The Neuroanatomy of a Psychedelic Trip: The Basics

The Neuroanatomy of a Psychedelic Trip: The Basics

There’s a good chance that anyone reading this article has genuine interest in psychedelics. And there’s an even greater chances you’ve already done psychedelics. And now you want to know what was happening in your brain that made you feel connected with some ethereal entity. Or at the very least stared at the leaves of a tree for an enormous amount of time. So let’s talk about the neuroanatomy of a psychedelic trip. Specifically what happens in your brain when you take a psychedelic. You’ll learn a lot, I promise.

The subjective experience of psychedelics (the trip) is something we can all connect with. With modern psychedelic neuroscience we’re learning that they play an integral part in the treatment of anxiety, stress-related behavior, depression. Along with a mix of other cognitive states that have alluded modern pharmaceuticals and contemporary therapy. The effects of psychedelics have been a catalyst for a surge of much-needed research within the field of neuroscience.

The Role Of Neuroreceptors

If you’re familiar with the term ‘serotonin receptors’ then you’re already on your way. The majority of psychedelics you see today are serotonergic agonists. Which means they bind to serotonin receptors, or 5-HT2A receptors in your brain. This applies to the usual cast of characters: psilocybin, LSD, DMT, also known as tryptamines. MDMA (and the 2C family) falls under the category of phenethylamines, but has relatively the same neurological effects of tryptamines.

These two types of psychedelics mostly bind to 5-HT2A receptors. And to a lesser extent, other 5-HT receptors like 5-HT2B and 5-HT2C. These 5-HT2 receptors are generally responsible for a person’s well-being, stress, and anxiety levels. And they can also be implicated in degenerative diseases like Alzheimer’s, and neurodivergence like aspergers.

So How Do They Work With Psychedelics?

We also know when a person takes psychedelics, these receptors (which are mostly located in pyramidal neurons in the brain) tend to strengthen and rebuild almost instantly when these serotonergic agonists, or psychedelics, are introduced. This is called spinogenesis (the strengthening of spine dendrites in axons of these neurons) along with neurogenesis (the repair and restoration of these neurons).

This is important because things like daily stress, worrying, and rumination make these neurons atrophy. And when they atrophy, they lose their structural integrity. This is a direct link to larger problems like depression and PTSD. We’ll cover exactly how this happens later in the article.

There are instances in which a serotonergic agonist like LSD can be taken in such large amounts that it also becomes a dopaminergic agonist or that it binds to dopamine receptors. Usually, this behavior does not occur much with psychedelics.

However, it’s a common neurological process that happens when a person takes drugs with addiction capabilities — like cocaine, meth, nicotine, and alcohol. In fact, the brain activates dopamine when a person generally does anything addictive, like compulsive eating. Or even when listening to music.

The Neuroanatomy Of A Psychedelic Trip: Not All Psychedelics Are Serotonergic Agonists

The psychedelic ketamine operates on an entirely different neurochemical process. While most psychedelics embrace receptors, ketamine does the opposite and works as an antagonist, or a receptor blocker. Ketamine isn’t concerned with serotonin, but, instead focuses on the NMDA receptor — working as an NMDA antagonist compared with most other psychedelics, which are serotonergic agonists.

You can actually get a shot of Spravato, a ketamine inhaler, most likely at a ketamine clinic near you.

All of these receptors (5-HT2, DA, and NMDA) are part of the monoamine system, a group in which nearly all psychedelics fall under. Receptors are only a small part of a much larger neuroanatomical process that goes down when you take psychedelics. Now, let’s get familiar with these areas of the brain that are modulated by psychedelics — or die trying. Actually, it’s not that severe. Just learn these parts of the brain.

The Neuroanatomy Of A Psychedelic Trip: Diving Into The Brain

The brain has an enormous amount of parts like gyruses, ducts, sulcuses, fissures, fibres, lobes, decussations. All of which you don’t need to know for this article. While I think neuroanatomy is a blast, there’s absolutely no way you share the same enthusiasm. So we’re going to focus on very specific areas of the brain that are known to be activated (or deactivated) during psychedelics.

When it comes to monoamine receptors in the brain, your thalamus, amygdala, medial prefrontal cortex (mPFC) and the cingulate cortex is where a lot of the action happens. There are other parts of the brain that have these receptors like the hippocampus, but for an introduction to the neuroanatomy of a trip we won’t be discussing these areas. The length of this article would be bonkers if we explored every brain area affected by psychedelics. Eventually, we’ll address them all. But, for now, we’ll start with the basics.

Thalamus

Located deep within your brain is the thalamus. Which is undisputedly one of the most active parts of your brain when on psychedelics.

Your thalamus is an interesting area located next to your lateral ventricle. And it’s responsible for processing all stimuli that’s internal (signals within your body) and external (signals received outside your body, like from your environment). Since every stimulus goes through your thalamus, it serves as a ‘reality filter.’ It processes everything you see and feel. It then feeds it back to your brain to create a ‘perception.’

How Do Psychedelics Affect Your Thalamus?

Psychedelics have been shown to disrupt mechanisms of the thalamus. This can lead to what’s known as ‘sensory gating’ in the brain. Imagine you’re watching Netflix. And in the middle of a movie, the audio becomes delayed by a half-second while the video remains the same. This is fractionally insignificant when comparing it to the length of the movie. But this small sensory gating, or desynchronization will have a major effect on the movie itself. Now imagine reality as a movie and you can easily see how sensory gating will have a peculiar effect on perception. 

Another interesting attribute of psychedelics is that it decreases your cerebral blood flow (CBF) in your thalamus. You shouldn’t be that alarmed, the blood flow in your brain is always shifting depending on what cognitive tasks you’re undertaking. However while under psychedelics, the blood flowing in your thalamus decreases. The more it decreases, the stronger the subjective experience of the psychedelic becomes.

The Neuroanatomy Of A Psychedelic Trip: When There’s A Decrease In Cerebral Blood Flow, It’s Usually An Indicator Of A Decline In ‘Functional Connectivity’

Functional connectivity is a common term in psychedelic neuroscience. It is the relationship that two (or more) brain areas have with one other. Areas of our brain have ‘factory setting’ functional connectivity with other parts of the brain. An example of this would be the thalamus and the primary visual cortex. We use our eyes and visual cortex to see something. The thalamus filters everything including color, light, even orientation of objects, and feeds it to the rest of our brain. 

When the psychedelics hit, it decreases existing relationships (or functional connectivity) your thalamus has with familiar parts of the brain. While simultaneously increasing functional connectivity with new, more unfamiliar parts of the brain. Your thalamus (along with other areas) begins to slide in the DMs of other random parts of the brain and weird, temporary relationships begin to form over psychedelics. That’s also the story of your life.

Amygdala

The amygdala is a small part of your brain located around your temporal lobe next to your thalamus. It’s often referred to as one, but we actually have two of them lodged in our brain. It’s pretty tiny, but it’s like an all-star for psychedelic brain activity. With most parts of the brain, the amygdala’s purpose is multi-faceted. But our understanding of its function is primarily to process fear and emotional-behavior relating to fear. It’s an area one wouldn’t normally expect to be associated with psychedelics, but when a person is tripping, interesting things tend to happen.

Like the thalamus, a decrease of cerebral blood flow in the amygdala correlates with the intensity of a psychedelic trip. Robin Carhart-Harris saw this connection in his 2015 study at Imperial College London in which he used MDMA to shift cerebral blood flow of the amygdala. Just two years later, Carhart-Harris discovered that as cerebral blood flowed within the amygdala decreased, it also lowered symptoms of depression within an individual.

What Do Psychedelics Do To Fear-Processing Within The Amygdala?

Well, glad you asked. It’s actually been a focus of psychedelic neuroscience for over half a decade. And the research has been some of the wildest psychedelic studies I’ve ever seen.

In 2015, Rainer Kraehenmann from the University of Zurich wanted to see what psilocybin would do to the amygdala when participants were presented with the Positive and Negative Affect Schedule (PANAS). It’s basically a test to evaluate reactions to positive and negative stimuli. Researchers found that reactions to negative stimuli were lower compared to placebo. This also correlated with an overall increase of positive mood within a person. They were vibing to the point where bad things just didn’t affect them as much.

Patients with anxiety (and anxiety-induced depression) generally show a higher amygdala response to fearful faces. Selective serotonin reuptake inhibitors (SSRI) drugs (like Prozac and Zoloft) combat that effect in the amygdala by suppressing amygdala activity, which lowers emotional responses to fearful faces (along with other fear-based stimuli).

In 2018, Imperial College London’s Leor Roseman administered psilocybin to people with treatment-resistant depression and surprisingly found that amygdala activity in response to fearful faces is heightened, which also correlated with a decrease in depression. This indicates that unlike SSRIs, psychedelics (combined with psychological support after the trip) helps a person confront negative stimuli and work through the experience for a positive therapeutic result. The same effects on the amygdala also tend to appear with LSD.

Cingulate Cortex

The cingulate cortex lays in the posterior (back) and the anterior (front). And it covers another part of your brain called the corpus callosum. Which lies basically in the center of your head. Along with the amygdala, it’s part of the ‘limbic system.’

And the cingulate cortex is mostly responsible for regulating behavior, emotional response, and decision making. When it comes to psychedelics, the cingulate cortex is responsible for what neuroscientists call ‘oceanic boundlessness.’ 

The Neuroanatomy Of A Psychedelic Trip: The Cingulate Cortex Is Where It All Goes Down

First off, there’s an incredibly high amount of 5-HT2A receptors located in the cingulate cortex. Which makes it a hotspot for psychedelic activity. The cingulate cortex also shows a very high sensitivity to LSD. Primarily when assessed with a scale called the ‘Perturbational Integration Latency Index’ (PILI). It’s a pretty extravagant name. But it’s designed to determine the difference between an ordered brain state (or equilibrium), and brain states of absolute chaos. If you’re wondering, the cingulate cortex on psychedelics tends to go towards a state of unconstrained chaos.

Most of this ‘chaos’ lies in how the cingulate cortex talks to the other parts of the brain, specifically the medial prefrontal cortex.

Normally these two parts of the brain have a pretty tight relationship and are always communicating with each other.

When a person takes a serotonergic agonist like psilocybin, the cingulate cortex and the medial prefrontal cortex do a thing called ‘decoupling.’

This means they’ve stopped talking to each other, left each other on read, and are talking to other parts of the brain, chaotically.

Normally this decoupling wouldn’t cause any alarm, in fact it’s a pretty common thing within the brain. However, when the cingulate cortex decouples from the medial prefrontal cortex during a psychedelic trip, it leads to an ego-dissolution. Ego dissolution (or oceanic boundlessness) is the sense of ‘self’ dissolving into your environment — or, in some cases, the entire universe.

The Ayahuasca Study

Before we leave the cingulate cortex for our next brain area, I need to tell you about one of the wildest psychedelic studies I’ve ever read, and it just so happens to involve the cingulate cortex. In 2015, José Carlos Bouso wanted to evaluate what effects ayahuasca had on the brain. When seeking participants for studies like this, the usual criteria is to find a person that has a little familiarity with psychedelics. However, having ‘little familiarity’ just wasn’t enough for Bouso. His study came with one requirement: Participants did ayahuasca fifty times in a two-year span. 

I’ll repeat that. The requirement was at least fifty ayahuasca trips in the span of only two years. Everyone reading this just lost their psychonaut card.

That’s like having an ayahuasca experience every other week for two years straight. He looked at the size of each participants’ cingulate cortex compared to people that never tried ayahuasca. What he found with people that dosed on ayahuasca was that their cingulate cortex was thicker on the anterior part but thinner on the posterior. What’s even more shocking is despite these clear structural differences, researchers did not find any decreased neuropsychological performance in the participants. They were all cognitively-healthy people. In fact it appeared ayahuasca helped them overcome maladaptive behavior, like addiction.

The Neuroanatomy Of A Psychedelic Trip: Medial Prefrontal Cortex

The Medial Prefrontal Cortex (mPFC), sometimes just referred to as the medial frontal cortex. And it has been a neuroscientific goldmine for scientists studying psychedelics over the past few years. Like its name implies, the mPFC is located right in the front of your brain, just above your eyes — your forehead essentially.

Unlike the other parts of the brain, the mPFC shows its highest activity when a person is at rest. We don’t fully know its purpose. However, one theory is that it involves things like contemplation, long-term memory retrieval, and decision making.

If you’ve made it this far, then you know the mPFC loves talking to the cingulate cortex. And when you take psychedelics this relationship goes haywire. There’s actually lots going on with the mPFC under psychedelics — and you’ll have no choice but to learn about them below.

The Neuroanatomy Of A Psychedelic Trip: When Did We First Learn About The mPFC?

We first discovered that the medial prefrontal cortex had anything to do with psychedelics in 2008. Back then scientists used DOI (2,5-dimethoxy-4-iodoamphetamine), a Shulgin synthesized psychedelic to administer the effects of serotonergic agonists on lab rats. If you’re human, the only reason to take DOI is if you want to trip sleeplessly for twenty-four hours. Because that’s exactly what it does. The study was groundbreaking in that it showed psychedelics will disrupt the mPFC, along with the pyramidal cells within the area, the same neurons that are usually serotonin (5-HT2A) receptors in the brain.

What About Since Then?

Since that study, there have been other experiments to determine the function of mPFC under psychedelics. Notably, by Robin Carhart-Harris in 2012, showing a decrease in functional connectivity of the prefrontal cortex when the intensity of a psilocybin trip hit. This effect gains support from a 2018 study by Maurizio S. Riga, showing a decrease in ‘neural oscillations’ within the mPFC while having a psychedelic experience under 5-MeO-DMT. Neural oscillations are basically the result of neuronal activity in the brain. Similar to how a person’s voice is the end result of that person communicating with you. 

Now that we know the medial prefrontal cortex is largely responsible for the subjective experience of a psychedelic trip, which therapeutic effects (if any) lie within this mPFC neural chaos? Is it just about seeing fancy colors and fractal shapes? Well, it just so happens the most significant neuroscience study on psychedelics’ interaction within the mPFC happened in 2021. And it has undoubtedly changed how we view psychedelics forever. 

If there’s one person you need to remember from this article on the neuroanatomy of a psychedelic trip, it’s Yale University’s Ling-Xiao Shao.

Before her paradigm-shifting study published this April, it was theorized that psychedelics may have a role in a process called neurogenesis. Basically neurogenesis is the growth and repair of neurons in the brain. This is an idea that has been associated with psychedelics’ role in certain parts of the brain, but never fully understood or realized. Shao’s historic study showed that psilocybin, through the interaction of 5-HT2A receptors, causes neurogenesis in the brain, specifically spinogenesis, as it repairs, strengthens, and grows dendritic spines within pyramidal cells.

This Sounds Amazing, But What Does It Actually Mean? 

Mental states like depression, anxiety, PTSD have been shown to atrophy neurons in the medial prefrontal cortex. This weakening of dendrites within these neurons (along with other neuroanatomical structures) happen when stressors occur in a person’s life. Whether it’s the dread of a Monday office workload or ongoing trauma from a relationship, stressors tend to hammer mPFC neurons which may lead to larger cognitive problems. However stress wrecking a person’s mental well being isn’t a new idea. It’s an overarching theme in most mental-wellness therapy.

Shao’s work showed that by physically repairing the biological evidence of stress (like weakened dendrite spines within neurons), it directly correlates to an improvement of certain maladaptive cognitive states (like depression and chronic stress).

Just like repairing tires worn down from daily wear-and-tear makes a car run smoother.

Likewise, almost immediately after neurons get an introduction to psilocybin, a variety of beneficial effects on the brain occur.

The growth of these neurons continues to happen at least a day after taking psilocybin. And this growth could remain days, weeks, even months after the initial trip. This neuronal growth also correlates with the subjective experience after the trip. Or the ‘afterglow’, as it is colloquially referred to in psychedelics. Afterglow is a timeline after a psychedelic experience long theorized to have therapeutic benefits for an individual. During this period people reportedly have a decline in anxiety. And, in some instances, experiences so transformative that it forces a complete redefinition of ethics and morals.

The Neuroanatomy Of A Psychedelic Trip – In Conclusion 

That’s a lot to take in, so be proud of making it this far. There is a secret though that I’ve been hiding from you this entire time. There are many areas of the brain I could have selected. But all the ones in this article actually work in tandem in brain networks like the Default Mode Network (DMN). Psychedelics also affect these wide-scale neural networks. And they have revealed further new neurological mechanisms of what happens to our brain under psychedelics.

We can’t venture into brain networks like the DMN, Salience Network, or the Frontoparietal Network (aka the Central Executive Network). We’ve shared entirely too much time together with this article. You have things to do — so do I. However, you now have just a little more knowledge on how the brain interacts with psychedelics. Don’t worry, ‘The Neuroanatomy of a Psychedelic Trip: Brain Networks’ will be coming soon.

RELATED: The Neuroanatomy Of A Psychedelic Trip: Brain Networks

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Zeus Tipado

View all posts by Zeus Tipado

Zeus Tipado is a neuroscientist based out of Los Angeles, California. He’s the founder of Stonedgamer and Middleeasy, and co-producer/host of Doubleblind’s ‘How To Use Psychedelics’ course. His published work has appeared in High Times Magazine, MERRY JANE, and Psychedelics Today. He received his Mphil from the University of South Wales and will start his PhD in Neuroscience with a focus in psychedelics in 2022. You can reach him on Twitter, Instagram, and Twitch.

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Comments (1)

  • Connie James
    October 20, 2021 at 3:46 pm Reply

    Is this in medical research protocol?

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