We’ve spent some time already on the definition of psychedelic – and we’ll spend more time before this series is over. But, Skraps is a podcast whose roots are run deep in the sciences, we couldn’t ignore the topic of the basic pharmacology of psychedelics. This episode is a primer for citizen scientists and holds some intriguing information for the bonafide scientists among us.

As always, we don’t just deliver science, we are going to start with core science and intertwine the stories of the people who made the discoveries – ultimately ending with an understanding of how psychedelics work. We’ll feature the work of Dr. Joanna Neill, a pharmacologist and Chair of the Psychedelics Working Group for Drug Science UK. Dr. Bryan Roth also joins us; Bryan is a professor of pharmacology at the University of North Carolina studying psychedelics with a pretty serious DARPA grant.

For a special treat, you’ll get to hear JoJo absolutely butcher some basic biology and pharmacology terms. Please DM Arun and let him know that you’d like to get the bonus out-takes of PsychedeRx.

Transcript:

Spurred on by the decades old prohibition laws which increased intensity with every passing decade since the 1920s, the counter-culture of the 1960s, anti-war protests, CIA’s unsuccessful effort to control the mind with disastrous consequences, meeting US president, Richard Nixon’s self induced paranoia, it was the perfect storm that resulting in the war on drugs.

The world it appeared, had come to a screeching halt on that fateful day in June 1971. So far, we have recollected all the cultural and scientific happenings, which included moments of remarkable serendipity, controversies, scientific fudging and massaging of data, unwarranted glorification that led to all the issues that resulted in the 1971 ban on drugs. But we only spoke of the societal issues and how, despite some promising clinical data from Humphry Osmond and colleagues in Canada – to some badly followed-up studies by Timothy Leary, those circumstances led to panic and societal turmoil much more than they advanced psychiatry and psychiatric medicine. This was the time when psychiatry was ruled by some very invasive practices like lobotomy and electro-shock therapy. While in the hands of the therapists, these substances provided a unique tool that helped to heal a host of issues for those suffering alcoholism, the elites used it for recreational purposes triggering a hysteria that led to widespread recreational use.

What is more startling was that the very person who proposed the concept of “set” and “setting” also promoted recreational use, asking people to turn on, tune in and drop out. It must come as no surprise that such fervor fuelled the paranoia of the establishment that already suffered the failures and the atrocities perpetrated by Sidney Gottleb. What was the logical political solution? – an all-out ban, of course! One where all substances that affect the brain could be lumped into one, asserting that none of these substances have a medical use.

The adverts proclaimed that all drugs includings psychedelics, specifically LSD where highly addictive and caused the brain to shrink. But was there any scientific data to suggest that psychedelics cause brain damage or were unsafe? Well, that’s what we are here to find out.

This is PsychedRx, a SKRAPS original Podcast exploring the therapeutic potential of Psychedelics. An enthralling story of an improbable drug class, as old as human-kind itself, banished into exile, yet comes back soaring like a Phoenix from the ashes, to save mankind’s affliction with mental health disorders.

One can easily explain, based on decades of accumulated know-how, that serotonin or serotonin-like compounds alter brain states like psychedelics. It is common knowledge that typical psychedelics have the indole backbone and resemble serotonin, an endogenous neurotransmitter that exists in the brain. Serotonin plays a critical role in many brain regions – prefrontal cortex which controls complex behaviours, Cerebral cortex which controls higher functions like attention, perception, awareness, thought, memory, language, and consciousness, hypothalamus which controls appetite, hippocampus that controls learning, memory and processing of stress signals. It is very tempting to say that psychedelic molecules affect these areas and functions. Therefore, it is tempting to say psychedelic molecules positively impact all of these but the truth and science tell us differently. So we are going to explain in a way that even a lay person can understand complex phenomena.

To understand the science behind psychedelics, we need to go right to the basics. Basics about what the brain uses to communicate and how these brain cells communicate.

Before we go there, I want to sound a disclaimer. Compared to any other drug class, where the influence of the drug on the brain is well understood, for example with opioid drugs like heroin, cocaine, other prescription painkillers, or alcohol, or nicotine, psychedelics are very different. We have established in past episodes that psychedelics do not numb the brain the way these other drugs do. Remember the British MP, who was vividly able to count backwards subtracting 7 from 100. Or Hoffman, Heffter and others who described that they were able to remember everything that happened to them during ingestion. Such things are not possible when someone is under the influence of a sedative or an intoxicant.

There is an inherent problem with how even the experts talk about psychedelics. In an excellent review by David Nichols, a pioneering researcher, David reports – “Stanislov Grof characterized LSD as a powerful “nonspecific amplifier of the unconscious”. This empirical observation was based on his personal

supervision of more than a thousand clinical administrations of LSD.”

Once again, the issue here is the choice of words. By Grof calling it non-specific amplifier of the unconscious, he has managed to lose the people who consider themselves as conscious in daily life. Then David Nichols, despite being the great scientist that he is, has convoluted the argument by calling it an “empirical observation”.

David Nichols continues further quoting another author, Barr et al’s (1972) paper “…the phenomena induced by LSD… cannot be predicted or understood in purely pharmacological terms; the personality of the drug taker plays an enormous and critical role in determining how much effect there will be and of what particular type.”

Not everyone reads scientific papers. But I am sure many of us watch movies. Remember the prequel to “The Lord of the Rings” – The Hobbit. If you remember the movie, there is a Rastafarian looking wizard, aptly called Radagast, who lives in the forest, smokes weed, looks half-stoned, highly introspective, grows mushrooms and even rides on a sled driven by rats! Remember what the elites – “The White Council composed of Elves, the Lady of Light – Galadriel and Gandalf “ think about Radagast. Well, if you can’t recall, we have it here.

It’s his excessive consumption of mushrooms, they’ve addled his brain and yellowed his teeth

So we know by these arguments in scientific literature that subjectivity is rife and the variety of responses elicited by ingestion of psychedelics is affected by how, when and what the person is ingesting. When one talks about therapeutic benefits of psychedelics, they should be subjected to the same rigour that any other drugs for other conditions are subjected to. One cannot point to 1960s counter-culture, without recognizing the effects of the prison experiments or efforts of Osmond and others who both oversaw clinical trials and inadvertently contributed directly to recreational use and say there is evidence. Unfortunately, these happenings do not pass the “acid” test.

Therefore, there is a big reason to harmonise all of this and conduct studies to inform therapeutic benefit. That is the only way to change the narrative. Therefore, whether one is taking a drug prescribed by a physician in a clinical trial or for recreational use, informed decision making grounded in facts and evidence is key. So this episode will outline the framework on how to understand and interpret these effects.

The brain like almost every other organ is a collection of cells that form a tissue. This tissue is rich in brain cells, specifically called neurons. These neurons or nerve cells have a basic cell body that houses the control processes which many of us refer to the nucleus and has these classic projections that look like the skeleton of the leaf, if you held it up to the sun.

These type of cellular projections that extend from the cell body are called axons, and the beautiful thing about these axons are that they much like electrical cables act to propagate information to its adjacent neurons, carrying information and nutrients from the control center called the nucleus. So in essence, once has a relay that is set up from one cell to another, and this can be exponentially higher if the axonal projections are many from each cells, that in return communicates to other nerve cells, thereby setting up a network made of nerve cells. So in essence, when you hear a nerd in silicon valley refer to neuromorphic processes or algorithms, or in today’s artificial intelligence, what one is trying to recreate is, essentially this complex network architecture, communication and as a result, decision making on a chip. So that’s the relation between the brain and its influence on computing. We will come to how these neuromorphic processes can be exploited in a bit.

But for now, we are not here to talk about artificial intelligence but on how these psychedelic molecules work. We can take a pretty normal view like wikipedia to say that Psychedelic substances bind to 5-HT receptors that in turn cases hallucinatory changes. But it doesn’t help you or anyone, does it? So we are going to explain the concept with stories of people who discovered and ultimately end with an understanding of how psychedelics work. First, a disclaimer, there are many substances that are known to man from the cactus like San Pedro & Peyote, to vines like Ayahausca, to toad toxins, to synthetic substances that bind to 5-HT receptors. Or there are atypical psychedelic molecules like ketamine or ibogaine which affect the NMDA or opiate receptors. For the sake of simplicity, we will take exemplars of these substances and explain. Once you know what they do, you can build on that knowledge to understand what a specific substance does. Makes sense? Should we dive right in?

Before we go any further, we must state that the brain is not composed of just neuronal tissue. Just like the bone joints that are found in your body, which are composed of two or more bones, held together by ligaments, supported by cartilage, and held its place by muscles around the bones, brain tissue has supporting structures too. These cell types that support and are interspersed between nerve cells are other cells that play a critical role in providing support both in terms of regulating local environments to ensure optimal function as well as protecting the nerve cells in the brain from intrusions.

With that understanding, it’s time to dig a bit deeper into how the brain cells communicate as a network. The best way to approach the brain is like a weighing scale. Not the digital ones that you use in your bathrooms to check on yourself and feel bad, but the ones that were used before things became digital. Remember them, you had two pans, one where you would place an object, and in another, place the weights. You had a needle mounted on a lever that supported the two pans, and when the weight was optimal, and balanced, the needle stayed in the middle. If it swung one way or the other, it meant that the pan on that side was heavier. Get it. Have you pictured it?

Now apply the same thinking to the brain. You have two states – an excitatory state and an inhibitory state. To explain this further, here is Dr. Joanna Neill. Dr. Neill is a pharmacologist by training and was trained by some of the most amazing scientists, she split time betwee n academia and pharmaceutical industry in the early days of her training and is now a professor at University of Manchester. She was also the past president of the British Association of Psychopharmacology and currently serves as the Chair of the Psychedelics working group for Drug Science UK, a charity organization set up to advocate for evidence-based drug policy reform. We consulted Jo because she has a strong pedigree that is not tainte d by any agenda apart from using scientific evidence to inform the public awareness and policy making Here is Jo Neill describing how she started studying neuropharmacology.

Dr. Jo Neill:

<I’ve worked in pharma, so spent my career working with with the pharmaceutical, colleagues, scientists in pharma, and testing their drugs. And the main unmet need at that time was cognition in schizophrenia, and in other disorders, but mainly the cognitive disturbances that arise through that chronic illness. And, and there was a lot of interest from pharma to develop molecules that would restore cognitive function. And I think you’re talking about the balance in a brain and for So, so the modelling set up will or is an A glutamate antagonists, given to rats for a week, adult rats, and then they never get it again. So it’s it’s been cycling, which is a close relative of cattlemen, and an MBA antagonist. Now, talking about the brain being imbalance that causes imbalance in the brain, because glutamate is all over the cortex. It’s the main neurotransmitter and there’s loads more of that than the other neurotransmitters. And it is in a balance with GABA. So gamma is the main inhibitory neurotransmitter in the brain. And if you think what happens if you go out drinking alcohol is a GABA agonist. And in fact, alcohol substitutes a GABA a GABA a receptor selective agonist, very clever idea. harmless alcohol substitutes, so that and that’s what causes a lot of the relaxation effects and you know, for social anxiety, or social situations, very helpful. But that actually because you get this increase in GABA over the period of the evening, when you get the hangover, then you have what you’ve done is you’ve put your brain into an imbalance really. So you have upped the GABA and reduce the inhibited the glutamate. And what you get in the hangover is the opposite of that. And you get this increase in glutamate and that’s can be one of the aspects, reasons why you feel so bad. And you know, you get the sort of disorientation and so on. But so so we think about the brain as being balanced GABA and glutamate. And if you’ve given nmba antagonists, you’ve upset that balance, and you get, so you. So glutamate is excitation. And you need glutamate to help you think and concentrate and learn new tasks. So you can see glutamate release, and of course, but you have to have a balance. So you, you can activate it when you need it. But you don’t want it to be increased all the time. And if it’s too much, you can get, you know, epilepsy and brain damage to too much glutamate definitely a bad thing for you. So you, and what we get is this disinhibited brain in where you have these severe cognitive disturbances. And that means that the brain can’t function properly. And if you’ve got the brain Yeah, so the brain has basically lost its balance. And for many disorders, it’s most likely that the brain has lost balances, which you know, if you think of depression, and SSRI work you need to restore that balance, if you’ve you’ve got a dysfunction in the serotonin system. I mean, it’s a fairly straightforward idea. I think that that is in fact what happens to people.>

Narration:

So, the brain operates like a balance. Excitation is needed for critical activities and too much excitation is not good, and one condition where too much excitation happens is in epilepsy where groups of cells, much like what happens in the case of heart palpitations, can start firing due to abnormal excitation and this leads to epilepsy. And if there is too much of the inhibitory neurotransmitters, it numbs you as alcohol at high levels of intoxication does. And there are two chemicals released that control these excitatory and inhibitor functions – Glutamate and GABA. GABA is an acronym, which stands for Gamma- Amino Butyric acid and if you are an Australian or an aficionado of the wonderful sport of cricket, GABBA with two B’s is a cricket ground in Brisbane Australia.

So jokes apart, If you had some basic chemistry and biochemistry in your curriculum, you will probably have figured out that these neurotransmitters, much like every protein made in our body, are derived from the food we eat. Some of them are innately synthesized by cells in the body, and moved to various organs via the blood, therefore called non-essential amino acids and others that cannot be made by the body, hence called essential amino acids to signify that one needs to obtain them from the outside via food intake.

So what does any of this have to do with psychedelics? Well, there is a reason why we bring all of this. So stick with us here.

The elegant experiments of Arthur Heffter back in the 1890s, were done without any understanding of the chemicals in the brain that mediated communication between regions of the brain. Don’t you find that fascinating, that much like philosophy, science is based on philosophizing what the conclusion might be, based on the results obtained via observation. And Heffter was the grand-daddy of pharmacologists who unpicked the effects of the alkaloids present in the Peyote cactus. And in those days, pharmacologists were also trained in chemistry, so Heffter used chemical techniques to isolate the alkaloids and then study them and reported their effects.

But we do know that the reports of the effects varied greatly between individuals and this was a source of confusion. So, time has moved on and now let’s look at these mind-altering effects through the prism of objectivity and with the benefit of hindsight. In fact, if you are listening out of curiosity and have not ingested a psychedelic substance, or even if you have ingested a psychedelic substance, you still need to understand how these drugs work. The stories are really fascinating.

Recall that the disagreements between Kirk Berenger and Heinrich Kluwer ran deep; they had opposite opinions of what these substances did. The field of neuroscience, in this case, evolved from very humble beginnings. Just like what Jo Neill described with Glutamate and GABA in the brain, the field of neuroscience was changing very rapidly around the time of the first world war.

The credit to helping us understand what the chemical substances that controlled some of the nerve communication has an interesting history. Around the time that chemistry was a fascination for Humphry Davy, an Italian scientist by the name of Luigi Galvani, stimulated the legs of a dead frog with an electrical current. And Galvani did not have a stimulator. In fact, the field of electricity itself had just begun. So Galvani was generating static electricity by rubbing the surgical instruments vigorously over the skin of the animals that he was dissecting. So while dissecting a frog leg, he happened to touch the sciatic nerve, which we all now know is the nerve involved in the painful condition called Sciatica. He inadvertently touched the nerve with a forceps after rubbing the skin of the frog, and observed that the dead frog’s legs twitched. That was the beginning of the revelation that animals used electricity to communicate and nerves were the cables that carried this electricity. Galvani’s experiments were the first to substantiate this theory. All of this was happening in the late 1700s, the same time that Humphry Davy was running his laughing parties. So for a long time, there was a massive controversy over whether nerve communication occurred via electrical or biochemical means. The reason for this was because the nerve was the cable, but how did the muscle that was at the end of the nerve contracted. So, scientists began to think that electricity triggered release of a chemical in the muscle that caused it to contract, whose origins were not known. Mind you, this in itself was controversial at the time, as the very presence of chemical neurotransmitters was not considered plausible. So how did we understand that the electrical impulses lead to release of neurochemicals that are released into these neuromuscular junctions that caused muscle contraction, similar to how Galvani observed?

This is where the next wave of discoveries in neuroscience started. And right in the thick of it were a British Pharmacologist called Henry Dale and a German-Austrian Physician called Otto Loewi. The two scientists were close friends and they were the first to isolate the neurotransmitter, acetylcholine. Acetylcholine regulates multiple functions in the body from size of the pupils – to salivary secretions – to slowing of the heart – to movement of the gut muscle – and even blood vessel size. For this, they were awarded the Nobel Prize in Medicine two decades later in 1936. And for the world that thrives on genomics, these discoveries were made 40 years before the structure of the DNA. So this should tell you that chemical messengers in the body are critical. In fact, it was Henry Dale who identified the different nerve cells and populations in the body’s nervous system by the type of neurotransmitters they produce and this is called Dale’s Principle.

With that understanding in its infancy in the 1930s, there was still an active debate if nerve communication, especially where one nerve meets another nerve or a muscle, referred to as the synapse, was electrical or purely chemical. Another neurotransmitter that is always described both scientifically and in common parlance is adrenaline which was starting to be described as early as the 1860s. The key point to remember is that, the area of pharmacology and the identification of these neurotransmitters came from testing plant based substances and its isolated chemicals on various animal tissues and in animals.

Ok, let’s bring it back to psychedelic pharmacology. There are multiple neurotransmitters in the brain, and one primary neurotransmitter that was only discovered in the 1950s was serotonin. And would it surprise you if I said serotonin was not discovered first in the brain. Here is Jo Neill.

Jo Neill:

So, let’s take it all in. Imagine a blank canvas, perfectly clean. Then a drop of colour falls on the canvas and an artist starts painting. Similarly, the best way to understand nerve transmission and how it modulates function is understanding how the artist’s creativity cascades from one colour and brush stroke to another.

Neurotransmitters are made in the body, either within the nerves or elsewhere, transported via the blood stream and then taken up the nerve cells, released upon an electrical stimulus that a certain nerve cells receives and this electrical stimulus causes release of the chemicals stored in the nerve terminals. This in turn binds to proteins on the cell membrane that the nerve cells communicate with. And this leads to decoding of the chemical message into a cascade of events that leads to a function.

And Dr. Jo Neill described a growing understanding of a number of serotonin receptors in the body. And she mentioned Ondansetron, which was a drug made by a fantastic British Pharmacologist called Sir David Jack and his professional rivalry with another Nobel laureate, Sir James Black. The two gentlemen’s scientific rigour and rivalry is what has contributed to some seminal treatments from the very first acid reflux medication to migraine treatments to inhaled medications for asthma to heart disease.

Now let’s come back to Serotonin. Jo Neill also mentioned two women who were pivotal to the discovery of serotonin and it might also surprise many, that serotonin – a neurotransmitter – was not discovered by neuro-pharmacologists but by cardiovascular scientists. Can we go on a little detour to find out how the work of a few cardiovascular scientists changed the course of our understanding of mental health disorders?

To do this, we need to rewind our clocks back to the 1930s – around the same time as when Heinrich Kluwer was trying to understand the reason why visual hallucinations were happening with mescaline and Kirk Berenger coined the term – Dermescalinerausch to signify mescaline intoxication. An Italian Physiologist, Vittorio Erspamer who actually wanted to be a lawyer but due to his family’s insistence took up science, was very interested in understanding the field of pharmacognosy – which is a fancy way of saying “study of drugs from natural sources”. Erspamer was interested in the smooth muscle constricting or contracting properties of various substances found in the skin and intestinal tracts. To study this, he examined many different species like rabbits, molluscs, and frogs. But Erspamer was interested in specific cells of the gut which were called enterochromaffin cells – meaning they looked a bit like the cells of the gut lining but seemed to have nerve endings. These cells he postulated secreted a substance that was fundamentally different to the adrenaline and noradrenaline that was discovered a few years ago. He figured out that these secretory cells released a neurotransmitter that caused the gut to contract. Remember, we told you that chemistry and pharmacology ran hand in hand, and now let’s add microbiology to the mix. Paul Ehrlich, a noted scientist in 1910s had described a great way to identify bacteria and to classify them. Since it was not known that the gut lining housed many bacteria and microbes that caused flatulence and also stained positive with stains used in microbiology, Erspamer, postulated, was a protein neurotransmitter? He ground the gut, extracted the mixture and ran an indole test with ehrlich’s reagent to find that the substance that caused the gut muscle to contract was an indole, meaning it must be a different compound than adrenaline. To differentiate from adrenaline, he coined the term enteramine to denote – an amine derived from the gut. Here is another interesting tidbit, this is how LSD drug testing is carried out today, by using an Ehrlich reagent.

Enteramine held a very important place and prominence and was shown to play an important role in the mollusc heart as well as in the releasing of ink from the salivary glands of the octopus.

Vittorio Erspamer was a very prominent researcher and played a key role in the discovery of several other neuropeptide compounds.

The scene now shifts to 1945 and to shores of Lake Erie in Cleveland, Ohio. A young scientist was working for a pharmaceutical company, Eli Lilly in Indianapolis and decided to make the move to Cleveland to take up the role as the head of the laboratory, as Cleveland Clinic was setting up a cardiovascular research unit and was investing $160,000 per year towards research on understanding high blood pressure and arteriosclerosis – that crazy plaque that forms in the arteries that feed the heart, legs, head etc. Irvine Page became the director of research at the Cleveland CLinic and set out to work to identify substances that caused constriction of blood vessels or vasoconstriction. Irvine Page postulated that in certain people, hypertension or high blood pressure could be explained by the presence of such vasoconstrictive substances in the blood. Since Page was from the pharmaceutical industry, he brought with him a very industrious organic chemist, Maurice Rapport and to complement the organic chemist, a biochemist who understood chemicals in the body – Arda Green. This is where if you are a non-scientist, you have to stop and marvel at the tools that scientists, especially pharmacologists use to understand body function and develop drugs. You ready?

Irvine Page had a preparation that he had developed rabbit ear artery preparation and this had its own issues. If you know rabbits and more importantly, if you know laboratory animals, some of the effects are seasonal and working with rabbits can be a bit of a nightmare. After months of perfecting, they assembled a fantastic testing preparation. Maurice Rapport would synthesize the substances derived from indole derivatives. If you remember, indole derivatives were hot for a while – this was also the same time that Hoffman was working on his indole derivatives. Arda Green had the animal preparation where she was studying the role of blood flow to the kidneys and how these susbtances constricted the kidneys as clinicians around this time observed that urine output was low in patients with hypertension. She also had the ear artery preparation in the same animal and Maurice’s compounds would be tested on both kidneys and ear artery.

The work on kidneys led to a very important substance called Angiotensin and the work on the ear artery led to a different route. Now if you are wondering why am I talking about high blood pressure on compounds on a podcast on psychedelics, please hold on. IT is all with an idea to tell you how scientific discovery works. Because remember, the clinicians Humphry Osmond, Smythies had always thought until the late 1960s that substances that caused schizophrenia was modified version of adrenaline and called it adrenochrome and used mescaline as a surrogate and called this native substance as M-substance?

Similarly, Maurice Rapport the organic chemist needed lots of blood to isolate the chemical substance that he could ultimately test. In fact, it is very probable that Irvine Page was a great scientist but a sucky boss. Maurice Rapport was not clear what he needed to do. All he was told was “we are working on substances that constrict blood vessels that are present in blood.” So Maurice decided he needed to go to the blood to understand what he needed to do. So what did he do? He did what any resourceful scientist would.

Early in the morning, he would go to the Cleveland slaughterhouse, and collect eight 15 liter buckets of blood. Back at the lab, the blood was poured into a garbage can lined with cheesecloth with a small hole at the bottom. As the blood coagulated, the resultant serum dripped through the cheesecloth and out the hole. After two days in the cold room, 15 liters of serum were collected. More than sixty runs to the slaughterhouse were necessary to generate enough starting material. Through a five-step procedure which required ethanol precipitation of proteins, acetone precipitation of salts, chloroform extraction of inactive substances, butanol extraction of the active substance, and finally, dilituric acid precipitation), a very small amount of the vasoconstrictor substance was isolated. This original sample, was then crystallized , and the original vial is still on display at the Cleveland Clinic. And guess what was the appreciation for Maurice Rapport when he reported the finding to the research committee. The committee voted on March 9, 1948 to give Maurice a nice dinner party and decided that the substance was to be called serotonin to indicate that it was isolated from the serum and one that controlled the blood vessel tone. Maurice Rapport a year later, had moved to Columbia and described the chemical structure of serotonin as 5-hydroxytryptamine.

So Maurice, the chemist and the female biochemist scientist, Arda Green went on to describe the role of serotonin in the animal preparations and for all the genomic profiling experts, she went to isolate the luciferase enzyme from fireflies that is used in a myriad of genomic assays as reporters. She died six years later in 1954 due to cancer but not before she described two additional molecules- angiotensin and an enzyme called PHosphorylase A which plays a role in breaking down glycogen stores in the liver.

Are we ready for the role of another fantastic woman scientist? Her name was Betty Twarog and she was a graduate student at Tufts College in Philadelphia. As an undergraduate student, she was fascinated by a lecture she heard about a phenomenon in molluscs, referred to as catch. You might have noticed it on the rocky beach or a marina where you might see mollusc attached to boats. They have a remarkable capability to stay contracted and this muscle contraction enables them to resist detachment by crashing waves. The muscles stay contracted for extended periods of time and what is even more wonderful is how they can stay contracted even after the the period of excitation has passed, enabling them to stay attached and to collect food on the incoming tide. It is almost the equivalent of being in a state of sustained muscle contraction called as tetanus.

Fascinated by this phenomenon, she decided to do her PhD on mussel muscle contraction at Harvard and came upon the paper by Maurice Rapport, Arda Green and Irvine Page. Through her work, she discovered that the neurotransmitter that caused the muscle contraction was acteylcholine but the one caused the reversal of the contraction was still an enigma. She saw two very different descriptions – papers from Erspamer that described enteramine in salivary glands of molluscs and octopus, and another from the cleveland clinic group that showed the vasoconstrictive properties. TWarog’s PhD supervisor was able to procure synthesized serotonin extracts from Abbott Laboratories and using these extracts Betty Twarog discovered that the unknown neurotransmitter that caused muscle relaxation was serotonin. Here is the interesting thing. She wrote up the paper but Journal of Cellular and Comparative Physiology sat on the manuscript for close to two years, as it was not considered time sensitive to review a paper , I quote, “on an unknown neurotransmitter by an unknown scientist”. But in those two years, something very interesting happened.

After her PhD, Twarog decided to move to Akron-Canton area and decided that she would take up a position at Kent State University, and knowing that it was a 50 mile car ride to Cleveland CLinic, wrote to Irvine Page and asked if she could work with him. She was convinced that the invertebrate neurotransmitters might have a role in mammalian vertebrate systems. Irvine Page was thought to be skeptical about the presence of such a substance in the brain, but agreed as TWarog was very driven, decided to give her a lab and a technician. To demonstrate the presence of indole substances, she replicated the Erspamer’s Ehrlich tests on brain tissue of clams. She again wrote up her findings and this time, it was accepted in Journal of Biological Chemistry in 1953, before her original PhD thesis research was published.

Irvine Page’s 1968 book Serotonin has an interesting recollection.

When cerebral metabolism or “brain chemistry” was being established as a field worthy of study, serotonin played an extraordinary role. It will come as a surprise to younger readers that even as late as 1937 many scientists were dubious as to whether “neurochemistry” was indeed a discipline. If I had to select a single effect resulting from the discovery of serotonin, I would unhesitatingly suggest its influence in shaping investigators’ ideas on cerebral activity.

So this is how, Serotonin, a molecule that has so much impact on mental health was discovered. But the role in describing, serotonin’s role in brain function, fell to another scientist – Dilworth Wayne Woolley. by combining the work of Betty Twarog, showing serotonin existed in the brain, with Albert Hoffman’s discovery of LSD, and his own work on LSD as an “antimetabolite” of serotonin, Dr. Woolley proposed a role for serotonin in mental illness. If you are wondering what an anti-metabolite is, we will help you. substances which are structural analogues of naturally occurring metabolites and which interfere with the functioning of those metabolites—as a tool to investigate those diseases. So LSD was interfering, in DW Woolley’s thinking to places on the cells that serotonin would normally be present.

Canadian, D W Woolley developed a fascination for anti-metabolities when he realized from reports from british colonies and poorer countries where diet low in niacin, or meals high in corn, prevented the conversion of tryptophan to nicotinamide, and this was causing a condition called pellagra. He developed the anti-metabolite idea further by isolating and characterizing nicotinamide, a substance involved in pellegra. While working on the isolation of nicotinamide, he noticed the work of Albert Hoffman’s LSD and the papers from Cleveland Clinic on serotonin and was the first to notice that the structure of Hoffman’s LSD was similar to serotonin described by Maurice Rapport, Arda Green and Irvine Page.

Interestingly, DW Woolley was severely diabetic and is said to have been half – blind at a young age due to diabetic retinopathy. So it is truly amazing what he accomplished despite this limitation. While the rest of the world was taking in LSD and revelling in visual hallucination, a half-blind DW woolley, With the help of rat uterine preapration, he noticed that serotonin contracted the rat uterus and LSD opposed its effect, thereby furthering credence to anti-metabolite hypothesis. He also noticed that the structure of the plant hormone, auxin was similar to serotonin and postulated that serotonin played a role in brain development much like what auxin did in plants.

DW Woolley did what most scientists do. He wrote up his findings and sent it to Lancet, for review he reported that serotonin was important for brain development and could play a role in mental health disorders. Guess what the reviewers said. If you are holding a hot cup of coffee or about to take a sip of anything, either finish it or stop.

The journal reviewers said – “It was not enough to make a suggestion but the author has to prove his point by curing mental health disorders”. While Lancet reviewers were a bit snotty, Proceedings of National Academy of Sciences, did see merit and accepted DW Woolley’s paper in 1954.

Yes! scientists, despite being perceived seen as rational and analytical, can also be pin-heads sometimes. Dr. Woolley’s work and hypotheses were summarized in his 1963 book The Biochemical Bases of Psychoses or the Serotonin Hypothesis about Mental Illness. DW Woolley, wasn’t too fazed by this. Irvine Page called him – “most vocal proponent of serotonin’s role in brain … (who) … made the best case for the participation of serotonin in mental illness.”

He continued his research and also took holidays. It was during one such holiday on a trek in the Peruvian Andes, DW Woolley died. It is very interesting that the earliest documented evidence of psychedelic substances was from the Andean region by the tribes of the Chauvin Civilization as Mike Jay documented in his book, was also the same region that accounted for the scientist, who proposed the role of serotonin in mental health disorders. Interesting, as we keep saying — Life, like history has a habit of going round in circles!

Can I also say that the anti-metabolite theory originally postulated by DW Woolley has found new life is anti-cancer agents. So once again, while the world was singing praises of “drug for the elite”, getting lost in doors of perception, introducing LSD to counter-culture and dosing was expendables with LSD, there were a group of few good industrious scientists, who were working on understanding the way the brain worked. Interestingly, the key steps did not come from a psychologist or a psychiatrist or a writer but from a orthogonal speciality of chemistry and cardiovascular science. While the world still celebrates the psychedelics, these individuals who played such a pivotal role in understanding what serotonin does, are long forgotten from public description.

So, can we focus? We heard in the midst of all the stories that serotonin or enteramine, both signifying one and the same molecule is a 5-hydroxytryptamine. It is produced via a series of chemical reactions from the amino-acid, tryptophan which needs to be provided via diet. This serotonin molecule, has various functions – it causes smooth muscle contractions like what Vittorio Erspamer described. It also caused the blot to clot as Maurice Rapport discovered and is now known to be present in high quantities inside blood platelets. We also learnt that serotonin causes blood vessels to contract, as shown by Arda Green. Then Betty Twarog demonstrated that serotonin was present in salivary glands was important for muscle relaxation, and this time, the muscle is not smooth muscle but skeletal muscle. Then DW Woolley showed that serotonin has a role in brain development and that drugs like LSD was an anti-metabolite.

So this is, in a nutshell what the pharmcology of serotonin looks like. Depending on the organ, serotonin has different effects. So now, does all the variety of physical effects that people felt with Peyote and LSD makes sense? Ok, so serotonin and LSD are alike. And it is fair to say that most psychedelic molecules either compete or resemble serotonin in eliciting the effects seen with psychedelic molecules.

BUt is it really that simple? Well….yes! And….No!

Remember the definition of psychedelic that we said we will come back to, in episode 1.

Back then, we stated the following: Psychedelics refers to a group of natural plant-based or synthesised substances that, at any given dose (as known for other medicinal products), modify basic neurological functions to enhance the user’s sense of perception.

Ok, so we have given you ample evidence that these psychedelics are plant based substances. They are derived from plants – be it mescaline from Peyote and San Pedro, or LSD from ergot fungi that grows on wheat. We will come to others later on in the podcast series. In fact, the structure of Auxin.

Next we brought in the concept of dose, by saying that, at any given dose, as known for other medicinal products, modify basic neurological functions. Can we dig a bit deeper on this argument?

So let’s recollect what we have discussed so far regarding dose? Remember mescaline and Heffter’s experiments? Heffter concluded via meticulous experiments that the alkaloid, mescaline responsible for the psychoactive effects of peyote cactus was effective at 400 mg dose. By taking lower concentrations of the alkaloid, the effects and kaleodoscopic patterns were not vivid. SImilarly, with LSD, Hoffman took dose of 250 micrograms for his bicycle ride, only to titrate it further with lower doses of LSD, as low as 100 micrograms a few times. All of these experiments by Heffter and Hoffman was acute experiments, meaning they were ingested once and not tried the very next day. So we do know that single dose of mescaline or LSD triggered kaledoscopic patterns and visual effects.

Then we saw the impact of what happened with chronic LSD dosing with CIA experiments where despite it being gruesome, deserves some discussion. When Gottlieb got Dr. Pfeiffer to dose inmates continuously, every day for 77 days, what was happening was a different phenomena to what Heffter and Hoffman did. They dosed the prison inmates every day for 77 days and as a result, the prison inmates became psychotic. One can argue what brought on this effect, whether it was a proper psychotherapy session or if it was just dosing and the prisoners, left to their own devices after dosing. The latter is probably true and this is important to understand from a scientific perspective. Can we dig a bit deeper into the concept of dose?

Ok, so every drug known to man has the following relationships. Most commonly, such relationships are devised for new products under development through a series of tests in cell cultures, animal studies, prior to human clinical trials. Based on these tests, a profile of a potential drug is identified. Today, it is almost taken for granted that every molecule under development undergoes these tests and a profile is provided to the regulators like FDA for review prior to any human trials. In fact, this is what I specialized in doing as a safety pharmacologist, in the early stages of my career. I think, for most drugs, especially for psychedelics, people ought to understand, simply because everyone seems to have an opinion based on use, misuse, self-experimentation and hear-say. It is time to educate yourselves whether you are a user or if you are a general public who will hear about the impacts soon and have a vote on a local or state issue. It is because, you as an educated and smart listener, needs to think through a drug and then vote on de-criminalization of possession or understand if you are in the situation of seeking help by undergoing psychedelic assisted psychotherapy.

So every drug, can be understood in a very simple graphical plot. On the X-axis, you have drug concentration increasing from zero to a certain number. And on the Y-axis, you have drug effects, irrespective of what the test performed to understand drug effects. Every drug binds to a protein on the cell surface to elicit its effects. In the case of serotonin or psychedelic drugs like LSD, it binds to a certain class of 5-HT receptors, type 2A. Upon binding, think of it like a key fitting into a lock, just like the key dislodges a number of interconnected cogwheels in a lock and enables opening of the lock, serotonin or serotonin like mimics unlocks a series of molecular processes. Scientists will have a number of names for these processes, but for the sake of simplicity, let us call it second messengers. The first was the drug, that carried an information to open the lock, and second messengers refer to the cogwheels that the key opens. These second messengers go through a series of molecular events like a cascade that determine the drug response in a single cell, which adds up in an organ like the brain, the heart or the gut.

One of the most published pharmacologists in the area is Dr. Bryan Roth, professor of pharmacology at University of North Carolina, Chapel Hill.

Here is Bryan, recounting why he was interested in studying psychedelics.

Dr. Bryan Roth:

“One boyfriend of my sisters took what I was told was a large dose of LSD. I don’t know if that’s true or not. But he ended up in a psychiatric hospital for a fairly long period of time. And when I was very young, my mother was diagnosed with schizophrenia. And so I, I sort of had this idea, which was not not original with me, but it was something that I had read, when I was sort of a young teenager, that psychedelic drugs could induce sort of a model schizophrenia, giving you insight into that disease. And there were other drugs that blocked the effects of LSD that were very effective in treating schizophrenia. So I was just, you know, just fascinated about what the hell was going on there. I didn’t know any chemistry, I didn’t know anything about the brain, but I, you know, basically read everything that was available in, in the library in my small town in Montana, which was not a lot. But I read it. And, you know, that I went to college. And I was pre med, I would say, you know, from the age of 14 or so, I, I had pretty much decided that, you know, I wanted to be a psychiatrist and study how these drugs work.”

Narration: Bryan decided that he wanted to do his PhD in psychopharmacology and did his PhD on opiate receptors. IT was during his postdoctoral work at National Institute of Mental Health with Mineo Costa that his mentor suggsted Bryan study serotonin receptors. The field was just blooming and Bryan has made some seminal contribution to how these receptors work.

But remember, the tool that the pharmacologist has to study responses to the drug was the drug itself. But LSD was banned. Here is Bryan again.

Dr. Bryan Roth:

well, LSD is sort of the prototypical psychedelic drug. And, you know, certainly as you know, you’d say the most famous or most notorious of all psychedelics and the other the other thing is that it was the one that I listed on my DEA licence. So, to work with these, to work with these drugs, you have to have a special licence from the Drug Enforcement Agency, what’s called the schedule one licence which are which are extreme, actually extremely difficult to get. And when I was in Costas lab, LSD was basically the drug they had that they had around. And when I when I got my schedule, one licence at A time I didn’t realise that every schedule one compound you have to justify separately. So there’s this huge amount of paperwork and bureaucracy you have to go through to get one of these licences. And so we just put down LSD and then a couple of others, we didn’t even put down psilocybin. Because it never occurred to me.

Narration: Ok, so now going back to serotonin and how we know anything about what serotonin does molecularly, is a lot from people like Bryan Roth. here is Bryan again recounting how much this field has bloomed.

There’s, there’s even evidence that you know, there’s serotonin has effects on the liver, the pancreas bones, basically every organ in the body is affected to some extent, or another by serotonin, and to mediate these effects. A huge number of receptors have have evolved and in humans, there are 15 different serotonin receptors. And a little historical note One of the early serotonin receptor conferences I went to I think in the 80s. They were basically serotonin receptors are being discovered by molecular cloning technology. And I remember I talked to one, one person who was at a company that was specialising basically in, in cloning receptors. And he said, Don’t worry, Brian, there’s enough there are so many serotonin receptors, everybody can have one to study. That was, that was actually a nice thing about the field, there were just so many receptors that you could focus on one and, you know, there probably are only two or three other groups in the world that were studying that particular receptor.

So how does a pharmacologist study these myriad of receptors. Are you curious, let’s hear from Bryan again.

Dr. Bryan Roth:

Well, so, let me let me just talk about the diversity of receptors first. So, because there are 15 different receptors, you know, one of the practical aspects of this is that in theory, we can make drugs specific for every receptor. And because each receptor is found in a, you know, different tissue, or a different part of the brain and has a different effect on say, brain functioning or, or functioning outside the brain, you can, you can basically make a drug that hits you know, receptor a, but not receptor B, it might have a beneficial effect, for saying migraine headaches, or may have a beneficial effect in depression, or beneficial effect in schizophrenia, or, you know, beneficial effect for people that have Crohn’s disease, etc. So it really opened up, up the floodgates for, basically, pharmaceutical development, which is continuing today. But one of the things that we we noticed early on was that it was it was fairly difficult to make drugs that were absolutely selected for one receptor versus the other, that that’s the problem. And so that’s the thing that my lab has, has basically been focused on the last the last 30 years, is to understand precisely how it is that serotonin and other drugs bind to these receptors, ultimately, at the atomic level, and then to use this information to design what we hope are safer and more effective medications. And as you know, as a side advantage, we can understand how psychedelics exert their actions. Since drugs like LSD have their actions by binding to receptors, if, if we can understand how they bind to and, and stabilise the active state of the receptor, then that can give us basically the first insight into the action of psychedelic drugs. So we can, our hope was we could capture this very first step of psychedelic drug action. Since we don’t know a lot about how psychedelic drugs act, my the the idea I had was, if we can, if we can ultimately capture this very first step of psychedelic drug action, then we can work out from that and ultimately understand everything there is to know about psychedelics. And it just took a long time to to capture that first step. So I started my very first grant, which I submitted, I think in 1992 or so was basically to solve the structure of this receptor and complex with various drugs, including psychedelics. And sadly it just took a long time to accomplish that. Luckily, I was able to get funding through the years to continue to work.

So from all that Bryan was saying, we know that serotonin binds to the receptor and more specifically LSD binds to serotonin receptors or what the scientifically inclined will refer to as 5-HT receptors. OK, so now I have some bad news for all psychedelic advocates, especially the ones who promote psychedelics for recreational use and more importantly, for those who micro-dose based on anecdotal evidence. So is LSD the panacea for everything? Or in other words, is LSD the perfect drug, which just happens to be a psychedelic?

Dr. Bryan Roth:

So LSD actually has a really complex pharmacology. So we’ve looked at this in great detail and where we, which we published and we’re, we’re actually getting putting together a big paper where we’re looking at every psychedelic known, every known psychedelic. But LSD is is very unusual in that it binds to, you know, binds to and activates virtually every serotonin receptor. So maybe third 12 or so of the serotonin receptors, LSD activates. It actually has an antagonist at one serotonin receptor, the five ht seven, interestingly enough, for reasons that are not entirely clear, but could have something to do with its antidepressant activity. And it also activates dopamine receptors fairly potently. So we have published this, I think it’s, it’s something that has been, you know, ignored or not, not taken into account, but as you know, there are five dopamine receptors, LSD is pretty active at four of them, at least three or four of them, it also activates various adrenergic receptors, this may be responsible for some of the, you know, peripheral side effects of LSD, dilated pupils, some people have flushing You know, this sort of thing. And then there are some, you know, miscellaneous receptors that it that it interacts with. So, you know, it’s, it has this extremely complex pharmacology silicided been, you know, by contrast, psilocybin itself is inactive, it has to be metabolised to silos and silos and actually has a fairly complicated pharmacology as well we have found so it activates many serotonin receptors has has some ability to activate dopamine receptors as well, although nothing like LSD. So slightly, you know, slightly different form. mycology in terms of the psychedelic actions, though, it’s pretty clear, based on human studies, that the psychedelic effects are mediated through the five htt to a receptor. And this comes from studies in which people have been given a five ht to a antagonist. cancer and, and then given LSD or psilocybin, and they report that the effects are are gone, basically. So, you know, pretty clear that at least for the psychedelic actions, it’s it’s the five htt to a. So you know, very, very complicated story, actually. Yeah.

Narration:

So, LSD binds to a myriad of receptors in the body and so what, one might ask? Why should anyone care about micro-dosing? Micro-dosing refers to the concept that the drug taken in really small quantities can provide the mild activation threshold, which in the case of psychedelics, is so -called anecdotal mention of enhancement of cognitive function. Here is Bryan again, as to why micro-dosing for mental benefits doesn;’t make any sense.

Now, one of the, one of the serious potential side effects particularly for LSD, particularly for people that are contemplating micro dosing is that LSD also activates this related receptor, the five htt to B receptor, which is found at heart valves. And it’s, so this is something my lab discovered 20 years ago, and drugs that activate that receptor cause valvular heart disease, so it’s, it’s well known. And so it doesn’t do it in everybody. So about, you know, 3020 to 30% of people who take targets, you know, LSD is an ergot. So we’re gonna mean, at the surge guide, and so on. dihydroergotamine drugs used in treating migraine headaches are drugs used in treating Parkinson’s disease that are related to LSD, cause valvular heart disease and around 20 to 30% of the people that take them for extended periods of time. So this is, this is a really, really big concern actually, for micro dosing, LSD in particular. It looks like in our, in our preliminary data, it looks like psilocybin probably doesn’t have that problem. That’s our initial data. Because it doesn’t, at least in our hands doesn’t activate the receptor. Right?

Dr. Bryan Roth:

Yeah, so micro dosing, you know, from what I understand from reading about it is doses of like 10 to 20 micrograms everyday or every other day, somewhere every third day, something like that. So, you know, a 10th of the psychedelic dose. And so, here’s the problem. So when LSD binds to the five ht to a, and a five ht two B receptor, it binds very tightly, and it doesn’t get off the receptor, basically. So it’s very, it’s very unusual in that, that aspect. And we have found, and we published, for instance, that once LSD is on the receptor, it’s on the receptor for like six to eight hours. It doesn’t, it doesn’t fall off. And so you get this prolonged sort of stimulation of the receptor, at quote, unquote, micro dosing, you’re not occupying a lot of the receptors in the brain. But those receptors that the drug is on are activated to some extent. And that’s, that’s the same for the brain or the receptors in the heart. And so that’s, that’s my concern that that, you know, it’s, it’s, it’s different from other drugs. So most other drugs, they get on the receptor, they fall off the receptor, when the drug is out of the body, they’re gone. Basically, that’s not the case with LSD. When it gets on the receptor, it’s stuck there. And, you know, this could be important for the efficacy of micro dosing, because you can’t explain it any other way. Right. But it could also be important for side effects such as valvular heart disease. And, you know, I’m concerned enough about it that whenever I’m interviewed about this, I mention it to people.

Narration:

So, it is crucial to understand the difference Here. A single dose and the quantity ingested determines the psychedelic experience and the physical symptoms. Then, There was a big chronic dose as was done by Sidney Gottlieb to the expendables to small chronic doses which can prime the receptors, simply because the drug like LSD can bind to the receptor long enough, therefore one might be pre-disposing themselves to adverse effects. Somehow, this is lost in the hype and hysteria once again, so you as the listener must approach psychedelic like any other drug, with the concept of dose in mind.

So let’s go back to that graphical plot we had. Increasing drug concentration on the X-axis and drug response on the Y-axis. So pharmacologists have a great way to mark what the effects of the drug are at a given concentration. So in understanding what the drug does, one can plot how serotonin binds to the 5HT2A receptor itself and how much of it travels to the brain vs. stays in the blood stream to affect the processes in the brain vs. the gut or the heart. Based on this, one can define an efficacy dose, which is effect that is desired, and adverse effects defined as non-intended effects like changes in gut function or increase in heart rate. Why am I saying this – because you can define efficacy dose, adverse effect dose, and the margin or the space between the efficacious dose and adverse dose is the concentration that you can test without impacting safety.

Let me explain even further, Sidney Gottlieb dosed the highest dose of LSD every day for 77 days in a prison experiment, and this triggered psychosis, so this is an adverse event. But a psychologist used a single dose of LSD at 250 micrograms once to treat a patient. This 250 micrograms was enough to engage the receptors and trigger a psychedelic response. But so far with microdosing, there is no scientific evidence to suggest that a reliable response can be elicited to improve cognitive function without producing a psychedelic trip. Our suggestion is to look at micro-dosing in the context of science and not as an effect of how one feels. Because the most recent survey study showed that micro-dosing was no different to a placebo. A randomized control trial is now underway but at the level of the receptors, it is hard to say that micro-dosing elicits a response.

Ok, now we know these are plant based or plant derived substances that at any given dose can enhance the user’s sense of perception. Really? We haven’t said anything with regard to why the user’s sense of perception is better.

Can we dig a bit deeper into that part- enhancing user’s perception? First, before we go, we have already established through previous episode and in the first part of this episodes where Dr. Jo Neill mentions that alcohol, opioids are inhibitory agents. But Psychedelics were said were perception enhancers. So what evidence is there to suggest this effect? Here is Bryan Roth again.

Dr. Bryan Roth:

Oh, so a psychedelic I, I define as a drug which has LSD like actions. So any drug that has LSD like actions, and that sort of distinguishes it from hallucinogens. So you know, salvia is a hallucination, not like LSD. talk to anybody who smokes salvia, and has taken LSD they’ll say, This is not like LSD. Right. Definitely a different thing. Ibogaine, not like LSD. Right. But it’s a hallucinogen. So I guess if you talk to people who’ve taken mushrooms and LSD, they’ll say sort of the same, I guess, or mescaline, something sort of similar, right. So more like something that’s a drug that has LSD like actions and I think that’s, that’s probably Merriam Webster’s definition of psychedelic as well. Okay, so we can talk about that a little bit. So no, it’s fine. It’s fine. No. So I’ll just couch my answer in terms of what I know about psychedelic drug action. So what psychedelics do drugs like LSD is they cause layer five pyramidal neurons to fire in a very asynchronous fashion. Okay, layer five pyramidal neurons, and integrate sensory information and cognitive information from all cortical areas, in particular, an area of the neuron called the apical dendrite, and that’s where the receptors are most highly enriched. So, five HTTP receptors are localised typical dendrites this was, again, something my lab discovered, you know, decades ago. And so basically, what’s happening is, you know, you can think one way to think about it is what psychedelics do is they induce noise in the system. They’re inducing noise in the brain.

Narration:

Inducing noise in the system!! How does inducing noise in the system enhance perception and produce visual hallucinations and deep reflective episodes under therapy.

Well, let’s go step by step. If you ask a pharmacologist, liek Bryan Roth and we did, here is his answer. In a nutshell, he can predict what these drugs do at a molecular level based on how well the drug binds to the receptor, but what happens after that is not well understood. Are you ready to dig into the psychedelic experience with a scientific lens? Here is Bryan Roth again.

Dr. Bryan Roth:

If we distinguish the brain from the mind, okay, so they’re inducing noise in the brain, the mind has a remarkable ability to make up a story

about anything. Okay? And it basically makes up stories about, you know, to come to grips with this noise, you know, this noise can be visual hallucinations, unusual feelings,

feelings of rapture, feelings of union, etc. And it basically makes, you know, I hate to tell people, this it’s just a story, the mind has made up about the experience. It’s a very memorable story. So one of the one of the remarkable things about psychedelics is the psychedelic experience has tremendous salience for people. So it’s very memorable. Okay. Why this is we don’t know, it’s, it’s something I, you know, hopefully, hopefully, eventually, we can, we can address, we think there are long term changes that occur in the neurons, physically, which are part of the substrate of this, but they, they form this sort of memory, this, this, this glow, this feeling. So if you look at the, at the clinical trial data with psilocybin, you know, people, they take psilocybin for the first time in their lives, you know, six months later, they say, this is the most memorable experience they’ve ever had in their life, ever. Okay. So there’s something about, about the drug, it’s a drug action on the brain, that that induces this feeling of of importance. More important than anything ever they’ve experienced. So this is, this is very, you know, this is interesting. I don’t think it’s due to any, you know, it’s a drug, basically, it’s binding to a receptor. It’s causing neurons to fire. I don’t think it’s, it’s due to any supernatural power of the drug. It’s just a drug. For God’s sake. I can synthesise it in the lab. It’s just so let me tell you, let me tell you one of the things so which I think I think maybe, maybe, maybe, or maybe not understandable. So when I, when I treated people with schizophrenia, and I was explaining things to medical students, they would say, how can this person believe that you know, aliens are planting beaming thoughts into his head, basically, how to how can you believe this? We tell them it’s not. And, and what I would say to them, is that their hallucinations are more real to them, than reality is for you. It’s more real, okay. And there’s something about the psychedelic experience that taps into that, basically, that it becomes a very real experience, you know, people may have the experience of, you know, seeing Jesus or Buddha or Ganesh, or, you know, Allah or whatever. Or aliens, you know, if they smoked DMT they, they see aliens, Mike multi dimensional aliens, right? And it’s very, it’s, it’s like real, it’s it’s real to them.

Narration:

What Bryan is trying to say is, unpicking what is real and what is not easy. This is probably why in our opinion, the word hallucinogen must be avoided. But also there is something about psychedelics that make them different. It’s the ability to remember what happened during a psychedelic drug experience.

So now, you probably understand why the native americans use peyote and told the white invaders that they speak with god directly, while the christian missionaries only spoke ABOUT god.

And much of this evidence comes from some imaging studies that were done in the UK. Before we go into that, there are some crucial things to understand. The brain is an organ that takes the path of most efficient energy use. Some of you might know that while many other organs like heart and muscle can rely on high energy producing oxidative phosphorylation, the brain primarily uses glucose and much of it through anaerobic glycosis. So brain computes in a way that makes it energy efficient. The best way to understand the concept that understanding vision. Imagine you staring at a pond filled with trees dotted around the pond and there are birds flying in and out. The eyes get fixated on one frame and the optic nerve sends impulses that only updates the changes to the image, say a bird flying in or out, or a squirrel running on a branch to make the birds fly away etc. The entire set or the background is ignored to enable more energy efficient focussing of the changes. So over time, there is a streamlining effect. Be it in health, to enable normal functions or disease. The brain gets locked into additive substituition rather than re-processing. Evolutionarily, it makes sense too, because, if the entire frame needs to be processed every time, then either we need faster computation in the brain or the processing needs to be slower.

What psychedelics do, is break down this and induce noise. So now with this idea, let us go to some of the brain imaging studies. Studies led by two scientists, Robin Carhart-Harris and David Nutt have shown that single dose LSD administration leads to two striking effects. One is an increase in cortical blood flow and another was a marked quietening of some deeper brain regions – like parahippocampus and retrosplenial cortex. These two centres provide a strong sense of self, so psychedelic substances like LSD and psilocybin break down this sense of self or what some call as ego-dissolution centres. This forces the person to look inside themselves promoting self-reflection. We will come to more on this very soon when we talk about the benefits of ego-dissolution in psychotherapy.

In addition to enhanced blood flow to the cortical regions, it also seems to promote more interconnectedness. The best way to explain this is to imagine the earth and the world before the internet, much like how the author Thomas Friedman describes the connectivity in a circular world. The information flow is always linear and slower and comes through nodal points, much like how telegrams or telephone used to work.

But psychedelics make the cortex flatter, much like how the internet flattened the world and enabled multitude of connections. So instead of a linear information flow, a single point on the map of the brain can be connected to multiple points and vice versa. This leads to flattening of the world and much like how internet evened out inequalities and democratized information access, psychedelics do the same to the brain’s cortical regions. As a result, the enhanced connectivity in the absence of filtering from deeper ego-centres, makes the subject more prone to see and perceive different signals – be it visual, auditory or kinesthetic.

This again is not exclusive to psychedelic substances. It is only interesting that psychedelic researchers have come to this realization now. For example, tinnitus is an area where auditory centres in the brain are hyper-active and causes ringing in the ears. It is interesting to note that both visual and taste perception areas are located adjacent to these. So over the last few years, an experimental treatment for tinnitus aims to synchronize sound waves through a headphones and electrical stimulation of the tongue to provide a network suppression of the entire region by creating noise. And guess what, in tinnitus, such bimodal stimulation of both auditory with sound via earphones and olfactory regions via tongue stimulation leads to a significant reduction in tinnitus symptoms, similar in magnitude to some of the psychedelic drug trials in depression and PTSD.

In addition, psychedelic molecules enhance plasticity and also enhance neurogenesis. Here is Bryan Roth.

Dr. Bryan Roth:

Psychedelics change connections in the brain, right. So, there is, you know, good data that they, you know, at least in mice, cause increased spines to proliferate on neurons. This is something, you know, my lab discovered, you know, 11 or 12 years ago, and is sort of rediscovered, has been rediscovered. So, they cause, you know, plasticity and, and, and biogenesis. And, you know, what we know about spines on neurons are those that are important for information trance flow transfer in the brain. And, you know, so one can imagine that, you know, increasing synaptic connectivity could make you more, you know, I can imagine it could make you more creative, or allow you to focus better. It would be great to have some real study on that.

Narration:

I am sure many of you will get more detailed information by reading various books or research articles, but the holistic pharmacology of psychedelics are dependent on dose, clear understanding of what these compounds do to how these effects are produced and can be titrated.

But what we haven’t told you is the amount of fight that the researchers had to put up, to study these substances again.

We will come to more of these stories soon!

Episode 5: Psychedelic Pharmacology – The Basics

It’s his excessive consumption of mushrooms, they’ve addled his brain and yellowed his teeth