Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: a systematic review

This systematic review (2021) of studies from 1990 to 2020 aimed to determine factors that can predict successful response to psychedelic treatment. In a variety of disorders, the authors found that the intensity of the experience was the best such predictor.

Abstract

“Background: The use of psychedelic treatments has shown very promising results in some psychiatric and addictive disorders, but not all patients achieved a response. Aim: The aim of this review is to explore the clinical and biological factors which could predict the response to psychedelics in psychiatric and addictive disorders.

Methods: A systematic research was performed on MEDLINE, PsycInfo, Web of science, and Scopus databases from January 1990 to May 2020. All studies investigating the predictive factors of response to psychedelics regardless of psychiatric or addictive disorders, were included.

Results: Twenty studies investigating addictive disorder, treatment-resistant depression, obsessive-compulsive disorder and depressive and anxiety symptoms in patients with life-threatening cancer were included in this review. We found that, in all indications, the main predictive factor of response to psychedelics is the intensity of the acute psychedelic experience. Indeed, we found this factor for alcohol and tobacco use disorders, treatment-resistant depression, and anxiety and depressive symptoms in patients with life-threatening cancer, but not for obsessive-compulsive disorder.

Conclusion: The intensity of the acute psychedelic experience was the main predicting factor of response. The action mechanism of this experience was not clear, but some hypotheses could be made, such as a modulation of serotoninergic system by 5-HT2A receptors agonism, a modulation of the default mode network (DMN) with an acute modular disintegration of the DMN followed by a re-integration of this network with a normal functioning, or an anti-inflammatory effect of this treatment.”

Authors: Bruno Romeo, Marianne Hermand, Amélie Pétillion, Laurent Karila & Amine Benyamina

Summary

Psychedelic treatments have shown promising results in some psychiatric and

1. Introduction

Psychedelic treatments were investigated in many studies with promising results in the field of psychiatry during the 1940s, but stopped in the late 1960s when lysergide (LSD) became illegal. However, during the past twenty years, a renaissance of psychedelic research has occurred, notably in some psychiatric and addictive disorders.

The action mechanisms of psychedelics are not totally known, but some hypotheses could be made. These hypotheses include an action on the serotoninergic system, a 5-HT2A agonism, a ‘regression’ of the default mode network, and an anti-inflammatory effect.

The environment in which the psychedelic session occurs plays a primordial role in the psychedelic efficacy. This environment includes a comfortable room with pleasant music and at least two staff members present to provide support to the patient.

Despite these promising results, not all patients respond to psychedelic treatments. Therefore, it is important to better identify the population of patients susceptible to respond to psychedelics.

2.1. Data sources and study selection process

A search was conducted on MEDLINE, PsycInfo, Web of science, and Scopus databases from January 1990 to May 2020 using the key-words ayahuasca OR psilocybin OR lysergic acid diethylamide AND depression OR anxiety OR major depressive disorder OR bipolar disorder OR anxiety disorder OR substance use disorder OR dependence.

The risk of bias of open-label uncontrolled trials was assessed using the modified Newcastle-Ottawa Scale, the Cochrane Collaboration’s Tool and the checklist for retrospective databases.

2.3. Data extraction

We extracted all the data investigating the prediction of psychedelic response in different psychiatric and addictive disorders. We looked at socio-demographic characteristics, baseline evaluation, intensity of the psychedelic experience, and other analyses.

3.1. Article identification process

Twenty studies fulfilled the inclusion criteria and were included in the review (Agin-Liebes et al., 2020; Bogenschutz et al, 2015; Carhart-Harris et al, 2017, 2018; Carrillo et al, 2018; Davis et al, 2017; Erritzoe et al, 2018); Among these studies, two investigated AUD, three investigated tobacco smokers, and two investigated cannabis, opioid and stimulant misusers according to the fifth version of the Diagnostic and Statistical Manual of Mental disorders (DSM-5). Nine studies investigated treatment-resistant depression, and several more investigated different characteristics of the same population. The last three studies focused on imagery, and the last one on serum Brain-Derived Neurotrophic Factor and cortisol levels. Three studies investigated the effects of psychedelics on depressive and anxiety symptoms in patients with life-threatening cancer. Psilocybin was used in most studies, with a dosage of 20-30mg/70 kg.

In three retrospective online survey studies, more than 70% of patients used psilocybin or LSD. In one study, Ibogaine (15 mg/kg) was effective in opioid use disorder.

3.2. Alcohol use disorder

In two studies, psychedelics were associated with a decrease in AUDIT-C after three months, a decrease in drinking days and heavy drinking days four weeks after the psychedelic session, a decrease in craving and an increase in alcohol abstinence self-efficacy one week after the psychedelic session.

Pre-psychedelic treatment severity, dose, intensity of the acute psychedelic experience, spiritually significant experience, challenging experience and age of the first drink were all associated with a decrease in AUDIT-C three months after the psychedelic session.

3.3. Tobacco smokers

The intensity of the acute psychedelic experience seems to be associated with better outcomes in tobacco smokers. Quitters had a higher alteration of consciousness after the psychedelic session than still smokers, but no association was found between the decrease in self-reported cigarettes consumption or smoking abstinence self-efficacy. A higher consciousness alteration, intensity of mystical experience or hallucinogen intensity were associated with a decrease in urinary cotinine at six and/or twelve-month follow-up.

In a population of tobacco smokers that have reduced or quit smoking after a psychedelic experience, patients who stopped smoking showed a higher personal meaning score at one-year follow-up, and a higher spiritual significance score than re-lapsers. The increase of SASE was associated with higher personal meaning, spiritual significance and wellbeing scores after psychedelic sessions, but the craving was not. The decrease of CO rate was also associated with higher personal meaning scores, but not spiritual significance and wellbeing scores.

Some characteristics seem to be relevant for the prognosis of psychedelic use in patients who want to quit smoking, such as the confidence to abstain from smoking and the age at the time of the psychedelic experience.

3.4. Other substance use disorders

Two studies investigated other substance use disorders, such as opioid use disorder or a combination of patients with cannabis, opioids and stimulant use disorders. Patients using prescribed opioids had a better response than patients using heroin to ibogaine treatment.

In two studies, the decrease in consumption of psychedelics was associated with age, severity of substance-use disorder and some characteristics of the experience, but not with country of origin, age of first use, MEQ and dose.

3.5. OCD

One study has investigated the response prediction to psychedelic treatment in patients with obsessive-compulsive disorders, but did not find any association.

3.6. Treatment resistant depression

The intensity of the acute psychedelic experience was associated with an improvement in depressive symptoms, and the number of previous unsuccessful antidepressant treatments was associated with a decrease in the remission rate.

A psychedelic experience of unity, spiritual experience and blissful state was associated with an improvement in depressive symptoms at week 5 after psilocybin. Moreover, the intensity of the psychedelic experience was predictive of better longer-term clinical outcomes.

One study used speech analysis to identify responders from non-responders in patients with treatment-resistant depression. The study found no difference in neuroticism, extraversion, openness to experience, agreeableness and conscientiousness between responders and non-responders at month 3.

Three studies have used fMRI to analyze functional connectivity during resting state sequence, functional connectivity during emotional processing, or only local BOLD activity. Cahart Harris et al. (2017) found that an increase in ventromedial prefrontal cortex-bilateral inferior lateral cortex resting state functional connectivity or a decrease in parahippocampal-prefrontal cortex resting state functional connectivity at day 1 after psilocybin use was associated with an improvement in depressive symptoms at week 5.

3.7. Depressive and anxiety symptoms in patients with life-threatening cancer

At short-term and at long-term follow-up, the intensity of the acute psychedelic experience was associated with the improvement in depressive and anxiety symptoms, as well as with the improvement in different outcomes evaluating living with a poor cancer prognosis.

4. Discussion

In this systematic review, the intensity of the acute psychedelic experience seems to be the main predictive factor of a response to psychedelics in alcohol and tobacco use disorders, treatment-resistant depression, and anxiety and depressive symptoms in patients with life-threatening cancer.

The environment in which the psychedelic session takes place, the modality of psychedelics administration, the course of the psychedelic protocol, and the dose of psychedelics administered could affect the quality of the psychedelic experience.

The setting as well as psychological insight are very important in achieving a high-quality psychedelic experience, as the religious or spiritual interests of the participants may increase the likelihood that the psilocybin experience is interpreted as having a substantial spiritual significance, thus promoting the effectiveness of the experiment.

The intensity of the acute psychedelic experience was a common predictive factor of response without any distinction between psychiatric and addictive disorders. This association could be explained by the action mechanisms of 5-HT2A receptor agonists, which are involved in enhancing neuroplasticity and neurogenesis.

5-HT2A receptor agonists can help improve depressive and anxiety symptoms, which might contribute to the efficacy of psychedelics in addictive disorders. A hypothesis that could account for the link between the overall intensity of experience and its clinical efficiency without distinction between addictive and psychiatric disorders is that the use of psychedelics could temporarily reverse the process of network integration and segregation that characterize the development of the brain.

Different psychedelic experiences can be explained by different modalities of psychedelics administration, or by different 5-HT2A receptors polymorphisms, which could be influenced by environmental elements such as early-life stress and maternal deprivation.

Brain imaging studies have shown that an increased vmPFC bilateral inferior-lateral parietal cortex (ilPC) resting state functional connectivity at day 1 after psilocybin is predictive of a better response at week 5. This result could suggest a ‘reset’ mechanism caused by psychedelics. Psilocybin increases amygdala responsiveness and decreases functional connectivity between vmPFC and amygdala and occipital and parietal cortices during face processing, which could be interpreted as a decreased inhibitory input from vmPFC to these different regions.

Psychedelics allow patients to fully experience their emotions, whereas conventional antidepressants down-regulate the emotional responsiveness.

The confidence to abstain from tobacco smoking and the age at the time of the psychedelic experience were also predictive of a better psychedelic efficiency in smokers. Moreover, the severity of substance use disorder could be predictive of a better psychedelic response as opposed to TDR. In patients with severe AUD, psychedelic treatments have a very quick efficacy on depressive and anxiety symptoms, thus facilitating remission in these patients. Additionally, first-degree AUD antecedents are also associated with a better response to ketamine in unipolar and bipolar depression.

This review has several limitations, including the low number of studies included, the low number of patients included, the retrospective nature of some studies, and the different methodologies used to obtain the results.

In conclusion, the efficacy of psychedelics has been demonstrated in some psychiatric and addictive disorders, but not all patients responded to these treatments. The intensity of the acute psychedelic experience was the main predicting factor of response.