The Serotonergic System: How the Body Interacts with Psychedelics

In recent years, the field of psychedelic research has undergone a significant revival, historically referred to as "hallucinogens" or "psychotomimetics," these substances—psilocybin, LSD, DMT, mescaline, and others—are now being reconsidered not just for their ability to alter perception, but for their profound therapeutic potential.

What makes this resurgence particularly compelling is not only the breadth of conditions these substances may address, like aiding in the treatment of depression, PTSD, and anxiety, but also the lasting psychological effects observed in 'healthy' individuals.

Central to these discoveries is the role of the serotonergic system, specifically how psychedelics target serotonin receptors—most notably the 5-HT2A receptor. This article will delve into the anatomy and physiology of the serotonergic system, explain its role, and explore how different psychedelics interact within the system.

What Is the Serotonergic System?

The serotonergic system is a network of neurons, receptors, and neurotransmitters, primarily responsible for regulating the release and activity of serotonin.

Serotonin, or 5-hydroxytryptamine (5-HT), influences everything from sleep and appetite to emotional well-being and sensory processing. It plays a crucial role in mood, cognition, and sensory perception and is synthesized in the brain and intestines.

The serotonergic system is primarily composed of:

1. Serotonin (5-HT): The neurotransmitter that acts as a signaling molecule.

   1. Serotonin plays a role in:

      • Mood regulation: It is often called the "feel-good" neurotransmitter because of its significant influence on mood, happiness, and anxiety levels.

      • Perception: Serotonin affects how we perceive sensory input, which is a major factor in psychedelic experiences.

      • Appetite: It helps control hunger and digestion.

      • Sleep: Serotonin regulates sleep cycles, particularly the initiation of sleep.

      • Cognition: It is involved in memory, decision-making, and learning.

2. Serotonin Receptors: Specialized receptors that bind serotonin and trigger specific cellular responses.

3. Neurons: Nerve cells that release and reabsorb serotonin, helping to transmit signals throughout the brain and body.

Key Components of the Serotonergic System

1. Serotonin (5-HT)

Serotonin is synthesized from the amino acid tryptophan. Once produced, serotonin is stored in vesicles within neurons until it is released into the synaptic cleft (the space between neurons) to bind with specific receptors. Once serotonin has delivered its signal, it is either broken down by enzymes or reabsorbed back into the neuron, a process known as reuptake, this will be important for later.

2. Serotonin Receptors

Serotonin exerts its effects by binding to specific receptors located throughout the brain and body. There are at least seven major types, labeled 5-HT1 through 5-HT7, and each subtype has a different function.

Psychedelics primarily affect the 5-HT2A receptor, which is responsible for many of the characteristic effects of these substances: changes in mood, perception, and consciousness.

The most relevant serotonin receptors for psychedelic experiences are:

• 5-HT2A Receptors: highly concentrated in regions of the brain responsible for cognition, perception, and emotional regulation, such as the prefrontal cortex and visual cortex. The 5-HT2A receptors is largely responsible for the hallucinogenic and perception-altering effects of psychedelics.

• 5-HT1A Receptors: plays a role in regulating mood and anxiety. These receptors are involved in the anti-depressant and anxiolytic (anxiety-reducing) effects of some psychedelics.

• 5-HT2C Receptors: linked to appetite regulation, mood control, and maybe contribute to some of the emotional effects of psychedelics.

3. Neurons and the Synaptic Cleft

The neurons that release serotonin are called serotonergic neurons. They are primarily located in the raphe nuclei, a cluster of neurons in the brainstem and project throughout the brain, including the prefrontal cortex, amygdala, and hippocampus.

When serotonergic neurons release serotonin into the synaptic cleft, it binds to serotonin receptors on neighboring neurons, activating them. This process is tightly regulated by enzymes that break down serotonin and by transporters that reabsorb it into the neurons for reuse.

How Psychedelics Interact with the Serotonergic System

Most classical psychedelics, including psilocybin (magic mushrooms), LSD (lysergic acid diethylamide), and DMT (dimethyltryptamine), are 5-HT2A receptor agonists.

This means that they bind to and activate the 5-HT2A receptors, mimicking serotonin but in a much more potent and sustained way. By doing so, psychedelics alter the way information is processed in the brain, leading to the altered states of consciousness, sensory distortions, and intense emotional experiences associated with these substances.

Here's the basics of interaction:

1. Psilocybin

Psilocybin is converted to psilocin in the liver, gets absorbed into the bloodstream, passes the BBB (blood-brain barrier) and, due to its similar chemical structure to serotonin, binds to 5-HT2A receptors.

This amplifies neural communication, especially in areas responsible for perception and emotional processing, leading to hallucinations, emotional insights, and a sense of interconnectedness.

• Effect on Perception: Activation of the 5-HT2A receptors in the visual and auditory cortices causes visual and auditory distortions or hallucinations.

• Effect on Mood: interaction with serotonin receptors in the prefrontal cortex and limbic system can lead to heightened emotions and mood changes (euphoria or emotional release).

2. LSD

LSD binds strongly to 5-HT2A receptors, along with several other serotonin receptor subtypes, including 5-HT1A and 5-HT2C. Due to its more expansive interaction within the system and chemical makeup, LSD's effects last much longer than psilocybin, often up to 12 hours.

• Effect on Cognition: By binding to 5-HT2A receptors in the prefrontal cortex, LSD can significantly alter thought patterns, hence the hallmark trait of enhanced creativity, introspection, and altered sense of self.

• Effect on Time Perception: affects the brain’s default mode network (DMN), disrupting normal patterns of thinking and time perception, which accounts for the sense of time dilation.

3. DMT

DMT’s effects are much shorter (yet more intense) in comparison to other psychedelics, often lasting only 10 to 30 minutes. It has a high affinity for the 5-HT2A receptor, the 5-HT2C receptor, though the role of this interaction in its psychoactive effects is less well-understood, and the 5-HT1A receptor, which may contribute to the modulation of mood and anxiety that some users report.

• Effect on Consciousness: activation of 5-HT2A receptors leads to deep, immersive visionary experiences, often described as entering alternate realities.

• Effect on Memory and Learning: DMT has been found to temporarily weaken the brain’s DMN, allowing users to access new ways of thinking and perceiving the world.

4. MDMA (Ecstasy)

While not a classical psychedelic, MDMA acts primarily by increasing the release of serotonin from neurons, leading to high levels of serotonin in the brain and why it's known to have euphoric and empathogenic (empathy-enhancing) effects.

• Effect on Emotions: MDMA floods the brain with serotonin, particularly affecting 5-HT1A receptors, resulting in feelings of connection, empathy, and emotional openness.

• Effect on Trauma Processing: Because of its ability to reduce fear and enhance emotional closeness, MDMA is being studied as a treatment for PTSD to helps patients process trauma in a therapeutic setting.

The Role of Serotonin in Psychedelic Experiences

As you can probably tell by now, serotonin is central to the psychedelic experience because of its role in regulating perception, emotion, and cognition.

Psychedelics can enhance or distort sensory input thus creating visual patterns, vivid imagery, and altered sounds. Many users report a loss of the sense of self or ego, where they feel a deep connection to everything around them (thought to be caused by the disruption of the brain's DMN). And by altering serotonin levels and receptor activity, psychedelics often lead to deep emotional insights and the processing of suppressed emotions.

It may be a controversial approach to the future of therapeutic care but with all these properties and potential benefits of utilizing psychedelics, it's clear to understand why researchers are entertaining the possibility of them in alternative treatment for especially tough cases of PTSD, depression, anxiety, stress, and more.

Conclusion

As psychedelic research continues to evolve, studies, like those from the Icahn School of Medicine at Mount Sinai, are shedding light on the mechanisms that underlie the therapeutic potential of psychedelic substances.

Their recent findings illustrate how psychedelics such as LSD and 5-MeO-DMT not only engage the well-known 5-HT2A serotonin receptor but also activate the 5-HT1A receptor, a promising target for treating depression and anxiety.

This opens the door to an entirely different looking future for therapeutic treatment options. As noted by lead researcher Audrey Warren, this ability to "fine-tune" psychedelic compounds could revolutionize mental health care.

As always, please consult with your main medical wellness practitioner before you take any next steps further. We do not have all the answers but hope this small glimpse into the serotonergic system was helpful for you to understand a bit more about the interplays between you and these plants.

Thank you and safe travels.

References:

Hanks, James B., and Charles D. Nichols. "Psychedelics as Medicines: The Promise of Serotonergic Hallucinogens." Neuropharmacology, vol. 142, 2018, pp. 1-14. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136989/. Accessed 7 Sept. 2024.

"Mount Sinai Scientists Unravel How Psychedelic Drugs Interact with Serotonin Receptors to Potentially Produce Therapeutic Benefits." Mount Sinai, 8 May 2024, https://www.mountsinai.org/about/newsroom/2024/mount-sinai-scientists-unravel-how-psychedelic-drugs-interact-with-serotonin-receptors-to-potentially-produce-therapeutic-benefits. Accessed 7 Sept. 2024.

"Serotonergic Psychedelic." ScienceDirect, Elsevier, https://www.sciencedirect.com/topics/neuroscience/serotonergic-psychedelic. Accessed 7 Sept. 2024.

Swanson, Larry R. "Unifying Theories of Psychedelic Drug Effects." Frontiers in Pharmacology, vol. 9, 2018, PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756147/. Accessed 7 Sept. 2024.