Psilocybin mushrooms being weighed by research scientist studying the application of psychoactive drugs for treating mental health disorders
Discovery
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Carina Peritore

Are Psychedelics the Next Approach to Treating Mental Health Disorders?

We are beginning to see an increase in the acceptance of psychoactive drugs as a form of therapeutic treatment, especially in North America

“I have the choice of being constantly active and happy or introspectively passive and sad. Or I can go mad by ricocheting in between.” – Sylvia Plath (Unabridged Journals)

After a half a century hiatus in the exploration of medical uses of psychedelics for treating mental health disorders, halted by Nixon’s declaration of war on drugs in 1970 and decades of demonization, there has been an explosive revival in this research with over 70 clinical trials planned or on going for psilocybin alone. Since the creation of selective serotonin reuptake inhibitors (SSRIs), 40 years ago, there has been limited innovation. Also, symptomatic remission increases the probability for recovery in some mental health disorders yet most patients do not achieve nor sustain full remission . The options for treatment when the patient is resistant to the available standard treatments generally involve combining, augmenting or switching medications, introducing electroconvulsive therapy, or other neurostimulation strategies. The risk for complications associated with those approaches include increased toxicity with higher medication dosages and combination regimens.

A new class of small molecules: What is a psychedelic?

A psychedelic drug is a class of chemical substances that is considered psychoactive, meaning that it produces changes in perception, mood and cognitive presence. Some examples of psychoactive compounds are magic mushrooms (psilocybin and psilocin), MDMA (3,4-methylenedioxymethampetamin), LSD (lysergic acid diethylamide), DMT (N,N-dimethyltryptamine), Ibogaine, Ketamine and Mescaline (3,4,5- trimethoxphenethylamine).

Anti-drug campaigns over the last few decades have led to the criminalization of psychoactive compounds and drove most researchers away from the field. However, the FDA’s landmark approval of Johnson & Johnson’s ketamine-derived nasal spray Spravato for depression in March 2019 may have helped open the floodgates for other controversial drugs commonly used recreationally but with significant therapeutic potential.

Researcher’s quest to win mainstream acceptance of psychedelics also took a significant leap forward when the journal Nature Medicine published the results of the popular drug known as Ecstasy and Molly (MDMA), to treat PTSD. These results came on the heels of a New England Journal of Medicine study that highlighted the benefits of treating depression with psilocybin, the psychoactive ingredient in magic mushrooms.

Psilocybin and MDMA are poised to be the most up-to-date new therapeutics since Prozac. Psilocybin is a molecule with structural similarities to serotonin, an endogenous neurotransmitter. It can be found in some mushrooms and has been widely used to induce hallucinations and altered states of consciousness. Its laboratory synthesis was performed by Albert Hofman, the discoverer of lysergic acid (LSD), while he was working at Sandoz Laboratories. It was later marketed under the commercial name Indocybin for basic pharmacology and clinical research. It was the likes of American psychologist, Timothy Leary, that brought awareness of LSD into the general public which ultimately led to the recreational use that revolutionized the movement toward regulating all psychoactive substances as drugs of abuse.

MDMA was first developed in 1912 by Merck and used to enhance psychotherapy beginning in the 1970’s. Once popular as a street drug in the 1980’s, MDMA, like other hallucinogens, became classified as a Schedule I drug of abuse by the Drug Enforcement Administration. Publications funded by the US National Institutes of Health were limited to proving the toxic effects of psychoactive drugs with no therapeutic potential.

Mechanism of Action: How is it different than traditional SSRI’s?

Psychedelic effects of psilocybin are believed to emerge through stimulation of serotonin 2A receptors (5-HT2A) while MDMA induces serotonin release by binding primarily presynaptic serotonin transporters . Because of the similarities between serotonergic psychedelics and ketamine in both preclinical models and clinical studies, researchers are reasoning that their therapeutic effect might result from a shared ability to promote structural and functional neural plasticity in cortical neurons . These compounds are predicted to stimulate structural plasticity by activating the mammalian target of rapamycin (mTOR). Serotonergic psychedelics are known to cause changes in mood and brain function that persists long after the acute effects of the drugs have subsided. They elevate glutamate levels in the cortex and increase gene expression in vivo of brain-derived neurotrophic factor as well as immediate-early genes associated with plasticity.

Because atrophy of cortical neurons is believed to be a contributing factor to the development of mood and anxiety disorders, research with cultured cortical neurons and in vivo models and various serotonergic psychedelics from a variety of structural classes were measured to visualize morphological features. Nearly all psychedelics tested (psilocybin, ketamine, DMT, LSD) increased dendritic arbor complexity. What does this mean? They promote neurogenesis via neurite outgrowth. This outgrowth appears to be stimulated by mTOR and 5-HT2A signaling pathways. Together, these emphasize the therapeutic potential of psychedelic scaffolds to identify alternative lead candidates for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective and fast-acting treatments for depression.

Compared to SSRIs, the current gold standard in antidepressant medication, psychedelics appear to have a faster effect on patients, sometimes effective with only a single therapy session . But why? The importance of the serotonergic system in regulating mood is evident yet research into all the receptors has also proven that no one subtype is singularly responsible for diseases like anxiety and depression. Even the paradoxical role of serotonin as both anxiolytic and anxiogenic highlights the complexity of the brain response. More work needs to be done to uncover the molecular mechanisms of signal transduction and receptor trafficking in healthy and diseased states.

Although the molecular targets of ketamine (NMDA) and serotonergic psychedelics are different (5-HT2A), they appear to cause similar downstream effects on structural plasticity by activating mTOR. Ketamine is also known to be addictive whereas many classical psychedelics are not, although the exact mechanisms are not clearly understood. Due to the profound perceptual differences that occur during treatment, there are still safety concerns; therefore, the identification of non-hallucinogenic analogs capable of promoting plasticity in the prefrontal cortex could facilitate a shift whilst the long-standing debate of ‘microdosing,’ may come into play.

The concept of micro dosing: What about the hallucinogenic effect?

Recently, it has been argued that psychedelic ‘microdosing,’ entailing a dose small enough to avoid noticeable perceptual effects, comes with benefits such as enhanced creativity, social interaction and mood. The phenomenon of ‘microdosing,’ which is the regular ingestion of very small quantities of psychedelic substances has seen a rapid explosion of popularity in recent years. Individuals who microdose report minimal acute affects from these substances yet claim a range of long-term general health and wellbeing benefits. Additionally, those who are microdosing are commonly doing so as a self-managed therapy for mental health, either as an alternative or adjunct to conventional treatments. This is despite psychedelics remaining prohibited substances in most jurisdictions. Recent findings from clinical trials with standard psychedelic doses for depression and anxiety suggest that a neurobiological effect beyond placebo is not unreasonable. Randomised controlled trials are needed. To date they have been limited and fail to produce results comparable to those reported in the grey literature.

What’s Next?

Propelled by these findings and the prospects of lucrative initial public offerings, venture capital firms have gone from investing $1 million in psychedelic biotech startups in 2017 to $329 million during the first four months of 2021 alone.

More than a dozen start-ups have jumped into the fray, and the handful of companies that have gone public are collectively valued at more than $2 billion. Field Trip Health , a two-year-old Canadian company that trades on the Canadian Stock Exchange, has raised $150 million to finance dozens of high-end ketamine clinics in Los Angeles, Chicago, Houston and other cities across North America. Compass Pathways , a Nasdaq-listed health care company, has raised $240 million and is conducting 22 clinical trials in 10 countries testing psilocybin therapy for treatment-resistant depression.

With more money invested in looking at the therapeutic potential of these psychoactive drugs versus previous campaigns that demonized them as neurotoxins, we can confidently march toward an openness of acceptance. If indeed this is the wave of our future, we can imagine a less costly, one-time treatment for long-term success in alleviating the pain and anguish of major depressive disorders via traumatic brain injury-related or potentially neurodegenerative disease-induced depression.