires correlate with the therapeutic effects of LSD two weeks after the second administration. Specifically, the %OB score, especially at the second LSD administration, significantly correlated with therapeutic improvement as evidenced by decreases in STAI-S, STAI-G, BDI, and SCL-90 global scores (all p-values ​​<0.05, Pearson correlation, n=20). Similarly, the acute effects of LSD on MEQ30 at the second LSD session significantly correlated with decreases in STAI-S, STAI-G, and SCL-90 global scores (all p-values ​​<0.05, Pearson correlation, n=20). Correlation coefficients are shown in Figure 19. The present invention demonstrates that a favorable drug effect of LSD predicts favorable therapeutic outcomes two weeks after treatment. This finding is consistent with studies using psilocybin (Griffiths et al., 2016; Roseman et al., 2017). Furthermore, the present invention demonstrates that the second of two sessions best predicted outcome two weeks later. Furthermore, only positive LSD effects, as assessed by the OB and MEQ30 scales, were predicted; more negative acute effects, as assessed by the AED scale, were not significantly associated with treatment outcome. Furthermore, visual changes, as assessed by the VR score, did not predict treatment response.

[0153] Adverse events Adverse events (AEs) specifically asked about during treatment sessions included anxiety at the onset of LSD action in two patients (never with placebo), severe anxiety / paranoia in one patient receiving LSD (never with placebo), nausea in two patients receiving LSD (never with placebo), and headache in one patient receiving LSD (never with placebo).

[0154] Paranoia occurred in one patient during the first LSD session and was treated with a benzodiazepine and an antipsychotic, which was scored as a serious adverse event (SAE). This patient's dose was then reduced to 100 μg instead of the planned 200 μg, and this treatment was well tolerated.

[0155] Adverse events (AEs) are shown in the table in Figure 20. The numbers are the sum of AEs reported at all visits during the period not including treatment sessions. The most common AEs were: fatigue (LSD 9, placebo 7), cold (LSD 7, placebo 3), headache (LSD 6, placebo 14), dizziness (LSD 5, placebo 4), difficulty concentrating (LSD 5, placebo 6), nausea (LSD 3, placebo 4), and depression (LSD 3, placebo 0).

[0156] SAEs in this study included the aforementioned paranoia during the LSD session in one patient, which was an expected response to LSD. Another SAE consisted of hospitalization in one patient during the placebo period, which was due to pre-existing obsessive-compulsive disorder and preceded LSD treatment in this patient; therefore, this was not a reaction to the substance. Another SAE consisted of scheduled surgery for a deviated nasal septum in one patient, which occurred during the LSD period and was considered unrelated to LSD treatment. Another SAE consisted of a spontaneous abortion in one patient who became pregnant at the end of the LSD treatment phase; both the pregnancy and the miscarriage were considered unrelated to LSD treatment.

[0157] Throughout this application, various publications, such as U.S. patents, are referenced by author and year, and patents are referenced by number. Full citations for the publications are set forth below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0158] The invention has been described in an illustrative manner, and it will be understood that the terminology used is intended to be in the nature of words of description rather than of limitation.

[0159] Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

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Claims

1. 1. A method of treating an anxiety disorder not specifically associated with a serious life-threatening physical illness, comprising: administering a hallucinogen to the individual; and treating anxiety and causing a reduction in a rating scale score measure selected from the group consisting of anxiety, depression measures, general psychological distress measures, and combinations thereof in said individual over a period of several weeks beyond administration of said hallucinogen. A method comprising:

2. 10. The method of claim 1, wherein the rating scale score measure of anxiety is selected from the group consisting of STAI global, state, and trait anxiety.

3. 10. The method of claim 1, wherein the rating scale score measure of depression is selected from the group consisting of HDRS and BDI scores.

4. 2. The method of claim 1, wherein the rating scale score measure of general psychological distress is an SCL-90 rating.

5. 2. The method of claim 1, wherein the hallucinogen is selected from the group consisting of LSD, its salts, its analogs and its homologs.

6. 6. The method of claim 5, wherein the LSD is administered in an amount of 25 to 400 μg.

7. 7. The method of claim 6, wherein the second dose of LSD is administered 4 to 5 weeks after the administering step.

8. 2. The method of claim 1, wherein the hallucinogen is a tryptamine or a phenethylamine and induces the same or similar acute effects as LSD on the 5D-ASC scale and comprises a substance selected from the group consisting of psilocybin, mescaline, dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), salts thereof, tartrates thereof, analogs thereof, and homologs thereof.

9. 10. The method of claim 1, wherein the anxiety is endogenous anxiety selected from the group consisting of generalized anxiety disorder, social anxiety disorder, panic disorder, phobia, adjustment disorder, and post-traumatic stress disorder.

10. 10. The method of claim 1, further comprising treating depression or low mood associated with or coexisting with said anxiety.

11. 10. The method of claim 1, further comprising reducing psychological distress and / or improving quality of life in the individual.

12. 10. The method of claim 1, further comprising the step of intensifying psychotherapy administered on separate days before and after administration of the hallucinogen.

13. 10. The method of claim 1, wherein the individual has a qualitatively different need for psychedelic response after use of other hallucinogens.

14. 1. A method of treating anxiety, comprising: Administering a hallucinogen to an individual experiencing anxiety that is not associated with a cause such as a life-threatening serious physical illness; and eliciting a positive acute drug effect and a positive long-term therapeutic effect in said individual. A method comprising:

15. 15. The method of claim 14, wherein the hallucinogen is selected from the group consisting of LSD, its salts, its analogs and its homologs.

16. 16. The method of claim 15, wherein the LSD is administered in an amount of 25 to 400 μg.

17. 15. The method of claim 14, wherein the hallucinogen is a tryptamine or a phenethylamine and induces the same or similar acute effects as LSD on the 5D-ASC scale and comprises a substance selected from the group consisting of psilocybin, mescaline, dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), salts thereof, tartrates thereof, analogs thereof, and homologs thereof.

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