Psychedelics: The Scientific Renaissance of Mind-Altering Drugs

This is why psychedelics are so effective for treating mental illnesses.

What if I told you that treating a variety of mental diseases with psychedelics is far more effective than the current mental health treatments and commonly prescribed antidepressants?

You probably wouldn’t believe me.

However, it’s true!

A surplus of new evidence supports the claim that psychedelics may produce acute, often after just 1 psychedelic ‘trip’, and long-term beneficial outcomes in mental illnesses, e.g., depression, anxiety, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, and even tobacco and alcohol misuse. In other words, psychiatry may never be the same. But what are these powerful psychoactive compounds? Why did scientific interest begin its revival in these mind-altering drugs? And what happens in the brain during a psychedelic experience?

A brief history

Psychedelics were consumed by early human cultures in ritual and sociocultural contexts and their origin even predates written history. Throughout recorded history naturally occurring psychedelics, such as psilocybin (the psychoactive substance in ‘Magic Mushrooms’) and N, N-dimethyltryptamine, or just DMT (the psychoactive substance in Ayahuasca), played a vital role in human cultures even as long as 5700 years ago.

Modern psychedelic research began after the accidental discovery of the powerful hallucinogenic effects of lysergic acid diethylamide (LSD) by Albert Hofmann in 1943. Psychiatric research used LSD as “psychedelic” and “psycholytic” therapy during the 1950s and 1960s. During these years, some 40,000 patients had been prescribed LSD therapy, and over 1000 scientific papers were produced about the potential therapeutic effects of LSD and other psychedelics.

During the 1960s, LSD hit the streets, its popularity grew quickly and by the summer of 1967 the hippy counterculture was flourishing. At the time, LSD increasingly came to be viewed as a drug of abuse and consequently outlawed by the U.S. federal government in 1968. After decades wherein psychedelic research was slowed to a halt human psychedelic research began its revival, in the early 1990s, and rigorous research utilizing psychedelics as tools of discovery and healing is sufficient today. Recently, neuroimaging techniques are employed for in vivo (Latin for ‘within the living’) brain imaging in humans after psychedelic administration to see what happens in the brain during a psychedelic ‘trip’.

Although these technologies provide us with a basic understanding of the brain under influence of psychoactive compounds, they are getting closer and closer to understanding why therapeutic benefits and hallucinogenic effects arise after the administration of psychedelics.

Classic psychedelics

Psychedelics are powerful psychoactive substances that produce profound changes in perception, processing, and responding to stimuli in the environment which results in altered states of consciousness.

In today’s experimental research the so-called classic psychedelics, such as LSD, psilocybin, and ayahuasca (DMT) are the main psychedelic drugs that are studied in both clinical and healthy populations. Furthermore, MDMA (a.k.a. ‘ecstasy’ or ‘molly’) and ketamine, which have been swept into the category ‘psychedelics’, are molecules that also have been used in clinical settings but their mechanisms of action are different compared to the classic psychedelics. Therefore, classic psychedelics are the main focus of today.

Classic psychedelics are also called serotonergic psychedelics because they exert their effects primarily by binding to serotonin receptors in the brain. By looking at the molecular structures below, the structure of serotonin is seen in the structures of the psychedelic compounds. Serotonin is a neuromodulator which means that they modulate the brain, i.e., they make it more or less likely that certain things are going to happen.

5-hydroxytryptamine (5-HT) or serotonin does a lot of things but in general, it makes us feel relaxed, blissful, and good with what we have, e.g., relationships we’re already in and the state of our mind and body. If you ramp up the amount of serotonin really high, it kills people’s desire, for instance, people will lose their libido and appetite. This sounds really logical because why would you go after anything if you already have everything you need. Furthermore, serotonin influences various neurobiological processes, such as anxiety, learning, memory, cognition, sleep, and depression and it is also the target of pharmaceutical or recreational drugs like antidepressants and psychedelics.

With all this in mind, let’s dive deeper into the mechanisms of action of these classic psychedelics.

Mechanisms of action

As mentioned above, psychedelics exert their effects by binding to the serotonin system in the brain, with the 5-HT2A receptors as their primary target, and setting off powerful responses.

This type of receptor plays a vital role in producing the hallucinogenic effects of psychedelic drugs. Vollenweider and his colleagues demonstrated that the hallucinogenic effects of psilocybin in healthy volunteers were blocked by the molecule ketanserin, which is a 5-HT2A receptor antagonist. This means that a drug, in this case, ketanserin, blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist, such as psychedelic molecules.

Moreover, a recent study concluded that an antagonist action at the 5-HT2A receptors in the brain plays a role in mood disorders, especially in treatment-resistant depression. Therefore, it cannot be ruled out that the antidepressant effects of psychedelics can be derived from its ability to bind to and activate this type of receptor.

Additionally, extracellular glutamate levels are increased through stimulation of postsynaptic 5-HT2A receptors in deep cortical layers. Glutamate molecules can bind to NMDA and AMPA receptors leading to increased expression of brain-derived neurotrophic factor (BDNF). BNDF helps to support the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses.

Furthermore, strong evidence suggests that the modulation and expression of genes, which influences neural plasticity, are caused by activation of the 5-HT2A receptor. So, what does this mean?

Neural plasticity is defined as the ability of the nervous system to change its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, functions, or connections. This means that the brain has the ability to grow neurons and reorganize neural pathways between parts of the brain.

Ok, I’ll break it down for you a bit more. See neurons as growing telephone wires that communicate with one another. Following birth, to process all this new sensory information, nerve cells must make connections with one another and have to transmit the impulses to the brain. Continuing with the telephone wire analogy, like the basic telephone trunk lines strung between cities, the newborn’s genes instruct the “pathway” to the correct area of the brain from a particular nerve cell. As we age, the brain grows to send out multiple branches (axons, which send information out, and dendrites, which take in information) and it deletes old connections through a process called synaptic pruning. This process eliminates weaker synaptic contacts while stronger connections are kept and strengthened

So in short, it is plasticity that enables the process of developing and pruning connections, allowing the brain to adapt itself to its environment. Although plasticity occurs over an individual’s lifetime, it dominates mostly the time from birth to the age of 25.

So, let’s go back to the classic psychedelics. As mentioned above, activation of the 5-HT2A receptor in the brain results in neural plasticity. In the illustration below, you can see that the normal ‘sober’ brain organization is disrupted during a psychedelic trip, resulting in a greater repertoire of strong functional neural connections between different brain networks, which is in line with the “entropic brain” hypothesis under the psychedelic influence.

The brain has the capability to “rewire” brain networks in psychotherapeutic settings wherein patients focus and reflect on their inner self, during the psychedelic-induced mystical experience, to a pre-disease state, likewise, a computer system can be rebooted when its system is slow or unresponsive.

To put this more in perspective, think of your mind as a snow-covered hill and your thoughts are sleds. A path is pressed into the snow. It gets deeper and deeper and soon it’s hard to escape that groove. A psychedelic trip is the fresh snowfall that lets your sleds explore a new path. That could mean changing a deep-rooted behavior like an alcohol or smoking addiction or depressive thoughts.

What happens in the brain during a psychedelic trip?

Due to the increasing technological possibilities nowadays researchers can measure activity in the brain by using functional magnetic resonance imaging or functional MRI (fMRI). This technique measures brain activity by detecting changes associated with blood flow because neuronal activation and blood flow are coupled. This means that when a certain brain area is in use, blood flow to that region also increases.

The main focus of the first psychedelic studies using fMRI was to measure changes in functional connectivity and activity within and between so-called resting-state networks, with a particular interest in the default mode network (DMN).

The DMN is a large-scale brain network primarily composed of the medial prefrontal cortex, posterior cingulate cortex (PCC)/precuneus, and angular cortex. The DMN is active when the brain is at wakeful rest, such as during mind-wandering and daydreaming, or when the individual is thinking about others, thinking about themselves, remembering the past, and planning the future. Among people experiencing PTSD, lower connectivity and activity within the DMN was found whereas hyperactivity of the DMN characterized depression and anxiety.

Carhart-Harris and his team observed, as predicted, profound changes in consciousness after psilocybin administration, but even more surprisingly, only increases in blood flow were seen in key areas of resting-state networks namely the PCC, anterior cortex, and thalamus, while blood flow decreased in the other parts of the brain. Moreover, ratings of the subjective effects and peak (ego-dissolutive, or mystical) experiences correlates with a reduction in DMN connectivity. Research even suggests that the quality of these acute psychedelic peak experiences contribute to long-term changes in mental health, i.e. the greater mystical experience results in more lasting antidepressant responses.

A few years later, they measured a decreased connectivity within several resting-state networks while there was an increase in connectivity between networks, after the administration of LSD. They interpreted the finding as a transformation between “integration and segregation”, meaning that the integrity of the individual networks is “breaking down” while the categorization between networks is blurred. Therefore, they reported that a decreased connectivity within the DMN and a state of temporary loss of the sense of a self, a subjective drug effect called “ego dissolution” was a significant correlation.

Conclusion

To this day therapeutic treatments for mental health disorders do not produce the desired effect. Therefore, psychedelics should be considered as therapeutic treatment, which could lead to establishing a whole new dimension of medical research if these positive therapeutic effects continue to be validated by well-designed studies.

So how can psychedelics acutely eradicate mental health disorders in just one or a few treatments?

If we take a closer look at various mental health disorders and compare them, we see the same deep-rooted patterns of behavior. People with mental illnesses are often in this ruminating pattern of negative thinking or actions, like smoking. Eventually, they’re getting stuck in loops of thought and on narratives of who you are. The earlier mentioned brain circuitry, the DMN, who is responsible for constantly mulling over the past and future creating this narrow sense of self, seems to be the seat of the ego. In depression, activity in the DMN is increased and it’s decreased acutely with a psychedelic drug like psilocybin. By dissolving the ego you may dissolve the hold of narratives on people, realizing that you’re not identical to this annoying chattering voice in your head. This in combination with the psychedelic-induced neural plasticity could enable the individual to construct new patterns of thoughts and/or action within the DMN during this mystical experience.

Nevertheless, we’re still ways off from prescribing psychedelics just like we do with antidepressants. Much more research needs to be done. However, these drugs are unique. The effects of these compounds depend on where you take them, who you take them with, and what you want them to do. And I don’t think that these drugs are for everyone, but for a great many of us, they offer huge potential.

A statement made by Stanislav Grof, one of the pioneers of LSD-assisted psychotherapy in the ’80s, has never appeared so efficacious as today: “It does not seem to be an exaggeration to say that psychedelics, used responsibly and with proper caution, would be for psychiatry what the microscope is for biology and medicine or the telescope is for astronomy. These tools make it possible to study important processes that under normal circumstances are not available for direct observation”.

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