This systematic review (2018) of 11 clinical trials (n=445) found that psychedelics (LSD, psilocybin) reduced symptoms of depression and anxiety in patients with life-threatening diseases (end-of-life).
Abstract
“Anxiety and depression are some of the most common psychiatric symptoms of patients suffering with life-threatening diseases, often associated with a low quality of life and a poor overall prognosis. 5-HT2A-receptor agonists (serotonergic hallucinogens, ‘psychedelics’) like lysergic acid diethylamide (LSD) and psilocybin were first investigated as therapeutic agents in the 1960s. Recently, after a long hiatus period of regulatory obstacles, interest in the clinical use of these substances has resumed. The current article provides a systematic review of studies investigating psychedelics in the treatment of symptoms of existential distress in life-threatening diseases across different periods of research, highlighting how underlying concepts have developed over time. A systematic search for clinical trials from 1960 to 2017 revealed 11 eligible clinical trials involving a total number of N = 445 participants, of which 7 trials investigated the use of lysergic acid diethylamide (LSD) (N = 323), 3 trials investigated the use of psilocybin (N = 92), and one trial investigated the use of dipropyltryptamine (DPT) (N = 30). The 4 more recent randomized controlled trials (RCTs) (N = 104) showed a significantly higher methodological quality than studies carried out in the 1960s and 1970s. Evidence supports that patients with life threatening diseases associated with symptoms of depression and anxiety benefit from the anxiolytic and antidepressant properties of serotonergic hallucinogens. Some studies anecdotally reported improvements in patients´ quality of life and reduced fear of death. Moreover, low rates of side effects were reported in studies that adhered to safety guidelines. Further studies are needed to determine how these results can be transferred into clinical practice.“
Authors: Simon Reiche, Leo Hermle, Stefan Gutwinski, Henrik Jungaberle, Peter Gasser & Tomislav Majić
Notes
This paper is included in our ‘Top 10 Articles Introducing Psychedelic-Assisted Therapy‘
Highlights from the authors:
- “Serotonergic hallucinogens are investigated for the treatment of anxiety associated with life-threatening diseases
- Trials show anxiolytic and anti-depressant effects after single administration
- Different mechanisms of action were suggested for the therapeutic aspects
- Substances exhibited a reasonable safety profile in a clinical setting
- Additional studies are needed to determine use in clinical practice”
Summary
Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review
Anxiety and depression are common psychiatric symptoms in patients suffering from life-threatening diseases. 5-HT2A- receptor agonists like lysergic acid diethylamide and psilocybin have been investigated as therapeutic agents in the 1960s. A systematic search of clinical trials from 1960 to 2017 revealed 11 eligible clinical trials involving a total number of N = 445 participants. The 4 more recent randomized controlled trials showed a significantly higher methodological quality than studies carried out in the 1960s and 1970s.
When receiving a diagnosis of a life-threatening physical disease, patients often experience fear, anger, despair, and social withdrawal. Some patients are able to cope effectively, while others develop a broad range of psychological problems. Existential distress is a common problem in patients with a life-threatening disease, and is often associated with poor treatment adherence and higher mortality rates. There are increasing number of psychotherapeutic interventions for existential distress, but currently no specific pharmacological treatment options. Recently, there has been some interest in the therapeutical potential of classic serotonergic hallucinogens (5-HT2A receptor agonists; “psychedelics”) in certain indications.
Psilocybin and LSD belong to the group of the classic or serotonergic hallucinogens (“psychedelics”), which can be divided into tryptamines, ergolines and phenethylamines. They share a common mechanism of action at different 5- HT receptors, primarily the 5- HT2A receptor.
The treatment strategies presented in the current article originally emerged in the 1950s and 1960s, but were halted due to regulatory restrictions in the mid 1970s. However, they are currently being re- evaluated for the treatment of anxiety and depression in patients with a life-threatening disease. A high dose of psilocybin (30mg) was administered to a group of 20 students of theology before they attended a religious service in a private chapel. The psilocybin group experienced a high rate of profound experiences (30- 40%), similar to the characteristics of nondrug-related ‘mystical’ experiences. In a more recent study, 22 out of 36 subjects who received psilocybin or methylphenidate had a ‘mystical’ peak experience, which was rated as one of the most personally meaningful and spiritually significant experiences of their lives.
Existential distress and spiritual crises are major issues for patients with depression and anxiety with life-threatening disease. Serotonergic hallucinogens may be effective in treating these patients.
A systematic review was conducted on the electronic databases MEDLINE (PubMed), Embase, Cochrane Library, Google Scholar to identify studies in which serotonergic hallucinogens were administered to subjects aged 18 or older diagnosed with a diagnosis of advanced or terminal life-threatening disease.
After screening 1674 hits, 11 clinical trials were identified in which the treatment of patients with a life-threatening disease with serotonergic hallucinogens was evaluated. Nine out of 11 studies only included patients suffering from cancer, but one study also included patients with non- malignant life-threatening diseases.
In the first clinical trial investigating the therapeutic use of LSD in patients with terminal cancer, LSD was found to produce a greater degree of pain relief than opioids, and to last longer than opioids. In addition, patients reported to have gained more open and positive attitudes towards their condition. In a subsequent trial, cancer patients were administered LSD in a more carefully arranged setting. The patients experienced an “expansion of immediate sensory life” and a loss of the ability to anticipate pain and death.
At the same time as Kast’s studies, another group at the Spring Grove Hospital (Baltimore, Maryland) conducted open-label pilot studies with terminal cancer patients. The sessions took place in a physically safe and psychologically supportive environment with additional positive stimuli and with two therapists of both sexes present.
In the first study, terminally ill cancer patients received a high dosage of LSD and showed positive changes in psychological symptoms. Six out of 14 patients showed a dramatic improvement. In a study by Grof et al. (1973), terminal cancer patients that received a high to very high dose of LSD (200 – 500 g) showed significant improvement in depression and anxiety. In a study by Richards et al. (1980), terminal cancer patients that received dipropyltryptamine (DPT) showed significant improvement in all six categories.
The first double- blind, placebo- controlled trial of psilocybin in advanced- staged cancer patients was conducted in 2011. Psilocybin had a shorter duration of action than LSD and a less negative reputation than LSD. In a cross-over design with two experimental sessions several weeks apart, patients received a moderate dose of psilocybin or niacin. The patients’ anxiety and depressive symptoms were reduced by nearly 30% one month after the second treatment session. Some patients have reported gaining new insights about their illness and having more positive attitudes towards their limited life expectancy.
A double- blind, randomized, active placebo- controlled pilot study examined the safety and efficacy of LSD- assisted psychotherapy in patients with a life- threatening disease.
Patients received either 200 g of LSD as experimental dose or 20 g of LSD as active placebo. After two months, significant reductions in STAI- state and STAI- trait subscales were observed, and these reductions were sustained for 12 months. In a recent trial, 51 patients received psilocybin- assisted treatment, and 78% of the patients responded clinically significantly. 65% of the patients showed symptom remission to normal range, and additional follow- up measures revealed significant improvements in the domains of overall quality of life, purpose in life, and acceptance of death and optimism. In another recent trial, 29 patients received a relatively high dose of psilocybin (0.3 mg/kg) in conjunction with psychotherapy. Seven weeks after the first dose, BDI scores decreased in 83% of the patients by half or more, and HADS anxiety scores decreased in 58% of the patients.
Approximately 60- 80% of patients exhibited a clinically significant anxiolytic or antidepressive response, and mystical experience scores correlated significantly with positive therapeutic outcomes. The applied cross-over design is a limitation of recent studies.
In some studies, patients reported transient physiological symptoms such as nausea or vomiting, headaches, tremor and breathing difficulties. None of the studies reported serious medical complications, and no clinical relevant flashback phenomena, Hallucinogen Persisting Perception Disorder (HPPD) or cases of prolonged psychosis were reported.
Eleven clinical trials involving serotonergic hallucinogens were identified in which therapeutic effects were evaluated in patients with a life-threatening disease.
In the 1960s and 1970s, clinical trials were conducted at Spring Grove, where psychological effects of psychedelics were primarily focused in the framework of “psychedelic (peak) therapy”. These trials showed that psychedelic-assisted psychotherapy showed effective and promising results. 3) Recent clinical trials have reconsidered previous methods to induce insightful psychological experiences with psilocybin at lower dosages, but they are of a substantially increased methodological quality. These trials show that mystical-type experiences might be important, but there are other important factors as well. Most studies before 2000 were based on anecdotal evidence and non-standardized outcome criteria, and no long-term follow-up studies were carried out.
The trials carry a high risk of bias, and the blinding process is only possible to a limited extent since psychedelics produce unique characteristic psychoactive effects. Furthermore, the obtained follow-up data are only conclusive to a limited extent, after control groups have also received an active therapeutic dose. The studies were limited by the strict exclusion criteria and the high percentage of highly educated people and prior history of hallucinogen use.
Serotonergic hallucinogens show a reasonable safety profile when administered in a clinical research setting, with the exception of transient physiological symptoms. No serious medical adverse effects have yet been described.
Psychedelics can produce intense experiences, sometimes accompanied by anxiety and panic reactions, and even transient psychotic symptoms. There have been anecdotal reports of dangerous behaviors following recreational use of psychedelics, associated with accidents or even suicide attempts. In the 1960s and 1970s, prolonged psychosis after administration of psychedelics was observed in clinical environments. Hallucinogen Persisting Perception Disorder (HPPD) is a probably rare disorder, characterized by re- experiencing predominantly visual effects of psychedelics in the absence of an acute substance effect. Studies on U.S. adults have found no association between psychedelic use and mental health problems, and psychedelics are also under investigation for the treatment of substance use disorders, cluster headaches and treatment-resistant depression.
There is some evidence that serotonergic hallucinogens can be used to treat mental health problems in patients with a life-threatening disease, and that psychedelic-induced mystical-type experiences can improve disease coping and quality of life.
Interest in clinical applications of serotonergic hallucinogens has resumed. Trials show anxiolytic and anti-depressant effects after single administration.