Psychedelic agents for treatment-resistant depression

Introduction

Classic psychedelics are serotonergic agonists that can produce profound changes in perception, mood, and cognition. The past two decades have been marked by a renewal of interest in these compounds for their potential to produce rapid and long-lasting improvements in a variety of mental health conditions including treatment-resistant depression (TRD). Psychedelics have been used sacramentally in non-Western cultures for thousands of years but did not receive widespread attention or recognition in the West until the 1940s when the psychoactive properties of lysergic acid diethylamide (LSD) were recognized by Swiss chemist Albert Hofmann. A first wave of clinical research in the 1940s–1970s suggested that these compounds may have had considerable therapeutic potential, but studies were halted in response to political and cultural pressures resulting from widespread use of psychedelics outside of clinics and laboratories ( ). With the passage of the Controlled Substances Act in the United States, psychedelics were relegated to Schedule I, a category reserved for substances with no recognized clinical benefit and substantial associated risk. Thus, for several decades following this shutdown, psychedelics were known primarily as illicit drugs of abuse with little attention paid to previously documented clinical benefits.

After a decades-long hiatus in clinical experimentation involving these substances, a second wave of research began in the late 1990s with increasing numbers of high-quality human and laboratory studies being published. Phase I studies demonstrated that psychedelics had a favorable safety profile, and growing numbers of phase II studies are demonstrating therapeutic potential for various mental health conditions including cancer-related psychosocial distress, alcohol and nicotine use disorders, major depressive disorder (MDD), and TRD ( ; ; ; ; ).

This chapter will focus on the more recent literature with classic psychedelic compounds, whose effects are primarily mediated by serotonin 2A (5-HT _2A ) receptor agonism or partial agonism. A variety of terms have been used to refer to these substances since their first description in medical literature. Initially called “psychotomimetic” agents, this term fell out of favor when it became apparent that their effects could not accurately be described as psychotic phenomena. “Hallucinogen” later gained popularity and is still widely used today including in the Diagnostic and Statistical Manual (DSM). However, this term suggests that the primary effect of these drugs is to produce true hallucinations, when such phenomena are in fact uncommon with most drugs in this class. An additional weakness of this label is that it is often used to refer to a broader category of psychoactive drugs that work by other mechanisms, such as 3,4-Methylenedioxymethamphetamine (MDMA), and dissociatives like ketamine and phencyclidine. The term “psychedelic” was coined by English psychiatrist Humphrey Osmond in the 1950s and is currently preferred among researchers working with these compounds ( ). The Greek root delos , meaning “to manifest,” is thought to more adequately capture these drugs’ potential “mind-manifesting” or therapeutic effects.

A number of key differences set psychedelic-assisted treatment apart from most currently available psychiatric treatments. Unlike first-line pharmacotherapies for MDD, which can take weeks of continuous use to produce clinically meaningful improvement, psychedelics appear to be capable of improving symptoms rapidly, as soon as one day after a single drug administration. Large effect sizes are apparent after just one or two doses and many patients appear to experience sustained improvement for months without the need for repeated drug administration. Additionally, treatment with psychedelics is typically delivered under the supervision of two therapists or “facilitators” with substantial adjunctive psychotherapy before and after drug administration ( ). This model is thought to be necessary for safety and efficacy, especially as clinical research with these drugs has shifted from healthy volunteers to clinical populations. This hybrid model contrasts with the typical delivery of care in the United States, where pharmacotherapy and psychotherapy have been gradually siloed over the last several decades. It has also posed challenges to conducting “gold-standard” placebo-controlled clinical trials with these drugs.

Though the use of these substances remains prohibited outside of laboratory settings in most of North America and Europe, multiple groups are currently conducting phase II and III studies to determine whether psychedelics can be a safe and effective treatment for MDD. Psychedelics are of particular interest in the possible treatment of TRD given that their mechanisms of action are distinct from existing treatments. In this chapter, we will review the chemistry, mechanisms of action, and recent clinical trial data on these compounds with special focus on their applications in individuals with TRD.

Chemistry

Most psychedelics relevant to our discussion of TRD are classified as tryptamines, which can be identified by their indole ring and structural similarity to serotonin and its precursor tryptophan. Naturally occurring tryptamines include N,N -dimethyltryptamine ( N,N -DMT), 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT), psilocybin, and psilocybin’s active metabolite psilocin. The synthetic ergoline LSD is also a tryptamine psychedelic. The second category of classic psychedelics is that of phenethylamines, of which mescaline is the naturally occurring exemplar.

Early clinical research focused principally on LSD, whose psychoactive properties were accidentally discovered in 1943 by Swiss chemist Albert Hoffman. In the process of attempting to isolate clinically useful compounds from the ergot fungus, lysergic acid was discovered ( ). Hofmann developed a synthetic process that allowed him to create novel ergolines by combining lysergic acid with a variety of other compounds. His 25th synthetic compound, LSD-25, was made with diethylamine. LSD-25 did not immediately appear to have any useful effects in animal models, and sat untouched for several years until Hoffman unintentionally ingested it and discovered its striking psychoactive effects. It was hypothesized that LSD’s effect profile may have had phenomenological similarity to psychosis and thus could be of interest to psychiatric researchers and clinicians. Sandoz Laboratories (now Novartis), subsequently distributed samples of LSD to clinicians and researchers worldwide under the trade name Delysid.

Most contemporary clinical research with psychedelics has used tryptamines other than LSD. Psilocybin has been most commonly used, and though it occurs naturally in the Psilocybe genus of mushrooms ( ), most research with psilocybin is conducted using synthetically prepared drug. N,N -DMT also occurs naturally in small concentrations in many plants and animals. It is the principal constituent of ayahuasca, a plant decoction that is used ceremonially in cultures in the Amazon Basin ( ). Ayahuasca is most commonly prepared using a combination of Psychotria viridis , which contains N,N -DMT, and the Banisteriopsis caapi vine, containing harmala alkaloids. When taken alone, orally ingested N,N -DMT has no effect due to rapid metabolism by peripheral monoamine oxidase (MAO). Harmala alkaloids have an MAO-inhibiting effect and when taken together with N,N -DMT allow it to pass through peripheral circulation and exert effects centrally. Though ayahuasca has been studied for its therapeutic potential in MDD and TRD ( ; ), it is an unlikely candidate for clinical use in the West due to the challenges of standardizing the dosage of a heterogeneous plant brew.

In some contexts, compounds like MDMA and glutamatergic dissociatives like ketamine and dextromethorphan have been discussed for their “psychedelic” effects, but due to their differing mechanisms of action, these will be excluded from this discussion. It is worthwhile noting, however, that a phase III trial of MDMA for the treatment of PTSD is currently ongoing and uses an integrated psychotherapy approach similar to that which is commonly used with classic psychedelics ( Clinicaltrials.gov identifier NCT04077437 ).

Pharmacokinetics

Psychedelic compounds vary in their pharmacokinetic profiles. Here we will briefly review the pharmacokinetics of the three psychedelic compounds most commonly encountered in clinical psychedelic research.