Results

Overview of studies

A total of 10 studies were included in the systematic review. The study subjects were as follows: depressive disorder (20%), tobacco addiction (20%), alcohol dependance (10%),

anxiety and/or depression with life threatening cancer (40%), and demoralization (10%) (table 4).

Publication Diagnosis/disorder Drug

Anderson et al 2020 Demoralization in AIDS survivor men Psilocybin

Davis et al 2020 Major Depressive Disorder Psilocybin

Ross et al 2016 Anxiety and depression in patients with life- threatening cancer

Psilocybin

Griffiths et al 2016 Anxiety and depression in patients with life- threatening cancer

Psilocybin

Carhart-Harris et al 2016 Treatment-resistant depression Psilocybin

Bogenschutz et al 2015 Alcohol dependence Psilocybin

Garcia-Romeu et al 2014 Tobacco addiction Psilocybin

Gasser et al 2014 Anxiety Associated with life-threatening diseases

LSD

Johnson et al 2014 Tobacco Addiction Psilocybin

Grog et al 2011 Anxiety in patients with advanced-stage cancer Psilocybin Table 4: List of studies, their therapeutic targets and the drug used.

Study participants

Method of recruitment was clearly described in all (100%) of the studies. 2 of 10 (20%) of the studies used physician referral as the main method of recruitment and 5 of 10 (50%) used physician referral as one of their methods. Most studies (80%) used online adverts or flyers.

Ensuring of treatment for existing psychiatric conditions here means that the study clearly explains how the continuity of treatment is ensured. This includes treatment during waitlist period and after the study has concluded and stating who is responsible for the care during the trial period. 3 of 10 (30%) of the studies, including both tobacco addiction studies and the study on demoralization, included only patients with no psychiatric conditions.

Therefore, continuity of treatment in these 3 studies won’t be analyzed given that the participants didn’t have pre-existing psychiatric illnesses requiring treatment.

Of the 7 remaining studies, 2 studies (29%) contained clear plan for the treatment of existing psychiatric conditions. Both these studies were conducted on patients with major depressive disorder. In one of them, no changes to psychiatric medications were made and the trial was conducted in co-operation with the patient's clinician. In the other depression study, patients were off antidepressant medication, but the decisions with the use (and tapering off) of medication was made by the patient’s physician and not by the study staff. Additionally, study physicians assumed the role of mental healthcare provider during the study in the study.

5 of the 7 remaining studies didn’t present a clear plan for the treatment for existing psychiatric conditions. 4 of these studies were conducted on patients with anxiety and/or depression with life threatening cancer and 1 study was on alcohol dependence. One study (on cancer patients) included only participants without existing psychiatric medications and conducted an interview to determine if referral for immediate psychiatric treatment was necessary before enrollment. The rest of the studies required participants to be off or taper off psychiatric medications before the study. None of these studies presented a plan on drug treatment or inform who is responsible for the patients’ psychiatric treatment and decision making regarding psychiatric medication. All these studies exclude patients with bipolar and psychotic illnesses. However, the studies did contain patients with depression- and/or anxiety disorders. In all 4 of the studies with cancer patients, an oncologist was responsible for cancer-related somatic treatment and made aware of the trial with psychedelics.

Study personnel

6 of the 10 studies (60%) contained information on the training, degree, or other

qualifications of the therapists. 1 of the studies that didn’t detail therapists' qualifications in the main text included thanks to a university professor “for providing training for study interventionists” in the acknowledgements section. In 1 (10%) of the studies all therapists

were either licensed psychotherapists or psychiatrists. The qualifications of the therapists varied significantly between studies and several studies had therapists with different qualifications. In one study session facilitators were “study staff with varying educational levels (ie, bachelor’s, master’s, doctorate, and medical degrees) and professional disciplines (eg, social work, psychology, and psychiatry)”. All 6 of the studies that contained

information on the training of study personnel had at least 1 psychiatrist or licensed psychotherapist in the research team. 3 of the 10 (30%) studies informed that the study protocol included relevant therapy training for the staff members

All studies provided counselling/therapy sessions both before and after the drug

treatment. The number of counselling sessions before the drug treatment is reported in all except one study which reports that “[the intervention was] embedded within an ongoing process of drug-free psychotherapy sessions for preparatory and integrative purposes”.

Most common number of counselling session before the drug treatment was 4-5 with the smallest number being in a study that reported the inclusion of “at least 2 meetings” before the drug treatment session. All studies included some form of psychotherapy and most of the studies tailored the therapy type to compliment the diagnosis/disorder(s) the

participants had.

Chart 2: Qualifications of study personnel in studies with psychedelics.

Informed consent

The availability of the written informed consent form was searched from the published research article and the trial registration page. The informed consent form was available online in 1 of 10 (10%) studies (Anderson et al 2020). Informed consent forms were requested via e-mail from research groups whose consent form wasn’t available on the previously mentioned online pages at the time of writing. 3 additional consent forms were sent to us adding to a total of 4 of 10 (40%) the studies’ consent forms for analysis.

In 5 of 10 (50%) studies it is clearly stated that the written informed consent form was given well in advance before the decision for enrollment (min. of 2 weeks). 40% of the studies clearly stated that understanding of the contents of the informed consent form by the participants was ensured. 5 of 10 (50%) of the studies clearly stated that the participant was informed of the possibility to withdraw from the study at any point without penalty.

Notably, all the previously mentioned information on informed consent practices was included in the studies whose informed consent for was made available for analysis.

0 1 2 3 4 5 6 7

Information of qualification(s)included in the published article

Types of qualifications

Qualifications of the study personnel

Yes No

All therapists were licenced psychotherapists or psychiatrists

At least 1 licenced psychiatrist or psychotherapist in the research team Therapy training for staff members included in study protocol

Disclosure of specific effects of the drug

For the topic of disclosure of specific effects of the drug, separate analysis is presented for the studies whose informed consent form was available for this review and for the studies whose informed consent form was not.

In all (100% of) the studies whose informed consent was available for this review (40%), the participants were informed of the most relevant risks and inconveniences of the drug as well as the possibility of psychological distress during the session. 3 of 4 (75%) of these studies reported having some description of psychedelic states disclosed to the

participants. 1 of 4 (25%) of the studies reported having informed the patient of potential long-term side effects (e.g. changes in personality or worldview). The informed consent of the study in question informed that “after the psilocybin session, there may be short-term to permanent changes in personality, attitude, or creativity”. Notably, nearly all the

information regarding disclosure of the specific effects of the psychedelic drug was found in the informed consent form rather than the published research article.

In studies whose informed consent form wasn’t available for analysis (60%), very little information on the disclosure of information on the specific effects of psychedelics were given. 1 of these 6 studies reported having informed the patient of the possibility of psychological distress during the session. No information on disclosure of the most relevant risks, descriptions of psychedelic states or long-term effects of psychedelics were found in these studies.

Intervention

90% of the reviewed studies contained some description of the “set and setting” of the drug intervention. Descriptions of the drug intervention contained a lot of similarities between the studies. In 5 of 10 (50%) studies, at the start of the session, the participants were directed to focus their attention towards their inner experience, or to “go inward”. Another common instruction was to “let go” or “surrender to the experience” (20% of studies). One

study describes a ritual where the participant was instructed to join hands with the therapist dyad and “state his/her intention for the day [of the psychedelic intervention]”.

In all the studies that described the drug session setting, attention to comfortability of the session room was described. Several studies described the space as “living-room like” and some studies mentioned including some decorations like flowers, paintings, and fabric wall hangings to promote a relaxing and an aesthetically pleasing atmosphere. Most studies described having minimized noise and external disturbances by, for example, turning off electrical devices. In all studies, the participant lied on a sofa, couch, mattress, or a bed with some studies specifically mentioning a possibility to change between different body postures during the session. All studies played preselected music during the session. Most studies included and encouraged the use of eyeshades during the session.

Monitors’ role during session in most studies was described as “non-directive”, taking the role of an observer and facilitating safety. All studies with drug session descriptions had the monitors’ or another staff member measure heart rate and blood pressure on set intervals during the session. In most studies, monitors also wrote down observations and

psychometric evaluations without directly contacting the participant. 4 studies (40%) mentioned brief discussions or “check-ins” with the participant to ask how they are feeling.

3 studies (30%) mention that brief reassuring dialogue or psychical touch (e.g. hand on participant’s shoulder) was made if the participant displayed signs of distress.

In addition to the setting of the psychedelic session, availability and information of “rescue drugs” (e.g. benzodiazepines) that terminate or alleviate the psychedelic effects during the intervention, was of particular interest with regards to patient autonomy. Possibility to terminate the psychedelic effect with drugs was informed to the participant in 3 of 10 studies (30%). In 2 of the studies, this information was found in the informed consent form.