Benevolent anarchy in the brain

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.

The biochemistry of the mystical - of magical bike rides, dolphin linguists and hopes for depression patients

Our brain is our context tool, the biochemical and electrical machine that makes sense of our surroundings and integrates our behavior with that of other members of our species, mingling our past and current experiences into a state of being that we perceive as consciousness, as self.

The feeling of self includes the constant flow of sensorial inputs, which are run through our brains’ relevance filters and integrated with a stream of thoughts and emotions. Sometimes this stream transports happy feelings. Too often though, nagging worries drift along, and can accelerate into the unruly currents of anxiety and depression.

Some people have experienced a state that goes beyond the feeling of self – a so-called mystical experience of boundless and oneness, which can occur in nature, through meditation or religious ritual.

As spiritual as those mystical states might feel to the individual, they are – naturally - part of the brain biochemistry too.

The intersection of the feeling of self and the perceived mystical self-loss-experience is exemplified by the action of Lysergic acid diethylamide (LSD) and other psychedelic drugs.

“When you study natural science and the miracles of creation, if you don't turn into a mystic you are not a natural scientist.” Albert Hofmann once said.

The Suisse chemist worked at Sandoz Laboratories (now Novartis), where he synthesized a substance called LSD in 1938. Finding no immediate use for his discovery he let it rest for a couple of years before revisiting it in 1943, after he’d experienced a “peculiar presentiment”.

The ball began rolling, when he accidently ingested a bit of the substance, which led to what he described as a “not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination”.

Intrigued he consumed what he considered the smallest active (in reality quite decent dose) of 250 micrograms of LSD. What followed was a memorable bicycle trip that Hofmann took from the lab to his home. While at first, he was terrified and paranoid those feelings gave way to enjoyment of what he was experiencing. “Little by little I could begin to enjoy the unprecedented colors and plays of shapes that persisted behind my closed eyes.”

On that day, Hofmann discovered LSD was a psychedelic substance. It changed him forever.

He would later say:

“LSD is just a tool to turn us into what we’re supposed to be.”

He wasn’t the first to see this potential in psychedelics - for centuries, different native cultures had used substances such as “magic” mushrooms, mescaline or ayahuasca as tools in religious rituals, to enhance spirituality.

Invigorated by his bicycle-trip, Hofmann hoped that his new discovery would find uses for treatment of psychiatric patients. The idea was picked up quickly and a number of psychiatrists investigated the effects of LSD in psychiatric patients, many reporting benefits, but few living up to scientific standards that would make the results interpretable today.

While LSD flooded the Hippie movement and broadened (or at least altered) the consciousness of the flower-power generation, the drug didn’t find the accepted medical use as Hofmann had hoped for.

Meanwhile, the supposed transformative qualities of LSD spawned new lines of experimentation which contributed to the drug’s notoriety. From slipping LSD to ignorant subjects in the CIA’s MK Ultra program (which was supposed to defend against communistic mind-control techniques), to  NASA-founded experiment of interspecies (as preparation for extraterrestrial) communication. In the latter John Lilly (himself a fond LSD user) tried to communicate with dolphins and injected LSD into the animals – which luckily didn’t do any harm to them but also didn’t make them speak English. There is some more beef to the dolphin story that goes from absurd to sad, but that’s for another time…

When the summer of love came to an end, the idea that psychedelics where a means to cure mental illness and gain a higher state of reality, be it in psychotherapy or in a recreational setting, was dwindling. As another Hof(f)man(n) said - this time part time revolutionary Abbie Hoffman:

“The 60’s are gone, dope will never be as cheap, sex never as free, and the rock and roll never as great.”

At the end of the 1960s, the Drug Enforcement Administration classified LSD a controlled substance. Other psychedelics followed the same fate. Hofmann’s miracle drug had turned into his “problem child.”

Psychedelics lurked in the shadows for decades, not bothering many people except for recreational users and a few dedicated scientists, artists and drug policy reformers who hadn’t quite given up on the idea that psychedelics could hold benefit for humankind.

In recent years though, the concept of using psychedelics for treating patients with mental illness is slowly rejuvenated and starts reaching the mainstream media. A few reports showed that psychoactive and psychedelic drugs helped patients with depression, post-traumatic stress disorder and other psychiatric diseases when combined with talk therapy. Those studies go beyond the mountain of anecdotal evidence accumulated in the 1950s and 60s.

Does this mean we should all take LSD and we will live happily ever after? Likely not. There appear to be severe psychological risks to psychedelics and a bad trip might be just as transformative (in a negative way) as a good one. But maybe there is a chance to exploit the substances in a controlled setting for treatment of psychiatric diseases, and – who knows – for personal enlightenment.

First, though, we will have to gain a better understanding what LSD and other psychedelics do to the brain.

Tune in next Thursday for a discussion of recent results of bioimaging and behavioral studies, which try to decipher the complex action of psychedelics on the neurobiology of our brains.

Until then I leave you with another saying from Albert Hoffman, who died in 2008, witnessing only the beginnings of the recent upsurge in psychedelics research:

“I go back to where I came from, to where I was before I was born, that’s all.”

Awoken by a kiss – Snow-White moments in science

In times of the Corona Pandemic, where new evidence emerges that the Corona virus affects other organs including the brain, lets  revisit a case of an amazing awakening of people who had fallen into a frozen state for decades after contracting the sleeping sickness in the early 1900s.

Awoken by a kiss

In the fairytale, Snow-White, the king’s daughter, takes up a shared living arrangement with a bunch of dwarfs after a big row with her stepmom. When things have just started to look peachy in her new life, she makes the unwise decision to bite into a poisoned apple and falls into a state of deep sleep.

Her dwarfy roommates find her unresponsive, almost frozen and nothing they try can reanimate their lady pal. Instead they arrange a fancy glass coffin for her – a kind if slightly creepy gesture.

But then, a prince arrives, and he seems to have a special mojo going that the dwarfs lack, because he revives Snow-White with a single kiss.

So far, so Disney.

But what about real life?

Frozen

What if our own brain, the command center of our spaceship, the organ which turns us into the masters of our fates, our bodies, our minds, what if this decision hub stops functioning the way it is supposed to? What if it stops giving commands to the rest of the body, trapping the mind in a frozen shell like a prisoner in an isolation cell?  Is that how Snow White felt, while stuck in her glass coffin, dwarfs bustling about – present but unable to move, to communicate?

There are different conditions of the brain that can induce such a frozen state: catatonic schizophrenia, drugs such as MPTP and brain inflammation.

Awakening

The neurologist Oliver Sacks describes this true-life Snow-White story in his book Awakenings. In the late 1960s, Sacks  was physician to a group of patients who were in a permanently frozen state after a 1920 epidemic of Encephalitis Lethargica, a disease which was dubbed the “sleeping sickness” for putting its victims into a Snow-Whitesk sleep state.

Sacks treated the patients with massive doses of the then newly discovered L-DOPA, a drug that is a precursor to dopamine, and which still a mainstay treatment in Parkinson’s disease, where Dopamine is notoriously absent in specific brain regions. and some of them responded to the drug and returned back to life. In his book Sacks tells the moving story of those individuals who woke up with a 30-year gap in their lives – a story few fiction writers would dare to dream up because it seems too outrageous for anything but a fairy tale or a soap opera.

Happily ever after?

Alas, the story does not have a Disney style happy end and neither do most other L-Dopa stories.

The effects of the drug aren’t permanent and come at the cost of severe side effects.

Some of Sacks’ awakened patients fell back into their frozen state and others experienced severe side-effects and personality changes.

For most Parkinson’s patients the initial effects of L-Dopa wear off with time, and they start to experience so-called OFF periods, in which the drug effect is gone. There are a number of side-effects, the most notable being involuntary movements, so-called dyskinesia, but also hallucinations or cognitive impairments.

A tale without hope then?

I would disagree. Even if L-Dopa does not provide a happily ever after, even though it isn’t a true cure, a magic bullet, the drug still allows the afflicted patients a continuation or return to something resembling a normal life for much longer than would ever have been possible without the drug. 

Wanna read more on the topic?

I recommend Dr. Sacks’ book Awakenings (or if you’re not into books you could watch the 1990 movie with Robin Williams and Robert de Niro.

Another great book on the topic is Jon Palfreman’s Brainstorms, in which the author, a  journalist and Parkinson’s patient himself gives an overview of the disease background, history of Parkinson’s research and new treatment options.

Science fairy tales – Upcoming series

There are fairytales in science – and like the real, old-fashioned fairy tales they don’t always have a glossy finale, a kiss and a happily ever after.

There are tales in science that have a happy ending…

Those are tales of the moments of great discovery resulting from hard, year-long work or sometimes from pinch of serendipity – like the almost accidental discovery of Penicillin a drug that helped shaped the modern world by significantly contributing to the increase in life expectancy - from a meager 47 years at birth at the beginning of the 20th century to close to 80 years (in the US). A happy ending for the scientist Alexander Fleming (who’d forgotten to throw out his experimental plates before going on vacation), and a happy ending for humanity who suddenly had a new ally in the war against the microbial invaders.

There are darker tales too…

Dystopian scenarios introduce us to a world in which the scientific discovery feels like an already open Pandora’s box. One of the things that emerged from this box recently is gene editing, a technique that allows changing the genomes of species from mosquitos to humans in an unprecedentedly simple way, so simple in fact that you could do it at home with a preordered kit (if you are in a country which hasn’t banned the technology). A group of researchers who had discovered gene editing, the ones who had opened Pandora’s box, called for a moratorium on gene editing early on, before the public or politicians had caught wind of the potential dangers of the technology (we will read a lot more on gene editing in upcoming posts).

In equally dystopian scenarios the scientific discoveries that have protected us from hostile outside invaders that want to hijack our bodies – vaccines and antibiotics – fail due to human unwillingness to behave reasonably.

There are science tales that almost feel like horror stories…

Maybe one of the most gruesome stories of modern science is that of lobotomies, in which a steel spike (the most prominent lobotomist Walter Freeman later changed to icepicks) is pushed into a person’s frontal brain to cure all kinds of symptoms from depression to schizophrenia, often leaving patients devoid of the symptoms, but also devoid of anything that resembled their former personality. Thousands and thousands of lobotomies were performed and the scientific community (or at least a part of it) was so convinced of the merits of lobotomy that its discoverer Egas Moniz, even received the Noble Prize for it.

Next Friday, we’ll start the science fairy tale series with one of the happy Science Tales – a true Snow-White story in which frozen people can be awoken with a kiss (though no dwarfs will be involved)…