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Enter TrkB: Understanding the Study that Shook Psychedelic Science

The psychedelic science scene ignited earlier this year with a study published in February from the David Olson lab that showed the anti-depressant and neuroplasticity effects of psychedelics occurred not because of serotonin receptors on neurons, but within the neurons themselves. It was groundbreaking research that sent a shockwave to scientists everywhere; and less than four months after this monumental discovery, another remarkable discovery appeared. One that comes to a completely different conclusion on how psychedelics’ anti-depressant effects occur. A theory so revolutionary that the entire idea of serotonin takes backseat to something known as TrkB.


A quick neuropsychopharmacology refresher

The idea that the neuromodulator ‘serotonin’ (along with its receptor 5-HT2A) served as the catalyst for the reported beneficial effects of psychedelics has been a foundational understanding in neuropsychopharmacology for over two decades. As a reminder, serotonin is the neuromodulator that’s released when a person consumes classical psychedelics (MDMA, LSD, DMT, psilocybin…etc). It attaches to 5-HT2A receptors (also known as serotonin receptors) in the brain.

A good way to understand this process is to imagine serotonin as little keys that float in your brain as a result from taking – in this example – a tab of LSD. With all keys, there exists a lock which will only open with that specific key. These are what 5-HT2A receptors are: locks located in various parts of your brain that, when ‘opened’ with serotonin, will do some interesting things to the brain. These ‘interesting things’ are still being discovered. For example, areas of the brain known as subcortical regions (like the thalamus, claustrum, amygdala) are densely packed with 5-HT2A receptors and are in constant communication with cortical regions – which are mostly sensory areas of our brain. These sensory areas (visual cortex, auditory cortex) are how we experience our external world. They’re also the wrinkly surface area that people mostly associate with the appearance of the brain.

When a person is not on psychedelics, these subcortical and cortical regions have a pretty steady communication. Things we see in our world go through our eyes to subcortical regions to get processed, then to cortical regions to be experienced. This is a pretty consistent and reliable process that your brain has been doing ever since you were born. However, when psychedelics are introduced, things get a little strange.

Taking a sub-perceptual dose of psychedelics can be as effective as a placebo.

Essentially, psychedelics disrupt the communication between your brain’s subcortical and cortical areas. Sensory information that’s designated to go to certain cortical areas is jumbled and end up in places where it normally wouldn’t go. It’s believed this bizarre process is what causes a series of other interesting phenomena, like the destabilization of entire brain systems, which causes systems to lose integrity. In fact, entire psychedelic neuroscience theories have been constructed about this process, including Carhart-Harris’ Relaxed Beliefs Under Psychedelics (REBUS) model, Katrin Preller’s cortico–striato–thalamo-cortical (CSTC) theory, and Manoj Doss’ cortico-claustro-cortical (CCC) model.

Psychedelic trips have often been associated and correlated with reported therapeutic benefits. Nearly all human studies show that an acute (or normal/large) dose of psychedelics result in positive antidepressant benefits and a reduction of maladaptive behaviour. Essentially, trip hard, heal harder. Many scientists believe that these antidepressant ‘healing’ properties were due to 5-HT2A brain activity, along with the experience of the psychedelic trip that follows. In fact, the idea that ‘the intensity of the trip correlates with the positive benefits of psychedelics’ is something that is widely believed in the neuropsychopharmacology field. The trip being a key component in the general increase in well-being also explains why something like microdosing, which is the practice of taking a sub perceptual amount of psychedelics, is only as effective as placebo.

The reason why many believe microdosing works as well as placebo is due to a study that emerged from Imperial College London in 2021. In this pivotal placebo-controlled study (which is still the largest university-led psychedelic study in history), 191 participants could choose between a microdose of LSD or psilocybin, and then self-administered a microdosing regime for four weeks. What was found was that people reported relatively the same positive benefits of microdosing psychedelics when also taking the placebo. This illustrated the sheer act of believing one is getting better perhaps overwhelms any beneficial property that could be obtained from a microdosed, sub-perceptual, amount of psychedelics.

However, what if the beneficial antidepressant properties of psychedelics were not reliant on serotonin receptors and perhaps a new receptor system entirely? A receptor unlike serotonin that doesn’t produce a psychedelic trip, but still creates all these benefits? Enter the TrkB receptor!

TrkB stands for Tropomyosin Receptor Kinase B. It’s the receptor of a substance in our body called Brain-Derived Neurotrophic Factor (BDNF). It’s the neurotrophin in our blood that appears to be responsible for neuroplasticity, anti-neuroinflammation, and the normalization of neuronal communication. These are crucial features for a healthy brain. We have data that shows that psychedelics tend to increase the concentration of BDNF. Even sub perceptual low-dose and microdose amounts of psychedelics appear to increase BDNF (interestingly enough, it seems ketamine actually decreases BDNF). It’s important to note that BDNF is important for the maintenance and restructuralization of neurons which allows neurons to form new connections, a vital action for memory and new learned behaviour.

The idea that TrkB being the receptor for BDNF isn’t necessarily a new discovery. It’s something that we’ve known in neuroscience since 1991, just nine years after the discovery of BDNF. However, thanks to a new groundbreaking study by researchers at the University of Helsinki, we now know that psychedelics have an incredibly high affinity to binding with TrkB receptors.

Psychedelics have an incredibly high affinity to binding with TrkB receptors.

Exactly how high?

In this study, it’s reported that LSD and psilocybin bind to TrkB receptors about 1,000 times better than standard antidepressants like Prozac (fluoxetine). This incredibly high TrkB binding by LSD and psilocybin could explain why psychedelics have the unique ability to aid in treatment-resistant depression – essentially depression that isn’t alleviated through antidepressants prescription. Another remarkable discovery that aligns with our current understanding of TrkB is that researchers also discovered that LSD and psilocybin bind to TrkB at a rate that’s 1,000 times higher than ketamine. This revelation makes sense considering research shows that acute or chronic use of ketamine actually reduces the amount of BDNF present.

Consequentially, this discovery should make every ketamine infusion clinic a bit concerned. This University of Helsinki study corroborates a wider understanding that BDNF is not increased (perhaps even decreased) by ketamine infusions.

Keep in mind that these classical psychedelics are serotonergic agonists, which means even though they may bind to TrkB, psychedelics still have a strong binding affinity to serotonin receptors. Theoretically, the beneficial TrkB effects we desire may still be reliant on serotonin activation in the brain. The only way to determine this would be to block all activation of serotonin receptors in the brain to determine if psychedelics would still bind to TrkB.

Fortunately, these researchers did just that.

Through the administration of ketanserin, a serotonin antagonist that blocks all neuronal binding of serotonin by psychedelics, these researchers still saw an increase in TrkB activation that was completely independent of serotonin!

Since TrkB is non-psychedelic, this suggests that antidepressant effects of psychedelics may not be so reliant on serotonin activation along with the psychedelic trip that follows as much as we thought. In fact, it appears these antidepressant effects aren’t reliant on the trip at all. Something that many start-up pharmaceutical companies have wanted for years.


What does this mean?

If the psychedelic effect of psychedelics can be removed, leaving only the antidepressant effects, we’ve successfully built a case for the regulation of new non-psychoactive compounds, while keeping traditional psychedelics under control.

Is this the smoking non-psychoactive gun some have been waiting for? While this research is wildly intriguing, drawing any concrete conclusions from this study is still premature. For example, the Helsinki study used rodents to determine the neurological mechanisms of psychedelics’ TrkB binding. There is no clinical research that shows any of this applies to humans. Another interesting note: we are only aware of mice experiencing a psychedelic trip by how much their head twitches after administration. This head-twitch behaviour has never been seen in humans (yet).

One of the more interesting things from this study begs the question: what happens if we remove all TrkB/BDNF activation from the psychedelic itself? Imagine we completely remove all of the hypothesized, neurologically beneficial aspects of these substances. What would happen if one were just left with the raw, subjective psychedelic experience? Are we able to handle these intense psychedelic trips only due to it being accompanied by antidepressant effects of TrKB activation?

If we wanted to test this theory, there is one TrkB antagonist, ANA-12, that appears to be safe in humans and would produce a central blockage of the receptor in a relatively short time. When tested in animals, blocking TrkB produced antidepressant effects. This is a surprising find, one that is completely counterintuitive to everything that was just discussed. In relation to cognitive benefits in animals, ANA-12 appears to block cognitive enhancement effects that are obtained from environmental enrichment, a finding that could be translated into how setting influences the psychedelic experience. However, making that connection would require another article entirely.

Once again, congratulations to the researchers at the University of Helsinki for, at the very least, pushing the boundaries of psychedelic scientific thought. Their TrkB find is intriguing not just for its potential to have neurological beneficial properties within psychedelics, but also to help imagine the idea of the psychedelic experience existing without these proposed antidepressant benefits. While their results may conflict with existing studies, science progresses when it’s first questioned, then rigorously tested.

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