Psychedelic Medicines in Major Depression: Progress and Future Challenges

This book chapter (2021) describes the current research on psychedelics for depression (MDD), the clinical trials as well as the neurobiological mechanisms are described. The chapter end with a description of future challenges.

Abstract

The volume of research on the therapeutic use of psychedelic drugs has been increasing during the last decades. Partly because of the need of innovative treatments in psychiatry, several studies have assessed the safety and efficacy of drugs like psilocybin or ayahuasca for a wide range of mental disorders, including major depression. The first section of this chapter will offer an introduction to psychedelic research, including a brief historical overview and discussions about appropriate terminology. In the second section, the recently published clinical trials in which psychedelic drugs were administered to patients will be analysed in detail. Then, in the third section, the main neurobiological mechanisms of these drugs will be described, noting that while some of these mechanisms could be potentially associated with their therapeutic properties, they are commonly used as adjuvants in psychotherapeutic processes. The last section suggests future challenges for this groundbreaking field of research and therapy.

Authors: José C. Bouso, Genís Ona, Rafael G. Dos Santos & Jaime E. C. Hallak

Summary

Research on the therapeutic use of psychedelic drugs has been increasing during the last decades. The first section of this chapter will offer an introduction to psychedelic research, including a brief historical overview and discussions about appropriate terminology.

26.1 Introduction to Psychedelic Therapy

Psychedelics are a series of compounds, active principles, plants, fungi and animal secretions that induce dramatic altered states of consciousness. These states are central in the worldviews and ontologies of many indigenous cultures around the globe.

The terminology for psychedelic compounds and plants is challenging because the effects are often ineffable and context- and cultural-dependent. For indigenous people, the use of psychoactive plants goes beyond the effects over the single person and is conceived as the main spiritual tool.

Leo Hollister characterized the effects of psychedelics as follows: small dose produces great effects, changes in thought, perception and humour predominate, intellectual or memory deterioration must be minimum with high-medium dose, they can be produced with large doses, and the addiction potential must be minimum.

The history of use of psychedelic drugs is probably millenary and includes the use of Psilocybe mushrooms in post-Palaeolithic Spain, iboga roots in tropical Africa, peyote and San Pedro cactuses in Mexico and Guatemala, and ayahuasca in Venezuela and Brazil.

Western culture has a long history of using psychedelic drugs for psychospiritual and social integration purposes. The Eleusis ritual was used in ancient Greece for 2000 years.

Modern chemistry allowed the isolation of the active principles of different psychedelic plants, and in the 1950s psychedelic psychotherapy was introduced in Europe. Psychedelics were used in disorders like anxiety, depression, alcoholism, autism, schizophrenia and even in survivor syndrome in holocaust survivors.

In the United States, psychiatrists used psychedelics under the psycholytic paradigm, but Dr. Humphry Osmond discovered that high doses could induce spiritual experiences that could lead patients to withdraw from alcohol.

Scientific research with psychedelics was interrupted for some decades, but has started again in the early 1990s.

Psychedelics enhance the psychotherapeutic process instead of having intrinsic therapeutic properties, and are often used in combination with other therapies.

26.2 Clinical Trials Assessing the Antidepressant Effects of LSD, Psilocybin and Ayahuasca/DMT

Four randomized, double-blind, placebo-controlled, crossover trials using LSD (one trial) or psilocybin (three trials) were published investigating the effects of these drugs on anxiety and depressive symptoms in this clinical population. All studies found significant reductions in BDI scores 6 months after drug intake.

Four clinical trials involving the administration of psychedelics in patients with depressive disorders were published since 2016, including one open-label and one controlled study with ayahuasca/DMT and one open-label and one controlled study with psilocybin. The results showed that ayahuasca intake was associated with significant reductions in scores of several depression scales.

The results of the open-label trial were confirmed in a randomized, double-blind, parallel-arm, placebo-controlled trial involving 29 patients with treatment-resistant MDD. Ayahuasca produced significant reductions in MADRS scores and HAM-D scores, and normalization of low cortisol levels and increases in brain-derived neurotrophic factor.

Ayahuasca, psilocybin and SHAPS were used in a 12-week open-label trial to treat treatment-resistant MDD. Psilocybin administration was associated with decreased blood flow in the amygdala, increased functional connectivity within the default-mode network and the ventromedial prefrontal cortex, and decreased functional connectivity in the parahippocampal-prefrontal cortex.

After the open-label study, a randomized, waitlist, controlled trial with two oral psilocybin doses was conducted in 22 MDD patients. The immediate condition showed significantly higher reductions in scores of the GRID-Hamilton Depression Rating Scale than the delayed condition.

Although the results with LSD, psilocybin and ayahuasca/DMT are promising, they should be interpreted with caution. Further research is needed to confirm these results.

The data for MDD and treatment-resistant depression is less compelling, but still promising. The results of open-label trials with ayahuasca and psilocybin are preliminary and exploratory.

Both ayahuasca and psilocybin showed antidepressive effects in controlled trials. The US Food and Drug Administration granted psilocybin therapy a breakthrough therapy designation two times in a year, and it is possible that psilocybin will be used to treat MDD and treatment-resistant MDD in the following years.

26.3 Neurobiological Mechanisms of Psychedelic Drugs

Psychedelic drugs can be classified in three distinct groups: serotonergic hallucinogens, dissociative anaesthetics and entactogens. Salvinorin A and tropane alkaloids, which have other mechanisms of action, are also psychedelic.

Serotonergic psychedelics, such as LSD, psilocybin and DMT, and some dissociative anaesthetics, such as ketamine, are used in the treatment of depression.

Psychedelic drugs activate different G-protein-coupled receptors (GPCRs), but most of their effects are due to their agonistic activity on the 5-HT2A receptor. This receptor is widely distributed in the human brain, and is involved in several cognitive processes, emotion regulation, introspection and self-awareness.

Psychedelic drugs have multiple mechanisms of action, including binding to serotonin receptors, dopamine receptors, adrenergic receptors and trace amine-associated receptors. Ayahuasca contains compounds that interact with many receptors, including sigma-1 (1) receptor, which is involved in depression, drug dependence, amnesia, cancer and pain.

We consider that the classical monoaminergic hypothesis does not provide a sufficient explanation for depression, and suggest that systems pharmacology could provide valuable contributions.

Most psychedelic drugs increase neurogenesis and neural plasticity through their antagonism on the 5-HT2A receptor, which increases cortical electrical activity and information processing. Certain psychedelic drugs like DMT and LSD promote rapid structural and functional neural plasticity, which is mediated by an enhanced c-fos expression in the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. However, the enhancement of brain-derived neurotrophic factor (BDNF) levels and the subsequent therapeutic effects does not necessarily inform about the pathophysiology of depression.

Psychedelic drugs increase and decrease activity in different brain regions, depending on the neuroimaging technique and protocol. A decrease in activity in key hubs of the default-mode network was observed in a study with psilocybin, while an increase in activity was observed in a study with ayahuasca.

It has been suggested that inconsistencies between PET/SPECT and fMRI studies could be related to the timescales considered in different techniques. Serotonergic psychedelics modulate brain areas associated with different cognitive functions, such as perception, introspection and emotion processing. Additionally, ayahuasca use is associated with cortical thinning in several brain regions and with a decreased cortical thickness in patients with mood disorders, including depression.

Inflammatory processes are closely related with depression. Psychoactive drugs such as LSD and DOI induce potent anti-inflammatory effects through the activation of the 5-HT2A receptor, and DOI has an EC50 of 15 picomolar in preventing tumour necrosis factor alpha (TNF-)-mediated inflammation in aortic smooth muscle cells.

Psychedelic drugs have anti-inflammatory effects and may also have neuroprotective effects. This is especially true for ayahuasca, where DMT and -carbolines induce increases in BDNF levels and neurogenesis, and harmine has MAO-inhibiting properties that decrease oxidative stress.

The neuroendocrine effects of psychedelic drugs have also been suggested as potentially implicated in their therapeutic effects. These effects can be partially attributed to improvements in social cognition and low levels of cortisol, which are associated with depressive symptoms. Different psychedelic drugs induce increases in cortisol. These increases were stable at least until 48 h after ayahuasca administration.

26.4 Future Challenges

There are still many challenges to be addressed in order to show that psychedelic drugs can become an available treatment for some mental disorders. These include conducting clinical trials with small samples and including patients with previous experience with psychedelic drugs without having lived challenging experiences or psychiatric complications.

Psychedelic therapy requires specialized practitioners, offering support to patients for hours. Esketamine, a drug recently approved by the FDA for treatment-resistant MDD, could be of interest for future psychedelic therapy.

Despite all challenges, current psychiatric treatments are limited, so new strategies in mental health are urgently needed. Psychoactive plants like ayahuasca represent an innovative approach, combining both psychotherapy and pharmacological tools, and having several mechanisms of action potentially associated with therapeutic outcomes.

Study details

Topics studied
Depression

Study characteristics
Book Chapter

Authors

Authors associated with this publication with profiles on Blossom

José Carlos Bouso
José Carlos Bouso is a Clinical Psychologist with a PhD in Pharmacology and is the current Scientific Director at ICEERS.

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