OPEN Foundation

L. Hermle

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


Anxiety and depression are some of the most common psychiatric symptoms of patients suffering with life-threatening diseases, often associated with a low quality of life and a poor overall prognosis. 5-HT2A-receptor agonists (serotonergic hallucinogens, ‘psychedelics’) like lysergic acid diethylamide (LSD) and psilocybin were first investigated as therapeutic agents in the 1960s. Recently, after a long hiatus period of regulatory obstacles, interest in the clinical use of these substances has resumed. The current article provides a systematic review of studies investigating psychedelics in the treatment of symptoms of existential distress in life-threatening diseases across different periods of research, highlighting how underlying concepts have developed over time. A systematic search for clinical trials from 1960 to 2017 revealed 11 eligible clinical trials involving a total number of N=445 participants, of which 7 trials investigated the use of lysergic acid diethylamide (LSD) (N=323), 3 trials investigated the use of psilocybin (N=92), and one trial investigated the use of dipropyltryptamine (DPT) (N=30). The 4 more recent randomized controlled trials (RCTs) (N=104) showed a significantly higher methodological quality than studies carried out in the 1960s and 1970s. Evidence supports that patients with life threatening diseases associated with symptoms of depression and anxiety benefit from the anxiolytic and antidepressant properties of serotonergic hallucinogens. Some studies anecdotally reported improvements in patients´ quality of life and reduced fear of death. Moreover, low rates of side effects were reported in studies that adhered to safety guidelines. Further studies are needed to determine how these results can be transferred into clinical practice.
Reiche, S., Hermle, L., Gutwinski, S., Jungaberle, H., Gasser, P., & Majić, T. (2017). Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 10.1016/j.pnpbp.2017.09.012
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Psychotherapy with Adjuvant use of Serotonergic Psychoactive Substances: Possibilities and Challenges


Background Recently, scientific interest in the therapeutic potential of serotonergic and psilocybin hallucinogens (psychedelics) such as lysergic acid diethylamide (LSD) and entactogens like 3,4-methylendioxymethamphetamine (MDMA) within the framework of psychotherapy has resumed. The present article provides an overview on the current evidence on substance-assisted psychotherapy with these substances.
Method A selective search was carried out in the PubMed and Cochrane Library including studies investigating the clinical use of serotonergic psychoactive substances since 2000.
Results Studies were found investigating the following indications: alcohol (LSD and psilocybin) and tobacco addiction (psilocybin), anxiety and depression in patients suffering from life-threatening somatic illness (LSD and psilocybin), obsessive-compulsive disorder (OCD) (psilocybin), treatment-resistant major depression (psilocybin), and posttraumatic stress disorder (PTSD) (MDMA).
Discussion Substance use disorders, PTSD and anxiety and depression in patients suffering from life-threatening somatic illness belong to the indications with the best evidence for substance-assisted psychotherapy with serotonergic psychoactive agents. To date, studies indicate efficacy and relatively good tolerability. Further studies are needed to determine whether these substances may represent suitable and effective treatment options for some treatment-resistant psychiatric disorders in the future.
Majić, T., Jungaberle, H., Schmidt, T. T., Zeuch, A., Hermle, L., & Gallinat, J. (2017). Psychotherapy with Adjuvant use of Serotonergic Psychoactive Substances: Possibilities and Challenges. Fortschritte der Neurologie-Psychiatrie85(7), 383. 10.1055/s-0043-103085
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[Hallucinogen-induced psychological disorders]



The purpose of this article is to provide an overview of the current research on hallucinogen induced psychiatric disorders. In addition to LSD and psilocybin hallucinogens of biologic origin are increasingly used by adolescents and young adults.


Relevant literature and related articles were identified by means of a computerized MEDLINE search including the years 1997 – 2007. As keywords “hallucinogen induced psychosis”, “hallucinogen induced flashback”, “hallucinogen persisting perception disorder (HPPD)” were used. Finally, 64 journal articles and books out of 103 were included in the review.


Acute psychotic syndromes in adolescents are rarely due to intoxications with hallucinogenic drugs. However, clinical relevance of flashback phenomena as post-hallucinogenic psychiatric disorder has to be disputed. Because of the high popularity of biogenic hallucinogens and LSD knowledge of intoxications and resulting psychiatric disorders as well as medical complications and therapeutical approaches are clinically important. Especially intoxications with drugs of herbal origin like tropanalcaloids play an important role in emergency situations.

Hermle, L., Kovar, K. A., Hewer, W., & Ruchsow, M. (2008). [Hallucinogen-induced psychological disorders]. Fortschritte der Neurologie-Psychiatrie, 76(6), 334-342.
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Increased Activation of Indirect Semantic Associations under Psilocybin


The spread of activation in semantic networks can be measured using semantic and indirect semantic priming effects in lexical decision tasks (Spitzer et al 1993a and b). For example, in thought-disordered schizophrenic patients, activation spreads faster and farther than in non-thought-disordered patients and normal subjects, which results in an increased direct and indirect semantic priming effect (see below). This has been interpreted as the result of a decreased signal-to-noise ratio in cortical neural networks that process semantic information. Such a decreased signal-to-noise ratio has been related to a decreased dopaminergic modulation (Servan-Schreiber et al. 1990; Cohen and Servan- Schreiber 1992, 1993), which we recently were able to confirm directly in a study on the effects of L-dopa on semantic and indirect semantic priming (Kischka et al 1995).

As dopamine was found to have a focusing effect on the activity in semantic networks, i.e., it increases the signal-to-noise ratio and reduces the spread of activation (measured as reduced indirect semantic priming), we set out to investigate the effect of the hallucinogenic agent psilocybin on this task. Since psilocybin is known to act on the serotonin (5-HT) system and has effects of “broadening” conscious experiences, we hypothesized that it might exert a defocusing effect on semantic networks (i.e., decrease the signal-to-noise ratio), which should lead to an increased indirect semantic priming effect.

To test this hypothesis directly, we conducted a double-blind, placebo-controlled study on the effects of psilocybin on semantic and indirect semantic priming as part of a larger project that was designed to assess the behavioral effects and pharmacokinetic properties of this hallucinogenic agent (the results will be reported elsewhere; cf. Holzmann 1995).

Spitzer, M., Thimm, M., Hermle, L., Holzmann, P., Kovar, K., Heirnann, H., … Schneider, F. (1996). Increased Activation of Indirect Semantic Associations under Psilocybin. Biological Psychiatry, 39(12),  1055–1057.
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