A brief review of psychedelics’ biological and psychological mechanisms of action attributed to their therapeutic effects.

In Spanish there is a saying that goes “Lo prometido es deuda”, which translates as “What is promised is owed”. In my first post in this series, I mentioned that in a future post I would share some of the information I researched to write my preliminary exam, which answered the question “What are the known and theoretical mechanisms by which psychedelic substances produce therapeutic effects, both short and long term?”. Given that this is my sixth and last post in this series, I will endeavor to summarize the highlights of my findings and offer some reflections regarding the future viability of psychedelic therapies as approved psychiatric treatments in mental health systems.

In that first post, I made the point that taking into consideration the amount of cultural stigma associated with psychedelic substances, that for decades impeded scientific research, the current growing interest they are generating in the fields of psychiatry and mental health research is a most interesting phenomenon to unpack.

Why is it that psychedelic substances are increasingly being looked upon as the ultimate drug treatment for highly intractable disorders like major depressive disorder and substance use disorders? I have argued that from my perspective, the reason is twofold; one is the significant unmet medical/clinical need that exists and the other is the evidence accrued to date that show psychedelic treatments produce rapid and sustained therapeutic effects after limited exposures (most studies have done 2 – 3 treatments and see positive treatment outcomes up to a year later). This contrasts sharply with standard antidepressants that you take every day for years on end,  and that typically produce a limited therapeutic response that can take weeks before the effect is felt, while simultaneously producing unwanted side effects.

So, what do we know about how psychedelics work? In my 40-page prelim exam, I organized the answer to that question in two main sections: biological mechanisms and psychological mechanisms. Let’s go over the main points of both.

Psychedelics are known for producing altered states of consciousness that are characterized by profound changes in perception, mood, cognition, and a sense of being a “self”. Converging research both from animal models and human studies has elucidated that at the molecular level, psychedelics exert their subjective effects primarily via activity at a particular serotonin receptor, specifically the 5HT2A receptor. LSD is also known to target other serotonin receptors, and adrenergic and dopaminergic receptors; and 5-MeO-DMT works primarily through the 5HT1A receptor. Nonetheless, the consensus based on the evidence to date is that the 5HT2A receptor subtype is a key and necessary component of psychedelic effects in mammals.

If the 5HT2A receptor is essential for the psychological effects of psychedelics, then the next question becomes, where in the brain are these receptors located, and what are those brain structures responsible for? 5HT2A receptors have been found to be most densely expressed in the evolutionarily new cerebral cortex,  particularly the prefrontal cortex, the posterior cingulate cortex, as well as in subcortical regions such as the hippocampus and the amygdala. Activation of the 5HT2A receptor in those brain structures, which broadly speaking are involved in cognition, learning, memory, and emotional processing, induces glutamate release, and increases brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex.

BDNF is a key protein involved in learning and memory.  In the adult brain, BDNF also regulates synaptic transmission and is known for supporting the survival of existing neurons as well as encouraging growth of new neurons and synapses. As such, BDNF has important implications for neuroplasticity. Indeed, Ly et al (2018) found that activation of the 5HT2A receptor by LSD and other psychedelics, by way of increasing BDNF, resulted in cortical synaptogenesis, an important biomarker of neuroplasticity. This is of important clinical relevance given that atrophy of neurons in the prefrontal cortex is widely believed to play a key role in the development of various hard to treat psychiatric conditions such as major depressive disorder. As such, this glutamate release leading to increases in BDNF, via activation of the 5HT2A receptor, is currently thought to be one of the main mechanisms by which psychedelics confer therapeutic benefits. As such, a newer term used to refer to psychedelics is “psychoplastogens”.

Taking into consideration the fact that BDNF decreases are involved in the development of various mental health conditions, and that psychedelics, via 5HT2A activation produce increases in BDNF, it is then plausible to hypothesize, as Ly et al have done, that at the biological level, these induced neuroplastic changes underlie the psychological improvements in various psychiatric conditions such as depression, anxiety, and Post Traumatic Stress Disorder.

Functional Magnetic Resonance Imaging (fMRI) studies conducted with psilocybin in healthy volunteers, have found acute cerebral blood flow (CBF) decreases in areas that are known to be important connector hubs in the brain, particularly in an area of the cortex called the posterior cingulate,  which is part of what is called the “default mode network” (DMN), and that these decreases correlate positively with the intensity of subjective effects reported, such that the greater the decreases of CBF, the more intense the subjective effects. This finding may carry important clinical relevance because the DMN is known to be overactive in depressed patients and is considered the neural substrate of the experience of ruminative thoughts so characteristic of this disorder.

In general, because of psychedelics’ key property of “expanding consciousness”, as referenced in popular literature, they had been thought to be acting by increasing brain activity, so the decreases of brain activity in high-level brain function areas, as evidenced by reductions in CBF, were somewhat surprising.

Another key finding from neuroimaging studies is that different regions of the brain, which under normal conditions don’t have direct communication with one another, do so during the acute psychedelic experience, reflecting enhanced global connectivity. This is an image that has become iconic in psychedelic science that depicts this brain communication that takes place under the acute effects of psilocybin.

Visualization of the brain connections in the brain of a person on psilocybin (right) and the brain of a person not given the drug. Source: Journal of the Royal Society Interface.

These neuroimaging findings have informed what is called the entropic brain hypothesis (EBH)  proposed by Robin Carhart-Harris. The EBH in turn has given way to what is called the “Relaxed Beliefs Under pSychedelics  and the anarchic brain” (REBUS), which is a synthesis of the EBH and what is known as the “free-energy principle”. The free-energy principle is a theoretical proposition of brain function that explains living system’s behavior, (i.e., brain) built upon the assumption that these systems are driven by an innate tendency to resist disorder and minimize uncertainty (free energy). Both the EBH and the free-energy principle in the REBUS model lean heavily on a cognitive neuroscience theoretical paradigm called “hierarchical predictive processing”. Put simply, hierarchical predictive processing embodies the idea that the brain is an inference machine that is constantly predicting a model of its environment based on encoded beliefs from prior inputs (high-level priors), with the objective of giving us a sense of assuredness or certainty in our environment (minimize free-energy/entropy).

The REBUS model posits that psychedelics, by making the brain more entropic in its activity, reduce the stability and rigidity of our beliefs, and the plasticity they have been shown to promote allows for the relaxation of the precision weighting of those high-level priors (i.e., the accuracy or certainty we may feel about the encoded belief is decreased), thereby creating the opportunity for information that was previously ignored, or out of conscious reach, to bubble up to consciousness (bottom-up flow), enabling a revision of those beliefs and a recalibration of our models about the world and ourselves.

Connecting this back to the neuroimaging findings discussed above, we can summarize that as parts of DMN deactivate, and its top-down control goes offline, the brain enters an unconstrained mode of cognition that allows bottom-up input from the evolutionarily older limbic system to percolate up (the anarchic brain part of the model) and facilitate insight experiences, and often times, the long-term correction of maladaptive, negative biases.

Carhart-Harris and Friston explain that many psychiatric conditions, such as depression, substance use disorders, eating disorders, etc. have in common the fact that, at their core, there is an entrenchment of pathologic behaviors encoded in overly-reinforced inflexible beliefs (psychological inflexibility) in high level processing areas of the brain (DMN) that result as a defense mechanism from experiences of adversity or trauma, and which exert an executive inhibitory control on global brain function.

Following this line of thought, the REBUS theoretical model goes some way towards explaining why psychedelics can be successfully used to address various mental health concerns like depression, substance use disorders, obsessive compulsive disorder, etc.: psychedelics’ transdiagnostic value stems from the fact that they target those inflexible beliefs and relax them, thereby fostering psychological flexibility.

In terms of the psychological mechanisms of psychedelics’ therapeutic effects, this is an area of ongoing inquiry. To date, the occurrence of what is called a “mystical type” experience has emerged as a robust predictor of positive treatment outcomes across various studies conducted with psilocybin. More recently, research conducted by Dr. Alan Davis has found that increases in precisely the construct of psychological flexibility, as it derives from the therapeutic model called “Acceptance and Commitment Therapy” (ACT), is emerging as a mediator of treatment effects, which maps out nicely to the neurobiological effects of plasticity via increases of BDNF that have been elucidated to date and which were summarized above.

At this point, having described at a very high level the biological and psychological mechanisms of psychedelics’ therapeutic effects, a question that comes to my mind is one posed by Dr. Rick Strassman in his 2012 book DMT: The Spirit Molecule. The question he poses there is: “If so, so what”? pondering the idea of what these psychedelic experiences may be good for. That is, “if psychedelics lead to this or that kind of experience, by this or that means, how is the world a better place or how are we better people”?

To my mind the question “If so, so what?”, comes in relation to the future accessibility of these compounds, which are not far from gaining regulatory approval by the FDA: will all those who are in need of these treatments be able to access them? The mechanisms elucidated to date seem to indicate that psychedelics, often times administered only once or twice, work well across a variety of mental health concerns, but in my mind, the concern becomes: what good is that if insurance companies don’t cover the cost, and a single treatment can cost a couple of thousand dollars? As psychedelic therapies are rolled out and scaled up in the years to come, who will be able to afford these potentially life-changing/saving treatments? Who will these therapies benefit, and whom will it leave untouched despite the need and potential for improvement that exists?

I think the work that my colleague Amanda Pratt does at the Archival Researcher Network, as she has shared in a recent post in this series, will be instrumental in keeping the psychedelic therapy space ethical and leveled as her work and that of her colleagues is able to successfully provide relevant information to the patent officers that may otherwise unknowingly issue patents that can severely limit the future accessibility of these treatments. Additionally, something else that gives me hope is the work of Usona Institute.

Usona Institute here in Madison, WI is practicing a new model of drug development as a non-profit medical research organization. Usona has made great strides in moving psilocybin closer to FDA approval, as demonstrated by its recent completion of a Phase 2 study for the treatment of major depressive disorder (MDD), under FDA granted Breakthrough Therapy designation, and is currently preparing to begin a Phase 3 study for psilocybin, as well as launching a new development program with 5-MeO-DMT. Usona’s commitment to access and affordability through their Open Science platform is inherent in their approach and truly promises to be a new paradigm for the field of drug development.


Feature image sourced from the Ly et al., 2018. It describes the effects of psychedelics on BDNF and where the term “psychoplastogens” is introduced.

Editorial Note: This post is part of the Pharmaceutical Inequalities series, funded by the Holtz Center and the Evjue Foundation.

Anny Ortiz
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Anny Ortiz is a PhD Student within University of Wisconsin-Madison’s School of Human Ecology. Her main area of interest, and intended research, involves novel treatment approaches for psychosocial problems like mood disorders — e.g. anxiety and depression — as well as addictive behaviors. She is interested in exploring peripheral pathways for addressing underlying factors that may be contributing toward making these conditions so pervasive in today’s culture

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