By João Caetano
In the United States during the 1950s and the 60s, hallucinogenic compounds were widely used for recreation, 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 on psychedelic research due to eased restrictions. So what’s all the hype about? and what is the mechanism of action that seems to offer so much promise?
Hallucinogenic or Dissociative?
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 compounds that when people consume these they can experience sensory alterations and mind-altering highs. These can also be differentiated from other hallucinogens because of the specific receptors or systems in the brain where they have their effect – in this case, serotonin receptors. Every psychedelic substance is a hallucinogen, but not all hallucinogens are psychedelic substances, as there are other compounds that can produce hallucinogenic effects. 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.
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 was still significant 6 months after the study1. 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 “neuromodulatory” neurotransmitter. This is 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 existing drug treatments for depression also influence serotonin transport in the brain, for example, selective serotonin reuptake inhibitors (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
There is a newly proposed “reset” hypothesis that could start to 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 – of which 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 and network analysis. The DMN (shown in figure 1) is a network known for being most active when we daydream, let our mind wander, and are not focused on a task at hand. 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 all 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
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 of the network decreased during the experience and increased again the day after. This is important, as DMN integrity is a hallmark of several neurological disorders.
The molecular mechanisms behind this functional reset remain unclear. One brain region heavily modulated by serotonin is the claustrum. It has also been demonstrated that this brain region is involved in many mental illnesses like depression. This region, sitting quite centrally located in the brain, also has one of the highest density of connections of any brain region, and it has been proposed to be the mediator of the activity of the resting state networks (figure 2). However, also because of its anatomical location in the brain, this structure has been notoriously difficult to study in the past.
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 it 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 pharmaco-therapies 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
I did my literature thesis about this topic, as I was always 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
Cover image credits: Figure 2 is from the book Gray’s Anatomy: The Anatomical Basis of Clinical Practice.