Psychedelics as Medicines: An Emerging New Paradigm

This review (2016) by three prominent researchers looks back at the latest research on psychedelics and their psychological and anti-inflammatory effects.

Abstract

“Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5‐HT_2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing anti-inflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network “resetting” after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in the treatment of inflammation‐related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.”

Authors: David E. Nichols, Matthew W. Johnson & Charles D. Nichols

Notes

This paper is included in our ‘Top 10 Articles Introducing Psychedelic-Assisted Therapy‘

Summary

After the controlled substances act of 1970, clinical research with psychedelic agents essentially ended. Now, a number of studies have employed psychedelics in conjunction with psychotherapy, leading to surprising but apparent robust therapeutic efficacy.

ANXIETY AND DEPRESSION

LSD and psilocybin were given to patients with advanced-stage cancer who had a diagnosis of anxiety related to their cancer. The patients’ Spielberger State-Trait Anxiety Inventory (STAI) trait anxiety subscale scores revealed a significant reduction in anxiety and Beck Depression Inventory (BDI) scores revealed an improvement of mood.

Two larger randomized placebo-controlled studies of psilocybin-assisted psychotherapy in patients suffering from cancer-related psychosocial distress are in press. The results show remarkable efficacy that is unprecedented for CRPD with any currently available conventional therapies.

The NYU study8 used niacin as the active placebo control instead of low-dose psilocybin, and documented dramatic symptom reductions, with large effect sizes comparable to the JHU study, and efficacy sustained for 6 months after treatment.

Gasser et al.11 found that LSD-assisted therapy in 12 patients with anxiety related to a diagnosis of life-threatening diseases demonstrated safety and positive stable treatment outcomes at long-term follow-up.

OBSESSIVE-COMPULSIVE DISORDER

Anecdotal reports led Moreno et al.14 to study the effect of oral psilocybin on obsessive compulsive disorder (OCD) patients. They found that all nine participants experienced marked symptom reduction during one or more sessions, and most experienced relief beyond the expected psilocybin pharmacological life.

Researchers in Saskatchewan, Canada used LSD and mescaline to treat alcoholism in the 1950s, and observed insightful “mind manifesting” effects that prompted sobriety. Several randomized trials showed nonsignificant trends favoring improved outcomes for LSD, but a meta-analysis showed significant decreases in alcohol misuse in the LSD groups compared to control groups. In addition to early alcoholism studies, one study examined whether LSD reduced drug use in the context of opioid addiction. The LSD group showed significantly lower biologically confirmed heroin use compared to the control group.

The first modern laboratory study examining a serotonergic psychedelic for addiction was conducted in 15 treatment-resistant tobacco/nicotine-dependent smokers. The study found that psilocybin increased the experience of those who were smoke-free at 6 months compared to those who had relapsed.

In a recent open-label pilot study, 10 participants with a diagnosis of alcohol dependence received 0.3 mg/kg oral psilocybin twice a week for 12 weeks. Their self-reported alcohol use decreased significantly following the first psilocybin administration, and remained lower than at baseline at 36-week follow-up.

LIMITATION

Psychoactive substances should not be used for self-monitored use at home, and two specially trained therapists must be present during therapy sessions.

INFLAMMATION

Researchers have discovered that serotonergic psychedelics may be effective against inflammatory diseases such as coronary artery disease, diabetes, asthma, inflammatory bowel disease, and rheumatoid arthritis. Inflammation is also linked to several psychiatric disorders including depression, addiction, and neurodegenerative disorders.

The immune response includes innate immune cells such as macrophages and T-helper cells, as well as adaptive immune cells derived from bone marrow. Current therapies include nonsteroidal antiinflammatory drugs (NSAIDs) and steroid drugs (prednisone) that prevent cells from synthesizing proinflammatory molecules called cytokines.

Researchers discovered that psychedelics act through activation of the serotonin 5-HT2A receptor to reduce inflammation. Although not yet in human trials, serotonin has been shown to have profound effects in animal models of human inflammatory-related diseases.

Psychedelics have been shown to affect the 5-HT2A receptor, which is found in nearly every tissue and cell type in the body. It is also involved in cell differentiation and proliferation, vasoconstriction, and immune regulation.

Psychedelics, including LSD, potently and selectively prevented inflammation elicited by the master inflammatory cytokine tumor necrosis factor alpha (TNFa) in smooth muscle cells isolated from rat aorta. These effects were mediated through activation of 5-HT2A receptors, which are different from those recruited to the receptor by serotonin activation through functionally selective mechanisms.

Studies examined efficacy in a mouse model of allergic asthma, a significant health issue that involves activation of several immune related cells in the lung. Several biologics directed against cytokines involved in the pathology of asthma have been in clinical trials with mixed success.

Psychedelics have been shown to prevent the development of allergic asthma in a mouse model. The lowest dose tested, 0.01 mg/kg, was able to completely prevent airways hyperresponsiveness, eosinophilia, and pulmonary inflammation.

Research indicates that (R)-DOI blocks the recruitment of Th2 cells and eosinophils to the lung, and suppresses the production of proinflammatory cytokines from Th2 cells and innate immune cells like macrophages. This suggests that (R)-DOI may be an effective therapy for asthma, atherosclerosis, coronary artery disease, and inflammatory bowel disease.

Psychedelics may have antiinflammatory activity at multiple sites in the brain, including neuronal and non-neuronal cells. This may help the brain maintain its healthy state after a therapeutic effect is achieved.

MECHANISM OF ACTION IN THE BRAIN

If psychedelic-assisted therapy is used for all of the above-discussed CNS indications, how can the same single treatment approach lead to improvement in such a diverse range of dysfunctions?

Neuroscientists and clinicians often think of the brain from a reductionist perspective, in which anatomical modules are regulated by discrete neurotransmitter pathways. However, recent advances in neuroimaging have made it possible to envision how all of these “modules” might interact and influence each other.

Advances in brain imaging technologies have revealed that resting-state brain activities are organized into multiple large-scale functional networks. RSFC analyses can reveal brain network dynamics that can account for emergent psychological phenomena.

Brain hubs are centrally embedded within anatomical networks and are susceptible to disconnection and dysfunction in various brain disorders. Using blood oxygen level-dependent fMRI, researchers have shown that brain hubs can be used to detect altered FC in individuals suffering from a variety of CNS diseases.

If we think of neurotransmitters/neuromodulators and their receptors as components of neuronal circuits, then receptor-based pharmacotherapy is more like tinkering with the components of a malfunctioning circuit.

Research shows that healthy brain networks have a combination of high clustering and short pathlength, which enables optimal cognitive function at a low wiring cost. Neurological diseases often deviate from this optimal pattern.

Researchers have observed that subjects undergoing a powerful transcendent experience, sometimes referred to as a mystical, or peak experience, have the most favorable outcomes in treating anxiety and depression, as well as nicotine addiction.

Psilocybin decreases activity in the posterior cingulate cortex and the medial prefrontal cortex, two key hubs of the default mode network, which is interesting because this region is increased in individuals with depression.

Carhart-Harris et al.59 observed that subjects given LSD had a decreased DMN, decreased within-RSN integrity, and decreased between-RSN segregation, which was correlated with ego dissolution. They concluded that psychedelics lead to a brain state where there is a greater repertoire of connectivity motifs that form and fragment over time.

Stam’s hypothesis suggests that disintegration of RSN organization, i.e., local connection outgrowth, or “hub failure” in neurological diseases, reflects a deviation from an optimal connectivity pattern. We speculate that psychedelic-induced disintegration within local networks, as well as increased global interconnectivity, may disrupt and break connections responsible for hub failures.

This discussion has not been comprehensive, but the authors believe these ideas are not far from the mark. Four human trials are now underway with psilocybin.

WHAT DRIVES CHANGES IN FUNCTIONAL CONNECTIVITY?

Psychedelics are agonists or partial agonists at the brain serotonin 5-HT2A receptor subtype, which activates phospholipase C, resulting in phosphoinositide hydrolysis, formation of diacylglycerol, and mobilization of intracellular calcium.

5-HT2A receptors on glutamatergic neurons within the brain generally do not lead to depolarization and the generation of action potentials; the cells simply become more excitable. This increased excitability is expected to have marked effects on cognition.

In 2016, Martin and Nichols65 demonstrated that psychedelics directly activate a small subset of 5-HT2A-expressing excitatory neurons in key brain regions, which in turn recruits other select cell types and initiates the cellular events leading to recurrent activity, cortical network destabilization, and the host of perceptual and cognitive behaviors associated with psychedelics. Different cellular populations in different brain regions respond differently to psychedelics, which may explain the alterations in brain network communication observed by imaging studies.

Martin and Nichols65 found that psychedelics activate astrocytes and glia, which may be contributing to the alterations in cortical blood-flow and metabolism detected by BOLD-fMRI and PET imaging.

The claustrum is a brain structure with high 5-HT2A receptor expression, which may be used to control temporal structure of network activity over component cortical areas of the salience network.

Torgerson et al.68 used in vivo diffusion tensor imaging tractography and graph theoretical analytics to examine the structural connectivity of the claustrum. They concluded that the claustrum is a primary contributor to global brain network architecture.

In the brain, spontaneous activity alternates between periods of relative quiescence interspersed with short bursts of activity that recruit a spatially delimited population of neurons. These bursts are called neuronal avalanches, and follow a power-law distribution.

The empirical demonstration that brain resting-state activity simultaneously exhibits functional segregation and integration has led to the suggestion that the cortex normally resides at a critical state, but this conjecture has been challenged by Priesemann et al.

Theoretical models of power-law avalanches assume the presence of functionally feedforward connections (FFCs) in the underlying dynamics of the system, and pharmacologically induced alterations in avalanche dynamics are accompanied by changes in FFCs. Psychedelics may also amplify neuronal avalanches through activation of 5-HT2A receptors.

The depolarization of cortical trigger subpopulations of cells by 5-HT2A receptor activation is consistent with a supercritical brain state.

Psychedelics affect the 5-HT2A receptor in cortical regions, which leads to a reduction in the threshold for cortical cell depolarization, and a supercritical state in which cells become more sensitive to depolarization. This leads to destabilization of local network hubs and changes in global connectivity.