The psychedelic “reset” mechanism- and how it could treat depression

By João Caetano

In the United States during the 1950s and the 60s, hallucinogenic compounds were widely used recreationally, as well as in research and therapies for mental disorders. A ban on these compounds during the 1960s essentially halted much of the research on these compounds, despite objections from the scientific community, until the 1990s saw a revival in psychedelic research, due to eased restrictions. Research in the 50s showed some success, and a lack of success in treating mental disorders with other methods called for alternatives.

Hallucinogenic compounds are substances producing psychological effects that can cause changes in perception, thought, and feeling, as well as distortions of perception and awareness. Psychedelic drugs are a subset of hallucinogens. Some can be found in nature, such as psilocybin, which is found in at least 200 species of mushrooms around the world. Other drugs are synthetically made, as is the case of LSD, produced synthetically for the first time in 1938 when a researcher was studying a fungus that grows on grains. 

Psychedelic therapy is different from a usual psychedelic experience. Patients are in a room with professional supervision. The therapy element is very important, as patients are asked several questions both before and after taking the medication. Supervision is also important to make sure that the patient is relaxed and sure that they are safe. Some studies have used more than one session, usually one or two weeks apart. The first session can consist of a lower dose to get the patient used to the feeling so that in the next session they are ready for a more intense experience (that often results in increased effects).

Two examples of very promising studies with psychedelic therapy are a 2011 study that aimed to determine the utility of hallucinogenic treatment on advanced-stage cancer patients with anxiety ended up showing very promising results, with mood improvement and reduced anxiety that were still significant 6 months after the study 1. In 2016, a study where patients diagnosed with life-threatening cancer were given psilocybin resulted in 92% of the participants that received the high dosage showing a clinically significant response, with less depressed mood and anxiety. Six months later, this number was still as high as 79% 2. The objective of these studies was to determine whether psychedelic therapy could be used to help terminally ill patients, to help them deal psychologically with their situation.

Many studies are trying to uncover the molecular mechanisms as to why these compounds are so effective in treating diseases like depression. Hallucinogens like psilocybin and LSD bind to a serotonin receptor. Serotonin is a modulatory neurotransmitter: a molecule secreted at neuron terminals to ‘tweak’ or fine tune many neurological functions at synapses. As a result, the serotonin system is involved in regulating many behaviours and activities including mood, learning processes, digestion, and even sleep.

It is no coincidence that many current drug treatments for depression also influence serotonin transport in the brain, for example, Selective Serotonin Reuptake Inhibitors, or SSRIs. Serotonin has many receptors expressed all over the brain, and therefore any intervention to this neurotransmitter system can have widespread effects on many brain regions and neural functions.

Resetting the network

A newly proposed “reset” hypothesis could potentially explain psilocybin and other psychedelics’ effect on depression and other mental illnesses. Before we explore this hypothesis, it is necessary to understand what’s known as the brain’s resting-state networks – the Default Mode Network (DMN). Resting-state networks are functional patterns or maps of activity in the brain that researchers can distinguish with brain imaging.  The DMN (shown in figure 1) is a network known for being most active when we daydream, let our minds wander, and are not focused on a task at hand. It is of utmost importance, and could be argued the neurological basis for the self 3: its correct functioning is key for a healthy brain.  This network appears to be different in character in patients with many kinds of mental illness or neurological disorders, such as depression, schizophrenia, Alzheimer’s disease, or Post-Traumatic Stress Disorder, and its disruption represents a hallmark of many of these diseases.

A 2016 study by Nichols and Johnson stated that psilocybin disrupts the stability and integrity of the brain’s resting-state networks, which could allow the connections and functional patterns responsible for mental disorders to be disrupted and broken, and then facilitate new functional connections to emerge when the networks reconnect, with persistent effects after the drug wears off. 4

Figure 1– Areas of the Default Mode Network (DMN), showed in an fMRI scan5

Other studies have proposed a similar mechanism, observing that brain activity during the experience is very different from after the experience. They found that the brain, during the experience, can be characterized by a loss of connections in modules (closed networks) and an increase in global connections (anywhere in the brain); the next day, the previously disconnected modules regain their connections, and these connections can be stronger than they were before. As for the DMN, its integrity decreased during the experience and increased the day after. This is important, as disruption of DMN is a hallmark of several neurological disorders.

The molecular mechanisms behind this functional reset are still unclear. One brain region heavily modulated by serotonin is the claustrum. This region also has the highest density of connections of all brain regions, and it has been proposed to be the mediator of the activity of the resting state networks (see figure 2). Because of its location in the brain, this structure has been especially difficult to study, but some studies have also shown its involvement in depression.

Figure 2 – Location of the claustrum in the brain

The reset hypothesis posits that psychedelic therapy is exerting its effects through resetting functional connections. Evidence for this might lie in studying a highly connected brain region like the claustrum.

So what is happening in this brain region, with its serotonin receptors, and its neuronal synapses during or after a psychedelic therapy intervention?

Research continues and many new questions will arise, however viewing this through the reset hypothesis lens is a manner for researchers to understand how psychedelics are working as antidepressant therapy. Regulation and caution will be necessary. If we look at past examples of pharmacotherapies that were hailed as quick successes, researchers must also not blind themselves to side effects or misuse, only because of signs of early promise. We need to understand these compounds better and their actions at a molecular level first.

About the writer

João is a final year Biomolecular Sciences’ Master student at the VU. 
He performed his literature thesis about this topic, and has always been interested about the effects of mind-altering compounds in the brain and their potential to help our mental health therapy.

Further Reading

1. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68(1):71-78. doi:10.1001/archgenpsychiatry.2010.116

2. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in  patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181-1197. doi:10.1177/0269881116675513

3. Andrews-Hanna JR. The brain’s default network and its adaptive role in internal mentation. Neurosci  a Rev J bringing Neurobiol Neurol  psychiatry. 2012;18(3):251-270. doi:10.1177/1073858411403316

4. Nichols DE, Johnson MW, Nichols CD. Psychedelics as Medicines: An Emerging New Paradigm. Clin Pharmacol Ther. 2017;101(2):209-219. doi:10.1002/cpt.557

5. Graner J, Oakes TR, French LM, Riedy G. Functional MRI in the investigation of blast-related traumatic brain injury. Front Neurol. 2013;4 MAR(March):1-18. doi:10.3389/fneur.2013.00016

Image credits: Cover photo object. by Photo Extremist, credit: Evan Sharboneau. Figure 2 is from the book Gray’s Anatomy: The Anatomical Basis of Clinical Practice.