The opioid epidemic gripping the United States has brought into public awareness a problem that has bedeviled the world of medical science for decades: is it possible to have a truly powerful painkiller that is not addictive?

The simple, unfortunate fact is that the most effective pain medications currently known to science can be both addictive and, when used incorrectly, lethal. While experts and pundits may go back and forth on who exactly gets addicted and why (not to mention the ongoing debate about what it means for something to be addictive, and what addiction really is, anyway), and doctors have successfully found ways to reduce the risks inherent in opiate use, the fact remains that painkillers can be a risky business. A meta-analysis of studies of patients prescribed opioids for chronic pain found that between 8 and 11 percent met the clinical criteria for addiction. For patients given short-term courses of opioids to control acute pain, the rates are much, much lower. The American Society for Addiction Medicine estimates that approximately 23 percent of those who use heroin develop a dependency.  As long as opium has been known, the bitter irony has always been that the drugs most effective for easing pain can create so much of it themselves.

While other, non-opioid painkillers do exist (as anyone who’s ever taken an ibuprofen for a headache knows), and can be incredibly useful for mild to moderate pain, it is an unfortunate fact that they are rarely suitable for extreme cases, when pain relief is needed most. I was once hospitalized for a 1cm-wide kidney stone, and no amount of Advil could compare to the stopping power of an intravenous shot of Dilaudid (a powerful, opioid analgesic also known as hydromorphone, which the attending nurse memorably referred to as ‘happy juice’). The need for a powerful but non-addictive pain reliever remains a glaring gap in the Western medical cannon. Some doctors and researchers think that it might be impossible, and pain relief will always be inextricably linked to addictive potential.

As is so often the case, when modern medicine fails to deliver (which it still does, despite the amazing successes of medical science), the eyes of both patients and researchers turn to the natural world: plants have been conducting organic synthesis for millions of years and are far more creative and adept at it than humans are. Very often Indigenous cultures have found different plants and incorporated their healing properties into their own pharmacopoeias. Often times this knowledge is taken by scientists and the medicinal plants are studied and new pharmaceuticals are derived, which would have remained unknown if not for the initial Indigenous discoveries. There is a deep and complex conversation about colonialism, and specifically science’s role in perpetuating colonialist attitudes. For many, the combination of natural evolution and Indigenous knowledge have provided relief from suffering when rational drug design fails to deliver.

So has any culture, anywhere, found something like a powerful, non-addictive, natural painkiller?

The Mazatec People & Salvia’s Historical Use

Amazingly, yes: Salvia divinorum, most well-known as the herb that reliably triggers miserable trips when smoked, has been used as a medicine and a painkiller for hundreds of years by the Indigenous people of Mexico’s Oaxaca region. While individual U.S. states have banned it (29 in all, including the territory of Guam), the federal government has, somewhat surprisingly, continued to ignore Salvia divinorum and kept it off the list of controlled substances.

Anthropologists working among the Mazatec people of Oaxaca, Mexico have known for decades that the Salvia divinorum plant plays an important role in Mazatec culture and medicine. Rather than smoking it (which is the preferred route of administration in the United States, which Mazatec shamans have apparently objected to), it is normally administered as a quid: leaves are chewed and swallowed rather than smoked or boiled (although there are records of infusions being made). While the psychic effects are still clearly present, and considered to be spiritually significant, salvia is used for far more than altering consciousness: it has also been used as a pain-reliever (headaches in particular were noted as being responsive to salvia) and to alleviate gastrointestinal upsets and problems associated with alcoholism. Unlike morphine-based pain remedies popular in the West, within the Mazatec culture, there is little evidence that Salvia divinorum is used recreationally or that anyone is becoming dependent on it. A survey by Erowid of Western Salvia divinorum users found similar results: addiction to salvia is largely unheard of.

While Western anthropologists had known about the psychoactive effects of Salvia divinorum since the early 20th century, the active molecule was not isolated and identified until 1983 by Ortega et al., in Mexico, and it wasn’t until 1993 that the unique receptor profile of Salvia divinorum was understood. Perhaps because of its unique and often unpleasant effects, and despite being known to such psychedelic luminaries as Gordon Wasson and Albert Hoffman (a popular strain of the Salvia divinorum plant is named Hoffman-Wasson after the pair), Salvia divinorum did not enter the popular consciousness in the same way that LSD, psilocybin, and mescaline did in the mid-20th century.

The Science of Salvia

So what do we know about Salvia divinorum’s pain-relieving properties? The active compound in any preparation of the plant is a molecule called Salvinoin-A, which is almost unique among psychedelic drugs in that, while almost all other psychedelics work by activating some combination of serotonin and dopamine receptors, Salvinorin-A has an affinity for the somewhat-obscure opioid receptor: the kappa-opioid receptor (usually abbreviated as the KOR), which, as far as we know, is not targeted by any other commonly-used drug. Unlike a plant like cannabis, which has thousands of individual molecules that synergize to create its effect, Salvia divinorum’s effects come exclusively from Salvinorin-A. While metabolites similar to Salvinorin-A have been isolated from the plant, none of them appear to have appreciable psychoactive effects (although synthetic derivatives have been created that show comparable effects).

In a very simplified sense, the kappa-opioid receptor can be thought of as the opposite twin of the more well-known mu-opioid receptor, which is what drugs like morphine target. Together, they seem to perform a balancing act that is integral to our own innate ability to learn. The mu-opioid receptor mediates ‘rewards.’ Behaviors that trigger its activation (like having sex, eating a good meal, or shooting a bunch of heroin), result in feelings of well-being and euphoria, which can become addictive. The brain learns to do whatever it is that triggers the mu-opioid receptor. The kappa-opioid receptor, on the other hand, seems to do the opposite. Stimuli that triggers that receptor and the feelings created are of stress, dysphoria and aversion. There are other interesting symmetries: mu-opioid receptor agonists cause itching while kappa-opioid receptor agonists suppress it. Taking something like salvia with something like heroin also seems to blunt the effects of both drugs, which is what you would expect to see if the mu and kappa opioid receptors worked in opposition. Together they help us navigate complex environments full of both rewarding and aversive behaviors, and when everything is working smoothly, they balance one another out. They both, however, seem to dull pain.

The pain-killing effects first discovered by the Mazatec people have borne out under scientific scrutiny. In a series of somewhat heart-breaking studies, scientists took rats and mice and subjected them to a battery of ways to induce pain, which range from putting them on hot-plates that burn their feet, to shooting their tails with lasers, both with and without infusions of Salvinorin-A. Across the board, the mice that were treated with Salvinorin-A showed fewer signs of experiencing pain. The effect is clear: Salvinorin-A is an effective analgesic. In fact, it’s very effective: it’s active at extremely low doses (200ug, making it one of the strongest known, naturally occurring psychoactive compounds) and doesn’t seem to have any point of lethal overdose, unlike opiate painkillers, where high potency usually translates into increased risk of death. Even chronic exposure to high doses doesn’t do damage to vital organs.

The non-addictive nature observed by anthropologists and user-surveys has also been validated by animal studies. The usual tests for addictiveness indicate that Salvinorin-A is extremely unlikely to be addictive. It may even have anti-addictive properties: beyond simply not having effects seen as indicative of addictive potential, Salvinorin-A has been found to exhibit the opposite effect. For example, almost all addictive drugs increase the amount of dopamine activity in a brain region called the nucleus accumbens. Salvinorin-A not only fails to increase dopamine in this region, it seems to actively suppress it. Similarly, in tests of addictive drugs, many animals will show ‘conditioned place preference,’ frequently returning to areas where they received infusions of the drug, even when they’re not receiving any. Salvinorin-A has the opposite effect, creating ‘conditioned place aversion.’ As with the pain-relieving properties, the evidence is clear: Salvinorin-A (and by extension Salvia divinorum) is unlikely to have the same addictive qualities that can make opiate painkillers dangerous. Drugs like Salvinorin-A have even shown promise as a treatment for addiction to other substances, including cocaine and alcohol.

So, thus far, we have a powerful, non-addictive painkiller that is physiologically safe, with no known lethal overdose effect. So what’s the problem? Why aren’t we getting Salvinorin-A infusions in hospitals?

Why It’s Not A Great Medicine

While Salvinorin-A does have some extremely appealing properties, there are a few things that make it completely unsuitable for use as a replacement for our current pain medications. One is that it is only active for a brief period. Anyone who’s smoked Salvia knows that a user will only be under the influence for a few minutes, and even when administered as a quid, the effect doesn’t last longer than an hour. While short-acting pain-killers can be useful in surgery (fentanyl being one famous example), for extended pain management, they leave much to be desired. The other negative, which is something of an elephant in the room, are the hallucinations.

The effects of Salvinorin-A when rapidly administered (such as smoking or injection), or administered in high doses have the potential to be extremely unpleasant. The ‘trip reports’ section of Erowid’s Salvia divinorum vault is full of experiences that range from mildly-distressing, to traumatically disturbing (one that sticks out in my memory is one of a young man who smoked it and felt himself become part of some kind of cosmic machine made of meat). While experienced psychonauts may be able to manage these experiences with appropriate preparation and knowledge, a hospital is possibly one of the worst places to experience a profound and florid psychosis. Earlier I mentioned being given an i.v. of Dilaudid while in the hospital for kidney stones, and I cannot imagine how awful it would have been to have my painkiller also serve as a ticket to Cthulhu’s birthday bash. Such experiences are hard enough in a normal frame of mind, and as far as sets and settings go, being scared, vulnerable, and in pain seem like the worst possible place to embark on a psychic journey.

Looking Forward: What We Can Learn From Salvia

Does that mean we’re done? Decades of research (not to mention a few minutes of your life) tossed in the bin? Not at all. While Salvinorin-A may not make its way into a medical setting, this research has generated a tremendous amount of new data which can be used to start looking for drugs similar enough to Salvinorin-A to take advantage of the positive effects. We now know that selective kappa-opioid receptor agonists are physically safe, effective pain-killers with low addictive potential.

From here there are many directions research can go. There has been some evidence of analogues of Salvinorin-A that cannot cross the blood-brain-barrier (and therefore cannot cause strange effects to consciousness). Clinical trials of a peripherally selective kappa-opioid receptor agonist called asimadoline have been very promising, especially for irritable bowel syndrome (one of the conditions the Mazatec have been using Salvia divinorum to treat for centuries. Other drugs have been developed that try to combine traditional opiate drugs with kappa-opioid receptor agonists in an attempt to balance the effects and reduce the risk of addiction. While psilocybin, LSD, and ibogaine have recently received significant press for their potentially anti-addictive properties, Salvia divinorum shouldn’t be forgotten and may yet have a role to play in the development of our understanding and treatment of addiction.

For individuals with painful conditions like migraines, or IBS, it is certainly possible that they could take inspiration from the Mazatec people and grow their own medicine. The Indigenous people of the Americas were using it as an effective medicine while European doctors were still debating whether it was a good idea to wash their hands before surgeries, and while simply chewing the raw leaf will have some consciousness-altering effects, some may feel that it’s a worthwhile trade-off.

Sometimes there can be a feeling that psychedelic research must necessarily lead to the legalization or prescription of the drug in question. The research into cannabis, psilocybin, MDMA, ibogaine, and LSD are all currently aimed at bringing these compounds into a Western medical framework so that they might one day be prescribed by doctors in white lab coats. There is another side of psychedelic research that is decidedly less glamorous but just as important: doing basic research on Salvia divinorum and Salvinorin-A may never result in someone filling a prescription for salvia at the local CVS, but the things we learn may help change the face of medicine.

Biochemistry is complicated. In this article I’ve attempted to distill one of the most complicated systems in the known Universe (human biology) down into an accessible 2,000 word piece. Consequently, I had to make some simplifications, deliberately tossing some details in order to communicate the larger patterns—the lock-and-key analogy is one example of this. If you want to learn more, I’ve included links to educational resources whenever possible.

 

AYAHUASCA: A MOLECULE EYE’S VIEW

As the psychedelic renaissance continues to build up steam and shake off a half-century of hibernation, the popular conception of drugs such as psilocybin and LSD is beginning to change. No longer are psychedelics just pharmacological cluster bombs, ready to push a hapless user to insanity. Instead, a new image, still in development, reveals these drugs as medicines for ailing souls.

No psychedelic drug has captured the popular imagination as a healing substance quite the way ayahuasca has. Celebrities from Lindsay Lohan to Sting have publicly endorsed its healing potential, and it has even wormed its way into popular television shows such as (believe it or not) Law and Order: SVU.

However, despite changing popular conceptions of psychedelics, particularly ayahuasca, the dialogue remains firmly planted in the domain of the therapeutic and the spiritual. While a quick Google search can return hundreds of articles, forum posts and trip reports that deal extensively with the psychological, therapeutic, and spiritual ramifications of experiences like those engendered by ayahuasca, what the discussion often lacks is a firm scientific footing—some context about how these drugs work on a chemical level, an explanation of what’s actually happening inside your body and brain when these drugs are consumed.

This feels like something of a missed opportunity: There’s a beauty and sense of wonder that comes from knowing how the world works, and the nature of the psychedelic experience dovetails almost perfectly with that awareness. There’s a profound symmetry between the wonder you feel learning how a biological or physical process happens and the wonder you feel when your mind is expanded by a psychedelic. Seeing a flower as a complex and emergent property of a hundred million chemical processes, and seeing that same flower as a beautiful manifestation of an interconnected, spiritual universe are not that different; they may even be the same.

DMT AND SEROTONIN

Ayahuasca is made by making a crude extraction from two very specific plants: Banisteriopsis caapi  (which is the ayahuasca vine itself) and Psychotria viridis. While different curandero/as have their own recipes that can include various admixtures (and some leave out the P. viridis entirely), if you find yourself talking to an up-and-coming tech bro at Burning Man about his visionary ayahuasca experience, you’re almost certainly talking about the combination of those two plants for one very special reason: DMT. While ayahuasca without DMT can be a profound experience, it is the oral DMT that creates the visual fireworks, and its near-mythical status in the family of psychedelic drugs definitely adds to the mystique surrounding ayahuasca.

After boiling the plants for several hours, a few important molecules have migrated from the plants into the water. DMT, obviously, is one, although the others are arguably more important: harmine, harmaline, and tetrahydroharmine, which are all very similar molecules and belong to a family called beta-carbolines. It is these three molecules that make the ayahuasca experience possible. Ordinarily, DMT is not orally active, which means that if you were to sit down and take a pill of DMT, it would have no effect on your consciousness. While it has visionary effects when inhaled or injected, when eaten it is (normally) worthless.

All of this is a quirk of biochemistry, which will be important later. Organic molecules, such as DMT, harmine, and our own neurotransmitters, gain their function from their shape: all of them are basically bundles of identical carbon atoms arranged into different configurations (with a handful of other atoms like Oxygen and Nitrogen thrown in). The shape of a molecule determines what its effect is; form determines function. At this level, biology and biochemistry are essentially applied geometry: The physical substrate of our body is largely carbon, no different than a diamond, or a charcoal briquette, but all that carbon in our bodies and brains happens to be organized into exquisite and dizzyingly complicated shapes which fit together in just the right way. From that intricate clockwork, life emerges.

When you look at the shape of DMT, you’ll notice it looks quite a bit like the shape of another well-known molecule: serotonin. As everyone knows (thanks to concerted advertising campaigns from the pharmaceutical giants) serotonin is a neurotransmitter, occurring naturally in the brain, helping to regulate the complicated dance of neural information processing. This symmetry means that in the body, DMT interacts with other molecules in much the same way that serotonin does: The classic metaphor is a lock and key. In this case, if serotonin is the key to a variety of different locks, DMT is a knock-off key similar enough that it can open some of the same doors. This is where its psychedelic effects come from. Before we get there though, we still need to determine why DMT isn’t ordinarily orally active, but is in ayahuasca.

When serotonin is released in the brain and body, it serves a very particular purpose; once that purpose is filled, it’s in the interest of the body to get rid of it. This is accomplished through the use of enzymes, which are biochemical machines that facilitate chemical reactions that otherwise would be too slow, or wouldn’t occur at all. The enzyme we’re interested here is called L-monamine oxidase A (MAO-A). From its name, someone literate in biochemical jargon can figure out it takes monoamine molecules (like serotonin), and degrades them through a process called oxidation. Coming back to our lock-and-key metaphor, imagine a lock that fit a particular key—but rather than locking or unlocking a door, it was immediately snapped in half. In everyday bodily functioning, this is all well and good, all part of the delicate balance of metabolism. But for those looking to explore consciousness, DMT looks enough like serotonin that it too fits into our imaginary key-chewing machine. When DMT is eaten, it passes from the stomach into the bloodstream, where it goes directly to the liver and is immediately chewed up by MAO-A into something that has no interesting biological activity whatsoever.

This is where those three beta-carboline’s enter the story. When they bump into MAO enzymes, they bind to the same place that DMT and serotonin do, but rather than getting degraded, they just sit there, clogging up the machinery and rendering the enzyme at least temporarily useless. Imagine stuffing the lock of our key-chewing machine with gum. When DMT (which would ordinarily be degraded by MAO-A) enters the body at the same time as the beta-carbolines, enough of the MAO-A is compromised by the MAO-inhibitors that the DMT can make it through the gauntlet of first-pass metabolism and continue on to its final destination: the brain, where the magic really happens.

DMT IN THE BRAIN

Before we keep going, it’s worth mentioning that while the story of the DMT, MAO, and MAO-inhibitors is somewhat specific to DMT and Ayahuasca, what comes next is not. Other orally active psychedelics can survive first-pass metabolism on their own and make it to the brain largely unmolested. Once they get there, however, they all behave in largely the same way, DMT included.

Once the DMT has reached the brain, the fact that it is the same shape as serotonin once again becomes relevant. In the same way that its geometric similarity means it will get degraded by MAO-A, it also means it can activate the same switches in the brain that serotonin does, acting like a ‘pseudo’ neurotransmitter.

When a neuron wants to send a signal to the next one in its pathway, it does so by releasing neurotransmitters into the small gap (called a synapse) between them. The molecules diffuse across this gap until they run into their target neuron. The surface of the neuron is covered in little proteins called ‘receptors,’ which, upon meeting a molecule they recognize, briefly change their shape from the ‘off’ shape to the ‘on’ shape. The signal, which began with the release of neurotransmitters, is completed and the information has jumped the gap from one neuron to another. Turning a receptor ‘on’ can have a variety of different effects, including changing the likelihood that its neuron will fire, or altering the internal function.

When the DMT (which began its life in a plant in the Amazon jungle) finally makes it into the brain, it will flow into those synapses; because it looks a lot like serotonin, it will flip those receptors looking for serotonin into the ‘on’ position, even though no neuron released any serotonin. This is the basic mechanism for all psychedelic drugs; from LSD, to psilocybin, to weird things like 25i-NBOMe: They sneak into the synapses and ‘trick’ the serotonin receptors into activating, causing all kinds of changes in the functions of everything from individual neurons all the way up to the highest levels of consciousness.

So far, we’ve talked about serotonin receptors like they’re all mostly the same and broadly, that’s true (they’re all looking for serotonin, after all). But that doesn’t make them identical, and scientists have found enough differences to classify serotonin receptors into seven types, which are then broken down into 17 subtypes with a wide variety of functions. Most are pretty uninteresting to psychedelic scientists, but there are two that seem particularly important: serotonin-2A (5-HT2A), and serotonin-2C (5HT2C).

All psychedelic drugs activate the serotonin-2A receptor: some do it more than others, but it’s a requirement for psychedelic effects. Despite knowing that the serotonin-2A receptor is very important for the biology of psychedelics, scientists are still figuring out what its normal function in the brain is. We know it’s involved in regulating mood, appetite, sexual behavior, learning and memory, as well as some physical responses such as blood vessel constriction and temperature control. It is mostly found in a particular part of the cerebral cortex (known as Layer 5), where it appears on neurons that help communicate information from one brain region to another. Some researchers have speculated this is how psychedelics create their mind-bending effects: By altering how different brain regions talk to each other, the brain becomes chaotic and somehow, this creates the experience of a higher state of consciousness.

The serotonin-2C receptor is a little bit more mysterious. It is similar enough to the 2A receptor in that almost any drug that activates one will also affect the other, so it can be very hard to tell what effects come from the 2A receptor and which ones come from the 2C receptor. There is a lot of evidence that the serotonin-2C receptor plays a role in regulating mood and anxiety: Many of the common pharmaceutical treatments for depression and OCD affect activity at the 2C receptor, and we know that it helps regulate the release of dopamine (another key neurotransmitter) in brain regions important for learning and addiction. It has been suggested that the non-addictive nature, and anti-addictive power of drugs like LSD and psilocybin come from their activity at the 2C receptor, which alters function in addiction circuits.

Eventually, the ayahuasca experience ends. After four to six hours, even with the beta-carboline’s slowing things down, enough of the drugs are metabolized away that normal consciousness reasserts itself and we return to this world. Different metabolites may float around your system for a while, but eventually it all gets washed away.

A SOURCE OF WONDER

While many psychedelics seem to force contemplation of profound and often overwhelming thoughts and questions, ayahuasca, in particular, seems to invite a sort of wonder. It is a drug that can only exist because it interacts in precisely the right way with our own incredibly delicate biochemistry. DMT, harmine, harmaline, and THH exist in just the right shape and fit into our neurochemical clockwork in just the right way to produce profound outcomes. Even small changes to the shape of any one of those molecules might result in an inactive pile of nothing, or even a lethal toxin.

That sense of wonder is what psychedelic science should capture. Rather than reducing a magical experience down to dull, technical jargon about agonists, antagonists, Ki values and dose-response curves, it should enhance the awe we feel and show us that whatever wonder we feel at the beauty and glory of Creation, it is probably more wonderful still.

Neurogenesis (the process by which the brain grows new neurons, which in turn can interact with other neurons to form connections and networks) has become something of a scientific buzzword recently, both in and out of psychedelic circles. It’s not hard to find supplements claiming that, through some pharmaceutical wizardry, you can harness the “power of neurogenesis.” Many psychedelic blogs have gotten very excited by the prospect that drugs like psilocybin might cause neurogenesis, hoping to generate momentum for the psychedelics-as-real-medicines cause.

After all, who could be against neurogenesis? Growing new brain cells does sound like the first step on the path to super powers, or at the very least, seriously enhancing abilities that we already have. But what is neurogenesis? Do psychedelics really cause it? If they do, what doors might that open up?

The vast, vast majority of neurogenesis happens before we are born: you come into this world with most of the neurons you’ll ever have, and over the course of your life they slowly die off. It has long been thought that the number of neurons you’d ever have is fixed at birth, but now we know that’s not quite true: adult neurogensis has been found to happen in a few select brain regions.

Even though adult neurogenesis is happening in the brain, it’s not happening a whole lot, and only in some pretty particular areas. The cerebral cortex (where most of the highest-level stuff happens) isn’t even on the map here. Sadly, neurogenesis isn’t going to turn you into some kind of mega-brain: most of your nervous system will remain unaffected by drugs that trigger neurogenesis. As far as we know, if you have damage to part of your cerebral cortex, taking psychedelics is unlikely to regrow the affected areas.

So should we all pack up and go home?

Not quite―just because neurogenesis isn’t as wide-spread or powerful as popular coverage might make it seem, there’s still reason to get excited. Of the few locations for neurogenesis, what’s happening in the dentate gyrus of the hippocampus is probably the most interesting, at least to those of us interested in psychedelic neuroscience. If those words sound like some kind of Harry Potter spell to you, you’re not alone and you may find some comfort knowing that generations of students have wept their way through neuroanatomy classes working on these same terms. The hippocampus is involved with many different aspects of cognition, but, at the risk of oversimplifying things, its primary role seems to be regulating both learning and memory.

Damage to the hippocampus can result in a variety of interesting and unpleasant effects, including permanent anterograde amnesia (the inability to form new memories), and it’s one of the first places damage from Alzheimer’s Disease manifests in the brain. For reasons that remain unclear, severe cases of major depression are associated with atrophy of the hippocampus, sometimes by as much as 20 percent, which may explain why, as anyone who has suffered from severe depression knows, being depressed is more than just being down all the time. It comes with its own unique constellation of cognitive effects, including memory problems and issues with focusing and concentration. This last finding is particularly interesting when we add in the fact that the balance of evidence suggests that exposure to psychedelics can, in fact, enhance neurogenesis in this region. This has some pretty profound implications for neuroscience and medicine.

It’s actually a little-known fact that there’s been some research that suggests psychedelics can enhance the natural ability to learn new behaviors and form associations. So far, all the work has been done with animals (rabbits and rats, mostly), but the promise is there.

Two studies using LSD found that the psychedelic enhanced the rate at which rabbits learned a new conditioned behavior, and that higher doses resulted in faster learning. The same researchers found that MDMA, MDA, and DOM all did as well. A more recent study using psilocybin found similar results, albeit only at low doses. It’s hard to draw any strong conclusions from a handful of studies like this―it’s a long way from simple associative learning in a rabbit or rat, to a complex human behavior (like playing the piano), but it’s a start. For researchers interested in treating debilitating psychological conditions like depression using psychedelic medicines, these are enormously promising results.

Why this doesn’t get talked about more in psychedelic circles is beyond me.

So what does this have to do with the idea of neurogenesis? Neurogensis is thought to be one of the mechanisms by which this kind of learning might occur. There have been studies that suggest that, for at least some kind of learning, neurogenesis in the hippocampus may be a key part of the acquisition of new behaviors and pattern recognition. In the interest of fairness, it is worth noting that not every study has validated this theory―there’s still quite a bit of science to be done, but the groundwork has been laid. The same team that was researching the effects of psilocybin on learning in rats found signs of new neural growths in the hippocampus in the rats that had been given the low dose psychedelic treatment and learned the new behavior faster. Unfortunately, as of now, this is the only study that has found a psychedelic triggered neurogenesis AND enhanced learning behavior.

Don’t despair though, there is some circumstantial evidence that should be of interest to those banking on this theory of psychedelic neurogenesis. It has been known for quite a while that the receptor that psychedelic drugs target (the Serotonin 2A receptor) helps regulate the production of a molecule called Brain-Derived Neurotrophic Factor (BDNF, for short). Activate the receptor, and the brain secretes more BDNF. My own (unpublished) research found that that the psychedelic drug DPT (a close analogue of the more famous DMT) increased signs of BDNF in the brains of adult zebrafish, and studies using neurons in a dish and the drug DOI found similar results.

BDNF helps regulate neurogenesis and neuroplasticity: mice that have been artificially rendered unable to produce BDNF show severely distorted nervous systems, with behaviors thought to be related to psychiatric illnesses like eating disorders and OCD. Using genetic techniques to increase BDNF expression can enhance neurogenesis in certain brain regions as well. So far, no one has shown that BDNF causes increased learning capability directly, although participating in learning tasks causes a rapid increase in hippocampal BDNF expression in rats.

My (tentative) hypothesis is that psychedelic drugs can enhance learning and memory capabilities by, at least partially, increasing the amount of BDNF (and related growth-factors) in the brain through activation of the Serotonin 2A receptor. The evidence for this idea is circumstantial right now―so far there hasn’t been a study that combines all of these different moving parts. At the very least, you would need to show that exposure to something like LSD increased how quickly an animal learned a new task, that levels of BDNF in the brain went up, and there was evidence of increased neurogenesis in the hippocampus. This is a fairly tall order, although not one that’s impossible, not by a long shot. All of the individual parts are well within the capabilities of modern science; it’s getting someone to throw time and money behind the question that’s the trick.

Interestingly, in 2016, the Beckley Foundation, working with scientists at the Sant Pau Institute for Biomedical Research in Spain announced findings that two of the key components in Ayahuasca, harmine and tetrahydroharmine stimulate the differentiation of stem cells into healthy neurons when they’re cultured in a dish. There’s still a lot of work to be done on this topic: researchers are moving ahead studying whether the same effect will be seen in living animals, and, if the findings are replicated, these findings would have big implications for the science of neurogenesis.

How these two molecules might stimulate neurogenesis is an open question: unlike drugs like psilocybin and LSD, which act directly at the 5-HT2A receptor, harmine and tetrahydroharmine act as inhibitors of the enzyme monoamine oxidase (MAO), which degrades natural neurotransmitters like serotonin and dopamine. It may be that, when MAO is inhibited, the increase in free-floating serotonin in the brain can trigger BDNF by binding to the 5-HT2A receptor, much like psilocybin would. It may also be an entirely new pathway that still needs to be discovered. For psychedelic scientists, this is the start of an exciting new world of possibilities.

So if all of this is true, what does it mean?

One of the front-line treatments for mental illnesses like anxiety, PTSD, and OCD is cognitive behavioral therapy (CBT), which is based on the same principles that the researchers are investigating with the classical conditioning studies. Anyone who’s participated in a session of CBT knows that the premise is actually very simple, and very reminiscent of the kind of mechanisms scientists use to train rats. Imagine you have PTSD with a specific trigger that sends you into panic attacks. A CBT approach to treatment might be exposure therapy: in a safe setting, guided by a therapist, you are gently exposed to your triggers, again and again. As time goes on and nothing terrible happens, your brain learns something new; the trigger isn’t dangerous and slowly, your original response is made extinct. Similar techniques are used for patients with OCD (who might be unable to stop doing a particular ritual because they’re afraid something terrible will happen) and anxiety disorders. CBT is also used to treat depression, and while the mechanisms are a little different, the same basic principles apply.

It’s easy to see why, if it’s true, psychedelic neurogenesis might be useful. If we could use psychedelics to bolster and enhance our own innate capacity for learning, the applications for treatments and therapies would be tremendous. Humans are fundamentally pattern-making machines. Our most impressive technologies stem from our ability to recognize and make patterns, while some of our deepest illnesses, such as drug addiction, OCD, and depression are the result of getting caught in patterns we cannot control. If the theory laid out here is correct (and it may be entirely wrong), this could be another foundational piece on which to build psychedelic therapy. Beyond knowing just that it works, this might give us a robust, scientific understanding of why and how. It also may help us design new paradigms of psychedelic treatment: currently, almost all of the big studies being done are investigating the effects of single, medium-to-high doses of something like psilocybin, but, if psychedelic neurogenesis is real, there may be just as much therapeutic power in a series of repeated lower doses, in the right context. A medical microdose. The possibilities are endless.

Of course, such simplistic solutions should always be taken with a grain of salt: if someone tells you they have an easy-to-digest answer to a problem involving the brain, they’re probably trying to sell you something (keep that quote in mind next time someone tells you that depression is just a lack of serotonin!). Simple theories can ultimately be built into far more complete, and complex pictures, and even if this isn’t the whole picture (which it almost certainly isn’t), it seems like a pretty good place to start.