Let’s take up, where we left off in the last post in which I discussed, Albert Hoffman’s discovery: the psychedelic drug LSD and its decades-long roller coaster ride, from high hopes for using it as a drug to treat psychiatric patients in the 1950s and 60s, over the flood of psychedelic enlightenment seekers in Hippie era, to its misappropriation for the CIA’s notorious MK-Ultra program, and finally its second spring as an experimental psychiatric drug.

After seven decades of LSD use, a huge pile of biomedical data accumulated, measuring what happens in the human brain under influence of psychedelics.

Enough to make sense of the psychedelic experience?

Brain company Inc

To appreciate the potential of the psychedelic drugs, we must take a step back and try to understand how they modify our brains. But in order to comprehend this, we need to take another step back and take a deeper look at the functional architecture of the brain.

When trying to explain the workings of the brain, I’m going to use the metaphor of a midsize company - let’s see how well this will play out.

On the highest level, we have the company itself, which is perceived as a single entity by outside observers, as well as by its own, individual units. In the brain this translates into macrolevel consciousness or feeling of self. 

One level lower, we have the individual divisions that deal with separate functions, like accounting, sales and so on. In the brain, those macrostructures are the areas that are assigned to different functionalities, such as speech. Their work isn’t entirely separate, often multiple areas partake in the same function. If one of those areas is damaged and drops off - like if everyone from accounting went out for lunch, had a bad burrito and none of them shows up for work the next day - one of the other departments, like the folks from marketing, can take over, though it might take them some time to learn the ropes. The same kind of functional take-over can happen in the brains of patients with brain areas that are damaged (for example after a stroke or head trauma) or underused (for example for patients losing a primary sense – such as vision)– a phenomenon called rewiring or neuroplasticity.

A further step down, we reach the molecular level, let’s say the company’s individual employees and their interactions. In the brain those are the signaling molecules (neurotransmitters) and the receptors they bind. Changes on this molecular level can backfire to the whole apparatus if they are magnified – think a single colleague is writing an email disclosing personal secrets of the boss to another person and soon everyone in the company knows all about it.

Small changes with big impact – the molecular level

We’ll start the psychedelic journey through the brain by zooming into the molecular level - the level of direct interaction between the psychedelic molecule and an individual unit of the brain architecture, a receptor.

LSD and other psychedelics bind different receptors in the brain, but one of them stands out from the crowd: the Serotonin-2-A receptor.

What does this Serotonin-2-A receptor do? Serotonin is an ancient molecule (already present in singe cell organisms), with diverse roles in and outside the brain. It is a neurotransmitter from the monoamine group, which are master modulators of the brain’s communication systems – one could say, they are in charge of the company’s mailing lists. Those neurotransmitters are involved in virtually all brain functions. Unsurprisingly if there is too much or too little of them, complications arise in the brain and can lead to psychiatric disorders, just like too much or too little, or too untargeted communication might hurt the organization of our company.

Lack of brain serotonin is linked to depression and anxiety. The major class of antidepressants, so-called selective serotonin reuptake inhibitors, such as Prozac function by raising levels of serotonin in the brain. Deregulation of the serotonergic system has also been linked to schizophrenia, and indeed, LSD was considered a means of inducing an artificial psychosis in the early days of its use, though its effect seems to capture only certain aspects of the disease.

Binding to the Serotonin-2-A receptor appears crucial for the psychedelic impact on the brain, a fact strengthened by the observation that an antagonist the Serotonin-2-A receptor (a drug that does the opposite of LSD), a molecule called ketanserin, abolishes all subjective psychedelic effects in humans on LSD.  Those effects include visual changes such as hallucinations or distortions but also changes in thoughts and emotions, up to the loss of self feeling.

Interestingly, the effects that psychedelics have on individual brain cells might be more than a short-term occurrence. Different studies have shown that psychedelics cause lasting changes in cortical neurons of mice – so-called neuroplasticity that we discussed earlier (like if the marketing department permanently took over some of the accounting functions). In the case of a psychedelics experience that doesn’t mean that the acute effects lasts longer than the actual trip, though it might mean that the transformations that are made during the trip – good or bad – can be permanently etched into the brain. It remains to be seen if this phenomenon seen in mice translates into humans, but it could be an explanation for sometimes described psychedelic ‘miracle cures’ for OCD or alcoholism.

Trying to grasp the bigger picture – the macro level

There are a number of newer brain imaging and connectivity studies that give hints to which areas and networks in the brain are altered by psychedelic influence. The results of those studies, however, often contradict one another and none of the current working models is supported by all available evidence. Of course, variations in dose and type of psychedelic used, as well as other parameter such as the exact brain imaging methods, and the type of study subjects (healthy volunteers or psychiatric patients) account for at least some of the incongruity.

One common observation is that psychedelics make the brain more anarchical – they increase its entropy. In our company one could imagine a breakdown of the rigid structures into different division and everyone in the company just does whatever they feel like that day.

There are different hypotheses for how this state of messiness arises in the brain, which don’t necessarily contradict one another.

One idea is that the filtering of input that reaches the higher command center, the prefrontal cortex by a structure called the thalamus is reduced. Subsequently, there is less top-down and more bottom-up processing, meaning there is a higher level of sensory input in the prefrontal cortex, which leads to increased blood flow and could finally be responsible for sensory changes, changed cognition and ego dissolution. While it was originally thought that this causes a completely untargeted bombardment with sensory stimuli, there are newer studies that show that there seems to be a certain level of targeting, for which areas in the cortex receive more information. On the example of our company this would mean that only certain, instead of all departments get the spam filter removed from their email programs.

Another working model that is supported by some of the current studies is that LSD and other psychedelics reduce the activity or connectivity of the so-called default mode network. The default mode network is a large-scale brain network involved in introspective thinking, including negative patterns such as self-criticism and ruminating thoughts, which is thought to be overactive in depression and anxiety.

Overall, psychedelic-induced disordering or reordering of the brain could unhinge negative patterns, be it by changes in filtering, changes in blood supply or rewiring.

I would imagine the effect in a way that is similar to rebooting a computer, a proven solution that has solved many of my IT issues.  

Let’s continue next time with one last post on psychedelics and try to shed light on the question how those molecular and macrolevel changes reflect to the management level, the feeling of self that seems to be so drastically altered during and sometimes after the psychedelic experience and how this might translate into treatments for psychiatric patients.