Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine

This review (2020) investigates a variety of psychedelics (classic, ketamine, MDMA) and highlights the similarities and differences in human (clinical) and animal (pre-clinical) studies.

Abstract

“A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.”

Authors: Danilo De Gregorio, Argel Aguilar-Valles, Katrin H. Preller, Boris Dov Heifets, Meghan Hibicke, Jennifer Mitchell & Gabriella Gobbi

Summary

Symposium

Psychiatric disorders are a major public health concern affecting 350 million people and imposing social and economic burdens worldwide. Psychedelic drugs, including ketamine, are being investigated for their therapeutic application in mental disorders.

Ketamine, psilocybin, and LSD are hallucinogens, but they do not produce the same so-called “trip” as psychedelics. MDMA, on the other hand, has been shown to increase sociability in animals and humans and to be useful in treating post-traumatic stress disorder.

This review summarizes the pharmacological mechanism of psychedelics, nonpsychedelic hallucinogens, and entactogens, as well as their impact on psychiatric research.

Psychedelics act as 5-HT2A receptor agonists, but their mechanism of action is more complex than originally thought. They also interact with 5HT1A,5HT2B,5HT2C, 5HT6, and 5HT7 receptors, and can modulate downstream signaling proteins, including b -arrestin, early growth response protein 1(EGR1), and EGR2. LSD activates the 5-HT2A receptor in rodents, followed by the dopamine D2 receptor in human cells.

Psychedelic compounds have many different mechanisms of action, including activation of dopamine D1 and D4 receptors and interaction with the trace amino associate receptor 1 (TAAR1).

Antidepressant effects of psychedelics: what can we learn from animal studies?

Rodent studies have shown that psychedelics, including LSD, psilocin, psilocybin, and DMT, can enhance associative learning, a cognitive function commonly impaired by neuropsychiatric disorders, particularly major depressive disorder.

Studies on the effects of psychedelics on rodent behaviors are sparse, and results may appear to align or conflict with each other without being truly comparable. Dosing strategies must be taken into account. Time intervals between dosing and behavioral testing are another factor influencing the results of studies with psychedelics. Wistar-Kyoto rats given psilocybin 1 mg/kg were tested in the forced swim test and the elevated plus maze at various time points after administration. They developed distinct behavioral responses depending on when they first encountered the forced swim test.

Animal studies suggest that psychedelic administration produces a period of behavioral flexibility in which new coping strategies can be learned.

What do psychedelics do to the human brain?

Researchers have used functional neuroimaging techniques to study the impact of psychedelic drugs on brain connectivity patterns and on the activity of specific brain regions in humans. They have found that LSD increases functional connectivity between the thalamus and sensory-somatomotor cortical regions.

These results suggest that decreased thalamic gating and diminished associative network integrity may underlie psychedelic experiences. This may help to reduce rigid or ruminative thinking patterns.

Studies using seed-based imaging approaches have shown that subjective effects induced by psilocybin are associated with changes in the amplitude of low-frequency fluctuations and the variance of BOLD signal in the claustrum, and that psilocybin decreases connectivity between the right claustrum and the auditory network and the Default Mode Network.

Neuroimaging studies of psychedelics in clinical populations with mental health conditions are still scarce, but decreased amygdala cerebral blood flow, decreased amygdala reactivity, and increased amygdala-PFC connectivity have been shown to correlate with positive mood in healthy participants.

Psilocybin administration reduced negative cognitive bias in patients suffering from depression, but increased emotional processing and amygdala reactivity was measured before any psychological or psychotherapeutic interventions aiming at integrating the psychedelic experience.

Ketamine, a fast-acting antidepressant acting through NMDA and mammalian target of rapamycin complex 1 (mTORC1)

Ketamine is a dissociative anesthetic that produces fast antidepressant effects in both animal and humans at subanesthetic doses. It is both a noncompetitive NMDAR antagonist and an activator of the mTORC1 pathway, but NMDAR antagonism appears nonessential for ketamine’s antidepressant action.

Chemical alteration of ketamine (via deuteration at the C6 position) nullifies its antidepressant actions in mice, and both HNK enantiomers exert dose-dependent antidepressant actions in several rodent tests. However, (2R,6R)-HNK is a less potent antagonist of NMDAR than ketamine itself.

Ketamine induces synaptic and structural plasticity in the hippocampus, mPFC, and lateral habenula, involving signaling pathways that control protein synthesis, such as the mTORC1 pathway. The allosteric mTORC1 inhibitor rapamycin blocks ketamine-induced synaptic molecular and behavioral effects relevant for antidepressant actions. mTORC1 controls several neuronal functions, including nucleotide and lipid synthesis, glucose metabolism, autophagy, lysosome biogenesis, proteasome assembly, and 59 cap-dependent mRNA translation. AMPARs mediate ketamine-induced synaptic facilitation in the mPFC and hippocampus.

Clinical perspectives of ketamine

Ketamine’s antidepressant properties have now been appreciated for almost two decades. Its rapid therapeutic onset and week-plus-long efficacy after a single infusion are its defining features, but it has significant abuse liability and long-term use is associated with notable bladder and neurologic toxicity.

The physiological mechanisms for inducing and maintaining ketamine’s lasting effects in humans are not yet well understood, but the drug’s action on the NMDAR and mTORC1 pathways may be more complex than previously thought.

The mTORC1 signaling pathway is downregulated in the hippocampus and PFC of MDD patients in postmortem tissue, which is consistent with this signaling pathway being relevant for the treatment of MDD.

Clinical studies are just beginning to map the similarities between ketamine and other psychedelic-assisted therapies, and it is still debated whether conscious subjective experience (typically described as “dissociation”) is necessary or sufficient to account for ketamine’s efficacy.

MDMA, a psychotropic drug with unique prosocial effects

MDMA is an amphetamine derivative that releases serotonin, dopamine, and norepinephrine and stimulates the release of hormones, including oxytocin, vasopressin, and cortisol. It may be useful as an adjunct to psychotherapy, but its potential for abuse and incompatibility with certain medications limit its use.

MDMA can enhance the therapeutic alliance by enhancing feelings of openness, trust, and social connection, as well as by modifying the sensitivity to social reward, and by disrupting fear memories in a widely used model for PTSD.

Investigators consistently find that SERT-mediated 5-HT release is necessary and sufficient to account for the putative therapeutic mechanisms of MDMA. Various 5-HT receptor subtypes appear necessary, although it is unclear whether any one subtype’s activity can reproduce MDMA’s pro-social effects.

MDMA in clinical studies

MDMA was first administered clinically in the 1970s and was suggested to be an effective adjunct to psychotherapy, especially in those suffering from anxiety. A Phase 1 dose-findingand safety study was conducted shortly thereafter and suggested that a range of doses (0.25-1.0 mg/kg, p.o.) could safely be administered with minimal side effects.

Early human data indicate that MDMA may be useful in assisting people suffering from PTSD. The effects of MDMA are long lasting. MDMA has been used in several Phase 2 studies to treat severe, treatment-resistant PTSD, and a Phase 3 clinical trial is currently in progress. The early trial data suggest that MDMA may be a fruitful therapeutic for several complex treatment populations.

Recent data suggest that MDMA may be efficacious in other clinical populations, including people with autism spectrum disorder and alcohol use disorder. However, more research must still be conducted to determine which therapeutic interaction works best for different clinical populations.

In conclusion, this review suggests that hallucinogens may produce different behavioral outcomes with different molecular and neuronal mechanisms of action. Clinical studies have demonstrated the effects of ketamine and MDMA in treatment-resistant MDD and PTSD, and several trials are ongoing for psilocybin in alcohol use disorder and OCD.

LSD showed promising results in patients with depression and anxiety, and clinical trials are ongoing for MDD.