Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

This review (2014) examines the effects of psychedelic drugs with regard to their pharmacodynamics and molecular biology, their electrophysiological and neuroimaging profile, and summarizes the evidence for potential therapeutic mechanisms of action, including effects on neurogenesis, cortical networks, and the immune system. It also examines the clinical profile of psychedelic substances with regard to risks for healthy individuals, as well as the potential to treat clinical conditions such as depression, notwithstanding the criminalized status of psychedelics, despite negligible risk and a lack of evidence for its alleged adverse effects.

Abstract

“Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.”

Authors: David Baumeister, Georgina Barnes, Giovanni Giaroli & Derek Tracy

Summary

Hallucinogens have been used in human spiritual practice for several millennia, but the United Nations Convention on Psychotropic Substances criminalized these substances without a clear scientific rationale.

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

Current drug laws severely limit scientific exploration of neurobiological mechanisms and clinical effects of substances that may prove valuable in the understanding of consciousness and mental illness, and offer novel therapies.

Classical hallucinogens are typically divided in three groups: tryptamines, lysergamines, and phenethylamines. They appear to exert their effects through the serotonergic system, and there is a small but growing body of research indicating that they may have therapeutic effects in treating depressive and anxiety disorders.

Pharmacodynamics and molecular biology

Despite the biochemical delineation of classical hallucinogens, evidence suggests that most of these substances produce cross-tolerance. The selective 5-HT2A antagonist ketanserin and the partial 5-HT2A antagonist risperidone block subjective psychedelic effects of psilocybin.

Activation of 5-HT2A receptors is a crucial mediator of hallucinogenic effects, but tolerance to hallucinogens is rapid and makes dependence less likely than with other illicit drugs.

Serotonin receptors are a phylogenetically ancient, heterotrimeric G-protein coupled receptor (GPCR) class that alters several different intracellular secondary cascades. They are divided into ‘families’ depending upon their primary signalling pathway(s), although there is significant crossover between subtypes.

Serotonin receptors contain sites that can induce post-translational modification, and this can lead to the alteration of signal transduction. PKC isozymes alpha and/or epsilon appear to mediate the desensitization of 5-HT2A receptors during intermediate (2 – 6 hours) but not later (>24 hours) phases of DOI exposure.

Long-term changes to intracellular signalling pathways may occur due to drug-induced alterations in gene expression, with evidence suggesting that c-fos, arc, sgk, ania3 and egr-2 may be increased by DOI. Further, a complex of 5-HT2A and the metabotropic glutamate receptor mGluR2 may underlie the hallucinogen-specific signalling cascades.

Injection of DOI led to expression of c-fos in both mGluR2-KO and wild-type mice, however egr-2 expression was abolished in mGluR2-KO mice only, suggesting hallucinogenic effects are mediated by co-activation of 5-HT2A and mGluR2, as well as Gi/o proteins and their downstream cascades.

Although all the substances have common shared mechanisms, they differ in their exact pharmacodynamic activities regarding both receptor affinity and the degree of subsequent activation of intracellular signalling pathways.

Electrophysiological and neuroimaging data

Recent electroencephalography data (EEG) and functional magnetic resonance imaging (fMRI) data (carhart-harris et al. 2012) demonstrated that psilocybin significantly altered visual processing, and that psilocybin may increase spontaneous neuronal excitement modulated by increased oscillations, which overwhelms cortical excitation from external stimuli.

The single positron emission tomography study on cortical changes induced by psilocybin demonstrated a global increase in cerebral activity, especially in the frontomedial, frontolateral, anterior cingulate and temporomedial cortices.

The Deakin/Graeff hypothesis

The serotonergic system plays a role in anxiety and depressive disorders, though the precise physiological roles of the subsystems, their varying dysfunction in mental illnesses, and the exact therapeutic mechanisms of action of even very well studied drugs such as selective serotonin reuptake inhibitors (SSRIs) remain incompletely understood.

The median dorsal raphe forebrain bundle releases serotonin that binds to 5HT1A receptors in the hippocampus and limbic system, and lateral dorsal raphe nuclei act as inhibitory restraints, diminishing ‘fight or flight’ reactions to stressors. Dysfunction may be associated with depression and anxiety disorders.

Post-mortem studies

Depressed and suicidal patients have increased 5-HT2A receptor expression in cortical areas, and decreased 5-HT2A binding in hippocampal areas. The 5-HT2A receptor may play a role in the regulation of mood state.

Animal models suggest that increased expression of 5-HT2C receptors in the forebrain is associated with anxiety-like behaviours and reduced activity, whereas knockout mice show a blunted response of the amygdala in response to anxiety stimuli. However, agonist action on 5-HT2C receptors may also have antidepressant-like effects in animal models.

5-HT1A receptors are expressed postsynaptically in the hippocampus, hypothalamus, amygdala and cingulate and entorhinal cortices and may have analgesic effects on acute, tonic and chronic nociceptive pain in animal models similar to those of opiate-based agents.

Animal models: 5HT2C

Studies have shown that hallucinogens increase glutamate-dependent activity in prefrontal areas, and that this increase is accompanied by increases in the cellular protein brain-derived neurotrophic factor (BDNF). BDNF may play a vital role in adult neurogenesis and depression is partially linked to insufficient neurogenesis and neurotrophic activity.

Catlow and colleagues investigated the effects of psilocybin, 25I-NBOMe and ketanserin on hippocampal neurogenesis and extinction of fear conditioning in adult rats. They found that low doses of psilocybin increased neurogenesis and rapid extinction of cued fear conditioning.

Modulation of the immune system

Messengers of the innate immune system, such as interleukin (IL)-6, IL-1, interferon- and other cytokines, may bring on symptoms associated with both depression and sickness, and dysregulation of cytokines may contribute towards depressive illness.

IDO metabolizes tryptophan along the kynurenine pathway, which is implicated in regulation of the innate immune system and potential neurotoxicity. 5-HT2A receptor activation by DOI suppresses the mediation of inflammatory processes by tumour necrosis factor , including the transcription of IL-6, thus leading to a reduced inflammatory response.

Alteration of cortical networks

The DMN and broader dysconnectivity between this and the extrinsic networks has been associated with mental illness, including depression. Mindfulness-based therapies have been shown effective in reducing symptoms of depression and anxiety, and reducing the risk of depressive relapse.

Clinical effects

There is data to support the safety and therapeutic effects of classical hallucinogens. Participants in 8 separate double-blind randomized controlled trials reported experiencing oceanic boundlessness, anxious ego dissolution, visionary restructuralization, alterations of auditory perceptions and cognitive vigilance, but with a much smaller effect for anxious ego dissolution. Psilocybin exposure did not cause any mental impairment or distress, but the findings may not be easily transferred to broader clinical populations.

In a double-blind RCT, participants reported increased joy, intense happiness and peace, and 22 out of 36 participants had a strong mystical type experience. These experiences were rated among the top five of their most personally meaningful experiences.

Grob and colleagues investigated 15 individuals who regularly ingest the DMT-containing brew ayahuasca as part of spiritual ceremonies in organised spiritual practice. The results showed that ayahuasca users performed mildly better on cognitive measures and exhibited less harm avoidance on personality measures than ayahuascanave individuals.

In a larger sample of religious ayahuasca users, regular users showed lower scores on all psychopathology scales, but higher scores on a measure of psychosocial well-being, and better performance on the Stroop test and the Wisconsin Card Sorting Task.

In a population-based analysis of a nationwide Norwegian drug-use survey, 13.4% of participants reported lifetime use of hallucinogens, and no negative relationship was observed between lifetime substance-use documentation, of any psychedelic, and any mental health outcome.

Studies on patient populations

There were more than 1000 studies on LSD and psilocybin in the 1950s and 1960s, but these studies had many problems and the present review will refrain from considering evidence obtained in these studies. Following anecdotal early case studies on the utility of psilocybin in OCD, nine OCD patients were administered this compound on four testing days at least 1 week apart. Psilocybin significantly reduced OCD symptoms in all participants, and the effect lasted for more than 24 hours. The only adverse reaction was mild hypertension, and the study was limited by a lack of control, adequate sample size and long-term follow up.

Grob and colleagues investigated the effect of psilocybin on advanced-stage, mood-disordered cancer patients on measures of depression, state – trait anxiety and mood states. They found that psilocybin significantly increased positive mood, positive derealization and elementary hallucinations, but not anxious derealization and thought disorder.

Gasser and colleagues utilized LSD as an adjunct to psychotherapy for anxiety from life-threatening illness. The study revealed a statistically significant reduction of state anxiety on the STAI and a trend towards reduction of trait anxiety at both 2- and 12-month follow up.

Risk data on classical hallucinogens

None of the studies reviewed here that utilized classical hallucinogens reported any significant adverse effects, whether physiological or psychological. The risks associated with classical hallucinogens appear to be low, but further studies are needed to determine their potential clinical application.

Conclusion

Hallucinogens have been used for millennia for their well-recognized mind-altering properties, but in the 20th century interest in their therapeutic potential was rapidly stymied by counter prevailing political and social currents. However, recent research has shown promise.

Hallucinogens might not require daily ingestion, and their unique mind-manifesting properties might make them complementary to existing antidepressant drug classes.

Legislation on hallucinogens is outdated, and the freezing effect it has on clinical research is harmful. Three out of 7000 UK hospitals have the necessary licence to research such drugs, but the cost is expensive and only lasts 1 year.

Conflict of interest statement

Derek Tracy and Giovanni Giaroli have received honoraria for educational talks and travel expenses from Lilly UK and Roche UK.

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