- Clinical Psychology
How and why could MDMA-assisted psychotherapy treat PTSD?
Does MDMA support known trauma recovery mechanisms or does MDMA tap into recovery processes characteristic for this treatment type?
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Research Associate at Heidelberg University
Tobias Buchborn is a German Psychologist with a PhD in Neurobiology. He is currently at the Institute of Psychopharmacology, CIMH at Heidelberg University.View full profile ››
LSD had always been a once-in-a-while drug. Compared to other recreationally used drugs, the serotonergic psychedelic lysergic acid diethylamide (LSD) is thought to have a rather low addiction liability1 and its consumption at high frequency has therefore never really been a topic, neither to the public nor to science. Things have changed.
Ushered in by press articles on LSD use in Silicon Valley,2,3 as well as James Fadiman’s Psychedelic Explorer’s Guide,4 a new way of taking LSD has gained public attention. Within the so-called psychedelic microdosing regimen, which is believed to enhance mood and creative thinking, people consume LSD and other psychedelic drugs in low (non-psychedelic) doses, but on a regular basis.5 Although the 21st century is said to mark a psychedelic renaissance with reawakened scientific interest in the acute effects of psychedelics, surprisingly little science can yet tell us what happens when LSD is consumed regularly, again and again.
A variety of recreationally used psychoactive drugs are notorious for their potential to lure consumers into frequent and/or long-term consumption. Although LSD does not share comparable qualities, the clinical experience with addictive substances teaches us an important lesson: the effects of consuming a drug only once in a while do not necessarily equal the effects of frequent or long-term consumption of that drug.
Addictive drugs, when taken once in a while, induce their acute effects: euphoria, excitement, or a sense of calm, to name a few of the sought-after drug rewards. When repeatedly consumed at short intervals, however, the desired effects often fade, leaving a state of pharmacological tolerance. The disappointed user might seek to overcome tolerance by consumption of higher drug amounts, which increases the burden on the body. New, usually more unpleasant effects might manifest over time, and quitting the drug may cause a withdrawal syndrome; where there used to be a burst of energy, for instance, there is now depletion.6
If the drug is properly stored and its purity remains the same, however, it is unlikely that the drug changes its properties towards the body over time. It must be the other way around instead: The body changes its properties towards the drug.
LSD is unusual. Tolerance with respect to LSD’s psychedelic effects comes in a rush, yet published reports on addiction-like patterns and/or withdrawal symptoms surrounding the use of classic serotonergic psychedelics are almost unheard of. Published anecdotes and experimental research in humans are generally consistent and indicate that the psychedelic experience almost completely subsides when psychedelic doses of LSD are taken around four days in a row.
And yet, tolerance seems to go as quickly as it comes. Within less than a week of discontinuation, the original intensity of the psychedelic experience can be reignited.7 In an early human study from the mid-1950s, psychedelic doses of LSD were given daily for two to three weeks, or even up to three months. By the end of the repeated LSD dosings, tolerance was so profound that when researchers replaced the drug with mere water, subjects did not even recognise that it was not LSD they had received. Nor were there any signs of withdrawal.8
Most of the research on human tolerance to LSD was done back in the 1950s and ’60s. While there is large agreement on the quick rise and fall of psychedelic tolerance, there are still a lot of questions that have remained unanswered ever since. In most of the performed experiments, LSD was given for a few days only, usually in daily increasing doses or in repeated, full psychedelic doses.7 Microdosing, as it is done today, was not common back then. Therefore, we do not know if and how tolerance develops when LSD is given in microdoses every other day for months and years. Importantly, the mechanisms whereby psychedelic tolerance arises in humans remains largely undiscovered: If it is not the drug that changes, what is it within the body that renders LSD inactive? What is it that the brain does to bolt the doors of perception seemingly at a moment’s notice, then go on and re-open some days later?
In order for LSD to alter consciousness, it needs to be carried to the brain via blood flow and bind to receptors embedded within the membranes of brain cells. A singular cell can be thought of as a tiny room in the brain. Its membrane, in this analogy, is like a flexible wall or a fine net that separates the individual cell from other cells. A receptor can be thought of as an even tinier bead-chain crumpled together into the cell’s membrane so that one part of the chain protrudes to the outside and the other part protrudes to the inside of the cell. There is a myriad of receptors within a given membrane, but the most important interaction partner for LSD is called the serotonin (5-HT) 2A receptor.
LSD approaches the cell from the outside, binds to 5-HT2A receptors, and allows for the receptors to relay LSD’s unique message through the membrane and into the cell. One of the highest concentrations of 5-HT2A receptors in the body can be found within the membranes of so-called pyramidal cells, which populate the outermost layer of the brain (i.e., the cortex)9. Pyramidal cells have far-reaching branches that are well suited for integrating sensory, emotional, and cognitive information from all around the brain. It has been suggested that proper integration along the given branches and the “decision” of the pyramidal cells to pass information on or to keep it mum is key to whether it enters consciousness or gets denied.10 LSD has been shown to increase the responsiveness of cortical pyramidal cells to incoming information11 leading them to release more of their neurotransmitter glutamate12. Glutamate carries an excitatory message which invites other neurons to follow suit, become more responsive themselves, and thus help to spread the word sparked off by LSD. According to the current scientific understanding, it is this LSD-5-HT2A-glutamate triad that represents one of the cellular key principles of psychedelic activity.
So far, so good; but what does all of this have to do with tolerance? Suppose it is indeed the cortical LSD-5-HT2A-glutamate interaction that holds the key to the doors of perception. In that case, it might be a wise move for the brain to interfere with this interaction to become tolerant and regain its original balance. Given the lack of human research into this field, possible evidence for such interference can only be gathered from the animal kingdom. As in humans, LSD targets 5-HT2A receptors in animals to affect their behaviour. Rats, similarly to humans, also develop tolerance to LSD.7 When treated with LSD for five days, rats not only become tolerant to LSD’s behavioural effects but also show downregulation of 5-HT2A receptors in the cortex of the brain.13,14 Downregulation means that the receptors are internalised (i.e., engulfed by the cell) and then decomposed within the cell15,21 so that they no longer provide a binding partner for LSD. The removed receptors are rapidly replenished when LSD is withdrawn, though, so that upon re-application LSD can bind to them again. At first sight, the cortical 5-HT2A downregulation found in rats nicely mirrors the come-and-go character of tolerance in humans. However, whereas first signs of tolerance in rats and humans are already detected on the second day following ingestion, cortical 5-HT2A downregulation has been shown not to appear before the fifth day of repeated LSD treatment.13 Thus, although important, 5-HT2A downregulation might not be the only process involved in the development of psychedelic tolerance.
To identify what other processes might be involved, we performed a study on tolerance to LSD in rats at the Institute of Pharmacology and Toxicology of the Otto-von-Guericke University in Magdeburg. We found that repeated LSD treatments reduced the capacity of glutamate to bind to its receptors in the cortex of tolerant rats, and that certain subtypes of glutamate receptors, namely mGlu2/3 receptors, became less responsive when stimulated.16 Intriguingly, these changes in the cortical glutamate system were visible before there were any signs of 5-HT2A downregulation. This could perhaps help explain those phases of tolerance that can be detected before five days of treatment. If we were to think of LSD binding to cortical 5-HT2A receptors as a “spark”, we could think of the downstream release of glutamate (or other such relay systems) as the “tinder” needed for the psychedelic message to spread. In this analogy, then, LSD tolerance can begin via thinning out the tinder well before the spark itself is quenched.
When consumed in psychedelic doses and only once in a while, LSD – relative to other drugs of recreational use – is generally thought to exert rather low toxicity on the body’s organ system.17 And consumption of low doses of psychedelics leads to lower plasma levels18 and lower binding to receptors than consumption of normal or high doses.19 Therefore, if psychedelic doses of LSD are rather safe for the body, one might expect low doses to be even safer. Although there is nothing to be said against this for once-in-a-while or short-term use,18,20 one should still keep in mind that acute safety does not necessarily equal chronic safety.
In our research on tolerance to LSD in rats, we investigated hyperthermia and so-called “wet dog shakes”, two bodily effects that, like psychedelia, are mediated by LSD activating 5-HT2A receptors. LSD-induced wet dog shakes continued to occur when small doses were repeatedly given once or twice per day but subsided as some of the small LSD doses were exchanged by medium doses, or were given at a four-hour interval. LSD’s effect on body temperature was even more resistant than wet dog shakes: Hyperthermia subsided only when most of the small doses were exchanged by medium doses.21
These findings point to two crucial characteristics of LSD tolerance: Firstly, tolerance depends on the dose and interval of consumption. The higher the dose and the smaller the interval, the more likely it is that animals become tolerant. Secondly, tolerance to LSD arises with respect to different effects in different ways, a phenomenon known as differential tolerance. Differential tolerance has also been shown for some of the bodily effects of LSD in humans: Effects on body temperature and blood pressure, for instance, only inconsistently indicate tolerance development.7
Similarly, when recreational microdosers were asked about their experiences, they reported a variety of side-effects. These included psychological effects like emotional instability, distractibility, or insomnia, as well as bodily symptoms like headache or dysregulation of body temperature.22 Thus, despite the rapid vanishing of psychedelia upon repeated intake of full-dose LSD, it overall turns out to be quite difficult to predict how the body adapts to a chronic supply of LSD – which effects decrease, which increase, and which pop up perhaps after long-term consumption. Purity and concentrations in a typical LSD blotter may vary, users might not strictly stick to the exact same intervals of consumption, or even be tempted to increase doses over time. Concerns of differential tolerance should, therefore, not be dismissed lightly when thinking about the safety of chronic LSD (micro-)dosing.
All of this, of course, does not exclude the possibility that repeated (micro-)doses of LSD may safely be applied in a (clinically) supervised context and/or even have therapeutically beneficial effects.23,24 It highlights, however, that the scientific understanding of the consequences of frequent and long-term LSD intake is in its infancy. Short-term tolerance to LSD might result from more discrete adaptions, such as 5-HT2A and glutamate receptor downregulation; long-term adaptions of the body to LSD – depending on the dose, interval, and length of intake – might be much more elaborate, though.25 More research is needed to tease out possible benefits and/or detriments of frequent use of psychedelics. Future research should not be restricted to the brain and psychological read-outs but perhaps also look at other organs, which express receptors psychedelics have high preference for.
Does MDMA support known trauma recovery mechanisms or does MDMA tap into recovery processes characteristic for this treatment type?
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MIND Academy and RKE Associate
Vlad completed an M.Sc. in neuroscience at the University of Bordeaux after his B.Sc. in biochemistry and cellular biology at Jacobs University, Bremen.View full profile ››
The question of whether the “psychedelic trip” is truly needed for the therapeutic benefits of psychedelics has become a matter of heated debate. This fact is best illustrated by two recent opposing publications: one by David B. Yaden, PhD, and Prof. Roland Griffiths,1 advocating for the importance of psychedelic experience, and one from Dr. David Olson,2 who claims we could (and perhaps should) discard it. This post gives a neuroscience-based argument for why we should not ignore the human experience.
A recent paper from Dr. David Olson’s lab at University of California, Davis, made waves in the psychedelic research community at the end of 2020, describing a non-hallucinogenic derivative of the psychedelic drug ibogaine, named Tabernanthalog (TBG).3 Ibogaine is known to have antidepressant and antiaddictive properties, but it is restricted in its use by an unfavorable safety profile that includes nausea, cardiac complications,4 and a duration that can exceed 24 hours.5 TBG, on the other hand, is shown to maintain ibogaine’s therapeutic effects in mice without the associated risks. Most importantly, this compound made it to the headlines of several science magazines because mouse experiments suggest that it lacks hallucinogenic properties. Although being allegedly trip-free, TBG is shown to enhance neuroplasticity in the mouse cortex, just like its psychoactive counterpart ibogaine. Comparing the effects of ibogaine with those of TBG may allow scientists to answer a heated question in psychedelic research: can therapeutic benefits occur without the subjective effects? If classical psychedelics increase neuroplasticity and decrease inflammation to an antidepressant effect, is the trip even necessary?
Interested in cutting-edge research on this issue? Check out our INSIGHT 2021 conference in September, which includes presentations by Prof. Gül Dölen on what octopuses and psychedelics can teach us about learning and sociality, and by Prof. Dr. Dr. Uwe Herwig on the neural correlates of emotion- and self-regulation under the influence of psychedelics.
Psychoplastogens [Greek psych– (mind), –plast (molded), and –gen (producing)]: small molecules that produce a measurable change in neuroplasticity (e.g., changes in neurite growth, dendritic spine density, synapse number, intrinsic excitability, etc.) within a short period of time (typically 24-72 hours) following a single administration, and that can lead to relatively long-lasting changes in behavior.6
Even though nearly all identified psychoplastogens (e.g., psilocybin, DMT, ketamine, scopolamine) are psychoactive, this characteristic is not part of their definition. The reason for this is that some scientists now believe that neuroplasticity can be rapidly stimulated even in the absence of a subjective experience, leading to an antidepressant effect.
One particularly effective pathway for stimulating neuroplasticity involves the serotonin 2A receptor (5-HT2AR),7 which is also necessary for the hallucinogenic effects of psychedelics.8,9 For several decades, drugs that stimulated the 5-HT2AR were considered to have a high risk for producing hallucinations, which severely discouraged their development. However, recent theoretical advancements in pharmacology indicate that neuroplasticity and the psychedelic experience may not be a package deal after all.10 To understand that, we need to zoom into the neuron itself and understand a process called biased agonism.
Figure 1: Potential therapeutic mechanisms of (non-hallucinogenic) psychedelics at the cellular level. On the left side, the antidepressant effect of classical psychedelics is achieved through both the psychoplastogenic and subjective effects, using different signaling pathways; on the right, the antidepressant effect of a non-hallucinogenic psychoplastogen is only achieved through an increase in neuroplasticity; the latter compound is a biased agonist – it preferentially activates the Gq/PLC pathway, bypassing – or at least greatly reducing – the subjective effects.
When a drug binds to a receptor on a cell, a number of biochemical chain reactions (also called signaling pathways) are triggered inside the neuron.11 Each of these reactions has a different end-point; this could be the production of a new protein or a change in electrical activity, which further lead to complex changes such as modifying the communication between different brain areas and producing new connections between neurons. When a biased agonist binds a receptor, it preferentially activates one or several of these reactions to the detriment of the others.10
In the case of the 5-HT2A receptor, there are three important signaling pathways inside the neuron: the Gq/PLC, the PLA2, and the beta-arrestin pathways.10, 12 While the details are not entirely clear, all of the cognitive and neurobiological effects that are attributed to 5-HT2AR activation (from visual hallucinations to neuroplasticity) can be traced back to one or several of these signaling pathways. A biased agonist could activate, say, the Gq/PLC pathway, without affecting the other two. In an ideal scenario, the psychoplastogenic effects sit at the end of one pathway, while the hallucinogenic effects are at another. Some evidence suggests that this might actually be the case: a recent paper concludes that beta-arrestin 2 is required for the “psychedelic-like” motor effects seen in mice (i.e. head twitches, retrograde walking, nose poking).13 As a complement, it was previously shown that neuroplasticity is associated to the Gq/PLC pathway,14, 15 which also appears to have a reduced influence on “psychedelic-like” motor effects in mice.16 Lastly, the Gq/PLC pathway is also activated by lisuride, a non-hallucinogenic relative of LSD, further suggesting that the subjective effects lay elsewhere.17
There is some consensus that a positive psychedelic experience can bring larger therapeutic benefits, as revealed in a spirited debate between Yaden and Olson, the two researchers who gave structure to this line of research. Nevertheless, scientists in the psychedelic industry are trying to engineer a compound that retains some of the therapeutic potential but is also scalable, marketable, and administrable to people who do not pass the screening process for a psychedelic experience. TBG seems to be a strong candidate for a widely administrable non-hallucinogenic psychoplastogen. But does it really live up to its hype?
Let us analyze this compound a bit more in depth, starting with its most outstanding feature: lack of hallucinogenic properties. Most animal studies on the hallucinogenic potential of psychedelics are based on the mouse head-twitch response. This is considered the gold-standard for assessing psychoactive effects of classical psychedelics in mice, as several studies have shown a correlation between how well a drug binds to the 5-HT2AR, the intensity of the hallucinations in humans, and the head-twitch response.18, 19, 20 However, apart from the obvious problem that a head motion is a far cry from a window into the subjective experience of a mouse (what is it even like to be a mouse?), there are some important limitations that are worth mentioning.
In the TBG paper, it is shown that a high dose of ibogaine also does not produce a statistically significant increase in head twitches, which is in line with a previous study.21 Yet ibogaine is undeniably hallucinogenic in humans.4 Moreover, the serotonin precursor 5-HTP produces a robust head twitch response in mice,22, 23 while being psychologically inert in humans. This means that until a human being ingests TBG, there can be no definitive claims regarding the hallucinogenic properties of this compound, nor can one yet postulate the existence of atherapeutically viable non-hallucinogenic psychoplastogen. TBG is not the first attempt in this direction, as other proposed psychoplastogens closely related to ketamine have either been proven psychoactive (traxoprodil), or ineffective in treating human depression (AZD6765, rapastinel).24
For now, we shall assume that this compound is indeed non-hallucinogenic in humans. On a close reading of the TBG paper,3 it is revealed that the maximal activation of the Gq/PLC pathway (i.e. the pathway more associated with neuroplasticity, rather than hallucinations) of the 5-HT2A receptor by TBG is almost half of that of ibogaine, 5-MeO-DMT (another potent hallucinogen), and serotonin itself. Remembering the hypothetical example given in the section above, an ideal non-hallucinogenic psychedelic would minimally activate the intracellular pathway that leads to a psychedelic trip, while strongly stimulating neuroplasticity. But TBG may or may not have any preference for one pathway or another at the 5-HT2AR, and due to its intrinsic properties, it may simply not be able to activate any of these pathways to the same extent as its hallucinogenic counterpart ibogaine. What this would really mean is that a large dose of TBG weakly stimulates 5-HT2ARs in a way that is similar to a microdose of DMT, which has also been shown to produce some antidepressant and anxiolytic effects in mice.25
TBG could be a billion-dollar molecule – it is patented, it may treat both depression and addiction, it is synthetized in one step, and it may not make people trip, even if they take more of it (A more in-depth critical look into the commercial incentives for such compounds can be found in this article on the APRA Blog). From a pharmacological point of view, however, TBG doesn’t seem much different from already existing solutions. And even though the authors of the TBG paper emphasize a shift in the perspective on mental health care from correcting “chemical imbalances” to correcting “damaged circuits,”6 there is still not a single mention of the human experience, making it seem like this is not the kind of paradigm shift some practitioners are calling for.26
Now that we explored the neurobiology of non-hallucinogenic psychoplastogens, let us get to the key point of neuroplasticity itself. Neuroplasticity has become a buzz word in psychedelic research recently, wherein many are reducing the therapeutic benefits of both novel (e.g. ketamine, psilocybin) and classical antidepressants (selective serotonin reuptake inhibitors such as fluoxetine) to it.27 But can an increase in plasticity alone do the job of changing one’s mind?
Firstly, what even is plasticity? Put broadly, it’s the brain’s ability to change its structure and functions through brain activity. More concretely, neuroplasticity is an umbrella term that encompasses several dynamic processes that modify how neurons communicate with each other.28 In a hardware-software analogy of the brain and mind, neuroplasticity would represent the processes through which the software (brain activity) modifies the hardware (neuronal circuits).29 These processes include modifying the strengths of existing connections, creating new connections (via newly grown neuronal branches called dendrites), and eliminating old ones.
Some believe that people develop depression through a pathological loss of connections, most notably in the prefrontal cortex,27, 7 and that psychoplastogens can repair or rebalance these circuits.6 What is rarely emphasized in this particular discourse is the fact that the brain is a profoundly organized, hierarchical organ. This means that each connection has a precise function and significance, and plasticity (just like brain activity itself) is not a haphazard process, but a carefully orchestrated cascade in which useful connections become enhanced and obsolete or redundant ones atrophy. Importantly, the usefulness of these connections is assessed locally, through principles of homeostasis and harmonious activity, and may only weakly correlate with good mood, happiness, or fulfillment. Evolution has likely optimized our nervous systems for functioning and survival rather than psychological flourishing. It is therefore unlikely that the brain will attune to these positive feelings by itself, through sheer cellular processes that are induced in an unspecific manner.
So, what exactly would those psychoplastogens restore? The elimination of connections is as crucial to brain development and functioning as the creation of new ones, meaning that more connections are not necessarily beneficial by themselves. Dr. David Olson, head of the team who coined the term psychoplastogen and discovered TBG, stated that “the most useful psychoplastogens will be the ones capable of promoting plasticity in a circuit-specific manner. […] Promoting plasticity indiscriminately is not likely to be beneficial.”6 Ergo, what truly matters is which connections are formed or lost, and the persistence of that change over time. Even in the seminal paperwritten by Ly et al.7 (summarized in this MIND blog post), which turbocharged the whole discussion about neuroplasticity and psychedelics, it is unclear how long the new connections between neurons persist, let alone what they mean.
Generally, plasticity happens as a direct consequence of coherent neuronal activity, as exemplified by the famous quote from neuropsychologist Donald Hebb: “Neurons that fire together, wire together”. Psychedelics and ketamine seem to enhance this process by opening a window of opportunity for plasticity, which is closely preceded by a flow of thoughts, emotions and imagery, some which follow a subjectively deeply meaningful narrative thread.37
In relation to a psychedelic trip, it has been shown that interpersonal exchanges, mystical experiences, and personal insights correlate with the persistence of the therapeutic effects in patients who had them.1, 30, 31, 32 What is interesting is that the presence and strength of a mystical-type experience — and not the overall intensity of the experience — correlated with the therapeutic benefits.1
The effectiveness of MDMA in treating PTSD is also highly dependent not only on setting, but also on the experiences that follow the acute dose. This appears to hold true as long as that window of neuroplasticity remains open – spanning at least two weeks, according to one study.38 As Dr. Gül Dölen, MD, PhD, Associate Professor at Johns Hopkins University and MIND Foundation Scientific Advisory Board member, said in an interview for the MIND Blog: “Any drug or any manipulation that can reopen the critical period has the potential for that therapeutic effect. But then on top of that, the setting dependence of it means that what the psychedelic journey is doing and the setting is doing is priming the brain so that the right memory and the right circuit is being brought into reactivation or made available for modification in this open state.” It is beyond doubt that all experiences have aneurological correlate, a trace or an “engram,” but due to the complexity of brain architecture, there is no technology that can identify and change circuits that are linked to a specific traumatic memory, or to a detrimental behavior. It seems like the only window we have into these circuits is through the act of remembering.
In other words, particular altered states of consciousness (like those induced by psychedelics, but potentially extending beyond them), which are triggered by (or at least generally oriented towards) the therapeutic problem, would be the curators of the beneficial and specific kind of plasticity that is likely to last and be reinforced. However, without that experience, psychoplastogens could just cause a transient increase in indiscriminate cortical connections.
The point of this article is not to belittle the efforts of the many scientists searching for non-hallucinogenic psychoplastogens, but to give some depth to the argument favoring the importance of the psychedelic experience, from a neurobiological point of view. Why is this important? Neuroscientific discourse has become central in any discussion about mental health, even in situations in which we don’t know exactly what psychological processes we’re dealing with. There is a tendency in psychiatry to delineate illnesses with fuzzy borders and equate them to neurobiological markers which are subject to repair. This tendency, fueled by a pharmaceutical system in which drug development, prescriptions, and shareholder value are inextricably linked, leads to the proliferation of simplistic and marketable solutions to poorly understood problems.33
The advent of psychedelic therapy raises hopes for a reform of how we understand the brain, the mind, and its various deviations from the norm. In spite of exuberant enthusiasm from some parties, psychedelics are not a magic bullet for the mental health crisis. But their re-emergence has – if nothing else – given center stage to the human experience, not just as an outcome measure of symptom severity, but as a mediator of change.39 Reframing psychedelics as psychoplastogens, turning the discussion from “correcting chemical imbalances” to “correcting circuit imbalances,” and framing the psychedelic experience as costly and unscalable misses that point entirely. Nobody doubts the transformative potential that the birth of one’s child, a peak experience,40 or a close brush with death can have on one’s life. Many people compare their psychedelic experiences to all of the above and even rate them as among the most meaningful experiences of their lives.34
It is true that those who undergo psychedelic therapy require special care and attention, but perhaps that’s what it takes. Viewing care as a cost to be cut has already produced a system of ‘managed care,’41 wherein people are prescribed antidepressants without seeing a therapist, leaving up to one third of patients inadequately treated.33,35 Patients who have undergone both types of treatments underline this sentiment: “[Antidepressants are] like taking a painkiller for a toothache, you don’t get to the source of the problem”.36 Many associate established antidepressant medications with an avoidance of the underlying cause of their depression, even exacerbating a feeling of disconnection, which contrasts with psychedelic therapy.36
For those who cannot pass the screening required for psychedelic therapy, non-hallucinogenic psychoplastogens could represent another chance, if they turn out to exist and work. If not, microdosing could also be an alternative, if proven effective as an antidepressant in the future. However, it clearly does not seem sustainable to simply keep prescribing pills and releasing a large number of patients back into the same environment in which they developed their depression in the first place.
There is a risk that the market could take trip-free psychedelics as a coarse but sufficient distillation of classical psychedelics, and choose not to deal with the trip due to the numerous complexities in its implementation in mental health care. What appears now to be the way to a mental health revolution could fizzle out into a skillful rebranding of failed treatments, at the expense of people who cannot recover a sense of meaning and connection to this world and to other people. If psychedelics would become psychoplastogens in therapy, psychiatry may once again close its doors to human subjectivity just as it is tip-toeing back to its rightful place.
Is microdosing LSD safe, and does it really have its alleged benefits? Answering this question requires understanding tolerance to LSD.
Among the potential targets for psychedelics in neurodegenerative diseases, neuroinflammation might be the most promising. Psychedelic researchers are gathering more information about how these compounds modulate different inflammatory processes.
Evidence is mounting that psychedelic drugs like LSD, psilocybin, and DMT can be successfully used as treatments for mood disorders like anxiety and depression. Beyond psychological benefits, insight into their physiological mechanisms of action, including positive effects on neuroinflammation and neuroplasticity, has inspired a new wave of research. Researchers are now investigating whether psychedelic therapies can be administered more broadly, treating not only mood disorders but also neurodegenerative conditions like dementia and Alzheimer’s disease. Will psychedelics usher in a more hopeful era for patients with neurodegenerative conditions? There are only two ongoing studies exploring the use of psychedelics for the treatment of Alzheimer’s disease, and this article reviews the rationale behind them.
With over 30 million global cases, Alzheimer’s disease (AD) is one of the world’s leading causes of cognitive decline. The disease causes cell and connectivity losses in the brain, and its progression leads to a loss of important mental skills, including working memory, attention, planning, and self-control.1 The causes of AD are complex and manifold. Specific genetic variants have been found to correlate with it, but they can’t account for all cases of the disease in the population. Apart from mutations, lifestyle factors including diets rich in processed foods, physical inactivity, smoking, and drinking alcohol, as well as social isolation, have all been identified as risk factors.2
AD has been causally linked to the pathological aggregation of proteins that clump into plaques between nerve cells (amyloid-ß or Aß protein) or twist into fibres or “neurofibrillary tangles” within the cell itself (tau protein). The abnormal deposition of these proteins is particularly pronounced in the hippocampus (one of the brain’s main memory centres), as well as the cortex and the basal forebrain.3 Exactly how these molecules drive neurodegenerative processes has not been determined. So far, it can be said that excessive plaques and tangles may drive cell death by disrupting basic cell functioning such as the stress response or nutrient transport.4,5
The cholinergic hypothesis – the idea that AD is caused by the dysfunction in neuronal signalling via the neurotransmitter acetylcholine (ACh) – has long been the primary paradigm in developing AD treatments.3 Indeed, AD patients’ brain cells produce less of this neurotransmitter, causing cholinergic (ACh-containing) neurons to die.6 The majority of clinically approved drugs for AD work by stopping the degradation of Ach, and while they have been shown to be effective for improving cognitive function, they cannot fully stop the decline.6,7
The cholinergic hypothesis doesn’t address the underlying causes of AD – Aß plaques or neurofibrillary tangles of tau protein. There are currently no approved drugs targeting these structures, although many are in clinical trials or under review.7 However, scientists are also exploring other options: Many now focus on treating chronic brain inflammation and cellular stress.8
A newly popularised way of looking at AD, as well as other neurodegenerative diseases such as Parkinson’s or multiple sclerosis, is a disease driven by chronic inflammation. In the last decade, it has become clear that the brains of AD patients exhibit a sustained inflammatory response.9 The main agents of this response are microglia. These are the brain’s mobile “cleaner” cells that constantly scavenge the brain for any sign of damaged cells, infectious agents, or indeed plaques such as the ones formed by Aß. When they encounter such threats, they get rid of them by ingesting and degrading them. In addition to ‘’eating’’ inflammation-promoting material, they also secrete many different chemicals that serve as inflammatory signals to the rest of the immune system and draw more cleaner cells to plaque sites.
Inflammation in the brain makes virtually every aspect of AD worse, including its pathogenesis.9 Some of the molecules secreted by microglia cause chemical changes in the tau protein and worsen neurofibrillary tangles. And Aß is inextricably related to the immune response: during healthy ageing, it contributes to non-pathological inflammatory responses and gets cleared by microglia afterwards. In AD patients, more Aß is produced—possibly due to more inflammation in the brain from the start)—and microglia become less able to clear it. Inflammation also worsens the symptoms and progression of AD: it impairs learning and memory and reduces synaptic plasticity (the ability of neurons to modify their connections).10
AD research has mainly focused on the role of the acetylcholine system because much of the disease progression can be attributed to the loss of acetylcholine signalling and the death of cholinergic neurons. But do other neurotransmitters matter?
It is now becoming increasingly apparent that changes in serotonin signalling might worsen cholinergic deficits in AD progression.8 Serotonin is one of the most abundant neurotransmitters in the brain, and it is found in neurons co-localising with cholinergic neurons in the cortex and hippocampus, where they are thought to regulate each other’s function. In the brain stem, AD patients show a major loss of serotonergic neurons, corresponding to a more severe progression of the disease.11 Furthermore, SSRI-antidepressants, which modulate the amount of available serotonin in the brain, have been shown to decrease the symptoms of memory impairment in neurodegenerative diseases, as well as to decrease microglia-mediated inflammatory responses.12,13
New research has shown that classical psychedelics such as LSD and psilocybin may be effective in the treatment of depression and anxiety.14 There are currently several clinical trials underway which test LSD and psilocybin, as well as DMT and ayahuasca (a DMT-containing brew) as treatments for these and other psychiatric conditions. Like SSRIs, psychedelics are serotonergic drugs, meaning they exert their effects by primarily affecting the serotonin system. Yet, both of these classes of drugs do more in the brain than just change serotonergic signalling. Extensive research in cell culture and animals has shown that 5HT-2A agonists (compounds that interact with the serotonin 5HT-2A receptor, including most prominently LSD and psilocybin) have anti-inflammatory effects.15 In humans, a recent study has shown that low doses of LSD increase the blood plasma levels of BDNF, a molecule implicated in neuroplasticity.16 Does this mean that psychedelics could be as effective as SSRIs in AD symptom treatment, on both a psychological and physiological level?14 And since SSRI treatment often leads to negative side-effects (including chronic fatigue, weight gain, and sexual dysfunction),17 what would it mean if there was a group of drugs that act similarly on the serotonin system, but with fewer acute side-effects?18
In the last decade, evidence has mounted that psychedelic drugs can have positive physiological effects. It didn’t take long for the discovery of the anti-inflammatory effects of 5HT-2A agonists15 to inspire researchers to examine psychedelic compounds as potential medicines against neurodegeneration. As of 2021, there are two ongoing studies probing the potential of psychedelics in AD and in cases of mild cognitive impairment.
Eleusis, a company researching the therapeutic benefits of psychedelics, is currently conducting a clinical trial investigating the effects of low-dose LSD (“microdosing”) in Alzheimer’s patients. They are building up on recently published results of a Phase I trial in which they demonstrated that repeated microdosing (21 non-consecutive days) is well tolerated with minimal adverse effects in healthy volunteers.19 These findings allowed Eleusis to move on to Phase II, where they are examining the effects of LSD microdoses on AD patients.
In the US, Johns Hopkins University has been one of the pioneering institutions in the research of psychedelic therapies for mental health conditions. Their Center for Psychedelic and Consciousness Research has recently started a study investigating whether psychedelic-assisted therapy can help treat depression in people with AD – a disorder that commonly co-occurs with the disease, estimated to affect almost 40% of AD patients.1However, knowing that psychedelics have positive effects on neuroplasticity and neuroinflammation, might they help with more than just depression?
Eleusis have recently published white papers detailing the scientific background of their ongoing LSD trial for AD. Around the same time, a review paper was published in Frontiers in Synaptic Neuroscience explaining why researchers have become interested in psychedelics as a means of treating neurodegenerative disease.20 What is their rationale? The main mechanisms suggested by both groups of researchers can be grouped into three main categories.
Psychedelics reduce inflammation in the brain. 5HT-2A receptor agonists act as potent anti-inflammatory agents, mostly by reducing cellular stress and modulating the activity of pro-inflammatory molecules, such as those secreted by microglia (although research directly on microglia is yet to be conducted).20,21
Psychedelics might affect neurogenesis and neuroplasticity. The loss of neurons and the connections between them has been linked to all symptoms of AD. It is unclear whether psychedelics might reverse or exacerbate some of these processes. In rat models, large doses of 5HT-2A agonists like psilocybin and LSD inhibit the growth of new neurons in the hippocampus (the area of greatest importance for neuron loss in AD).22 On the other hand, another rat study demonstrated that low doses inhibit cell death in this brain region.23 From this, it isunclear whether the net effect in humans would be positive or negative. Apart from neuron growth, however, a number of psychedelics have been found to enhance neural connectivity. Studies in cultured human cells treated with different psychedelic compounds demonstrated growth of the projections that receive signals from other neurons (dendrites), as well as increased numbers of connective junctions with other neurons (synapses).24
Can psychedelics improve learning and memory? Treatments that reduce cognitive decline are among priorities for intervention in neurodegenerative diseases. Presently, no studies have conclusively demonstrated that 5HT-2A agonists can significantly improve cognition, although data on this matter are limited. While many users of recurrent low-dose psychedelics (microdosing) claim this practice enhances their memory, studies so far have found no memory benefits of LSD and psilocybin at these doses.19,25,26 However, as the researchers point out – ‘’While these results contradict reports of enhanced cognition in the context of recreational use, it should be noted that not all pharmaceutical drugs that target cognitive and behavioural impairments have nootropic [cognitive-enhancing] effects on healthy participants.”19
Promising as psychedelics may be, we know of no medicine that can regrow dead neurons. Psychedelic therapies are unlikely to cure AD, and since their mechanisms of action are not primarily directed at the most important systems of AD pathogenesis, their physiological benefits will likely be limited. However, as they show exceptional promise for mental health conditions, they are not to be discounted as potential aids in the treatment of neurodegenerative diseases and particularly their psychological comorbidities. More so, neurodegeneration and mental health may be linked even beyond depression as a side-effect of AD. Mindfulness training has been shown to benefit early-stage AD patients’ mental health by reducing depression and stress, but also their physical health by reducing neuroinflammation.27 Many of the benefits of mindfulness can be provided by psychedelics, and these two methods of intervention are thought to complement one another well.28
Among the potential targets for psychedelics in neurodegenerative diseases, neuroinflammation might be the most promising. Psychedelic researchers are gathering more information about how these compounds modulate different inflammatory processes. With time, this may enable scientists to maximise the potential of psychedelic drugs in a variety of therapeutic contexts. This research can go in the direction of optimising the dosing protocols in terms of frequency and concentration, but also in the direction of biochemical studies exploring other compounds and receptors.
Psychedelics don’t end with psilocybin and LSD. Other molecules, including popular and naturally occurring ones like DMT, but also completely novel synthetic molecules, may play a future role in the treatment of mental disorders and neurodegenerative diseases. In addition to its positive effects on mental health,29 the immunoprotective and anti-inflammatory properties of DMT have been suggested in different studies,30 and there are indications that they may be mediated not by 5HT-2A, but by another, novel receptor, Sigma1. And, in the increasingly rich world of synthetic psychedelic molecules, there are several that could serve as an interesting research focus. Some studies have already identified psychedelic molecules with anti-inflammatory properties stronger than those of LSD.15 Others have managed to isolate the locus of anti-inflammatory activity and generate psychedelic-like molecules that lose their mind-altering properties while maintaining the physiological benefits.31 In the future, these drugs may yet be recognised for their therapeutic qualities by psychiatrists and neurologists alike.
Is microdosing LSD safe, and does it really have its alleged benefits? Answering this question requires understanding tolerance to LSD.
Professor at the Neuroscience Center, University of Helsinki
Prof. Castrén's research focuses on the effects of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) on the adult brain.View full profile ››
Antidepressants are some of the most commonly prescribed drugs in the world, with a number of proposed antidepressive mechanisms. A new paper takes a closer look at classical antidepressants like SSRIs & SNRIs, and newer antidepressants like ketamine, to answer the question: is there one underlying mechanism whereby all these different drugs exert their antidepressive effects? (To learn more about ketamine check out MIND’s online lecture series on ketamine and our Psychedelic Compendium on ketamine) In this paper, published in Cell, the authors argue that across all these substances there is one common mechanism that is essential for their antidepressant effects, which promotes synaptic plasticity in the brain. I interviewed one of the authors, Prof. Eero Castrén, with the goal of understanding what this new mechanism is all about.
Lukas: Welcome to this research interview! Thank you for being here today. We’re doing this interview to discuss one specific study you have been involved in. To start off, I would like to know a bit about the background of this research. How did you come up with your research question?
Eero: Well, this is actually something that we’ve been doing for 20 or 25 years already. So it’s a really long-term project. I have an extensive background in neurotrophic factors and neuroplasticity, with a particular focus on BDNF [brain derived neurotropic factor, a protein that is important for the growth of new brain cells] and TRKB [tropomyosin receptor kinase B] receptors [to which BDNF binds]. All the time that I worked in this lab, we have been investigating these molecules and particularly want to find out if psychotropic medication might influence or act upon these receptors. One of the classes of drugs we have investigated are antidepressants, and already found 20 years ago that, when you treat mice with antidepressants, signalling via this TRKB receptor is increased. From that point onwards we spent a lot of time investigating how this happens and which mechanisms are involved. So this recent paper is basically the result of 20 years of work.
Interested in seeing more cutting-edge research on depression, mental health, and psychedelics? Check out our INSIGHT 2021 conference in September, which includes presentations on these topics by Prof. Dr. med. Franz X. Vollenweider, Prof. Dr. med. Gerhard Gründer, and Dr. Katrin Preller.
Lukas: That is impressive. I suppose this explains why you present the results from so many different research techniques and methods. Could you shortly summarise what these different methods are? And what were the approaches you used to investigate this specific receptor?
Eero: Well, my laboratory is focused on biochemistry and molecular biology, and we have mostly investigated signalling molecules, such as BDNF, and their changes in response to drug treatment. We often look at how phosphorylation [a process in which a phosphate group is chemically added to a molecule with the help of an enzyme] activates these signalling molecules (e.g. neurotransmitters or hormones). In addition, we were doing several different kinds of binding studies, looking at how drugs with very specific structures, such as SSRIs [selective serotonin reuptake inhibitors, the most common type of antidepressant drug], bind to TRKB receptors.
One critical component of this particular study was the modelling. We had the pleasure of collaborating with the lab of Ilpo Vattulainen. He’s a very talented physicist and a specialist in investigating the structure of transmembrane proteins through computational modelling [transmembrane proteins are biochemical structures that span the entire cell membrane and have intra- and extracellular functional units]. For our study, his group created models of small molecules like cholesterol and steroids influencing the structure and function of the TRKB receptor. So our work was actually a sort of back-and-forth collaboration with this group. They generated ideas that we would then test in our lab, upon which and they used the results from our lab to improve their model. I think this collaboration was an essential part of this paper, and what I’m most happy about is the model that we ultimately came up with. We managed to design a specific model detailing what exactly happens when antidepressants bind to the TRKB receptor, and this is something we could not have come up with without this cooperation.
In addition to this, we ran studies in cell cultures, where we investigated the effects of these drugs on the growth of neurons and saw that, if we mutated the TRKB receptor, this effect was lost. We also did behavioural studies with mice, in which we saw that a genetic mutation which prohibited antidepressants from binding to the TRKB receptors, led to a loss of their antidepressant effects in these mice. Taken all together, we had a very large repertoire of methods that we used.
Lukas: You already mentioned some of the results you saw from these different methods. Could you summarise the main results for us again? And what were the results you personally thought were the most important?
Eero: As I said, my lab already found some evidence 20 years ago that TRKB signalling is increased by these drugs, and now we have direct biochemical evidence that these drugs indeed bind directly to the TRKB receptor.
The modelling additionally indicated a specific site on the TRKB receptor where antidepressants bind. This binding site is actually at the junction of two TRKB receptors that have come together in a specific way, creating a site for the drug to bind. In the lab, we could verify this binding site using genetic modifications.
Also, imaging studies showed that the presence of the TRKB receptors on synaptic membranes is increased through this binding of antidepressants lending further evidence to the hypothesis that antidepressants bind to them. Usually, TRKB is visiting the synaptic membrane only for a very short time and then it’s excluded from the membrane, which means BDNF can’t bind to it anymore. But through the binding of the antidepressants this presence of the TRKB receptor in the membrane is increased, which means there is a higher chance of BDNF binding to it as well.
This is something that I found very rewarding because many drug companies have been investigating and trying to find molecules that would directly activate TRKB receptors, in the same way that BDNF activates them. I was always kind of sceptical about this approach, since there is a reason the TRKB receptors normally stay in the membrane only for a short time: The idea is that this short time for BDNF to bind to the receptor allows the brain to select and stabilise only those synaptic contacts and connections that are actively used. But if you directly activate TRKB receptors everywhere you would also stabilise synapses that were not actively used, which would negatively affect the signal to noise ratio in the brain and lead to less optimal performance.
What we now see as a result of the antidepressant action, is that the TRKB receptors are more active and stay in the membranes for longer, but they still need the release of BDNF to have any effect. This means that, even though synaptic TRKB receptor presence is increased across the board, only those synapses are strengthened where BDNF is being actively released, i.e., the active connections are strengthened. For me this is very gratifying because I always thought this kind of action would be a dream come true and it turns out that antidepressants might actually fulfil this dream. We suspected something like this for quite some time, but we had no idea how this could happen, and now we have a model and we’re testing this model and hoping it will stand the test of time.
Lukas: Is this “dream come true” also what you are hinting towards when you state that antidepressants are “smart drugs” in your paper? Could you explain in what sense antidepressants are “smart”?
Eero: What I mean in this particular context is that the drugs themselves do not activate the TRKB receptors, but they increase the probability of BDNF binding to it. Antidepressants only provide an opportunity for BDNF to bind, which means that the activation of the TRKB receptor still is dependent upon neural activity. And neural activity is in turn influenced by your own actions, so you can actually influence the outcome of this drug treatment through behaviour. This is what I mean by “smart drugs”. This kind of action being a dream come true means that these substances are not imposing things on you, but basically giving you an opportunity to influence the structural function of your nervous system through your own actions.
Lukas: That is very exciting! In the study, you further report that this occurs across different types of antidepressants [SSRIs, SNRIs, Ketamine]. Do you think that this effect might also be the cause of antidepressant efficacy of other drugs? Meaning that all substances with potential antidepressant effects would work through this same mechanism.
Eero: Essentially all the antidepressants drugs that were investigated have been shown to involve signalling via TRKB receptors. I think that BDNF and TRKB are only mediating the process of activity-dependent synaptic selection and stabilisation. If you can activate this same process using other molecules, then I think that this molecule might also be an antidepressant. I don’t see any reason why in principle you could not come up with another molecule that would fulfil the same type of physiological effects [promoting neuroplasticity] but using different molecular pathways. It seems that TRKB and BDNF signalling have evolved to fulfil this particular function and that’s why acting on TRKB receptors seems straightforwardly to produce these effects. As I was saying, so far it looks like essentially all the drugs that are antidepressants seem to be doing this thing.
Lukas: Let’s turn now to the implications of your findings. What do you think your results mean for the interpretation of the antidepressant effects of SSRIs, which classically has focused on the role of serotonin? Do your results imply that serotonin signalling is actually not necessary for the antidepressant action?
Eero: Serotonin is a very important and very old neurotransmitter that has existed for a very long time in animals and even in plants. It definitely has many effects in the brain and it’s very clear that these antidepressant drugs actually influence serotonin transmission, there is no question about this, but our data suggest that serotonin may not be needed for the antidepressant effect. We saw that when we genetically manipulated TRKB receptors in mice and then put these animals into behavioural tests, the antidepressant effects seem to be lost. From that point of view it seems to us that TRKB is a critical mediator for these behavioural effects, but there is definitely serotonergic action going on as well. Such effects occur together, and I think more work is now required to look at what the specific effects of antidepressant drugs actually are. It could be that different drugs have slightly different ways of affecting TRKB but also of affecting monoamines including serotonin, which could indicate in which situations to use which drugs.
Lukas: In addition to neurotransmitters, in your paper, you also mentioned the effects of cholesterol in the brain. Could you clarify the difference between cholesterol in the brain and in the rest of the body?
Eero: Cholesterol is often considered a bad guy that you need to get rid of, but in fact cholesterol is an important part of the fatty membranes that are surrounding all cells. It also plays an important role in coordinating many proteins and different factors.
Interestingly cholesterol does not pass from the rest of the body to the brain, which means the brain is dependent on its own cholesterol synthesis. This is mostly done by astrocytes in the brain, which transmit the cholesterol to neurons that take advantage of it. It has been shown before that cholesterol is important for connectivity and synaptic function in the brain, and if you’d reduce it too much then you would have problems with synaptic function. Basically, the high cholesterol in the body has nothing to do with cholesterol in the brain and does not get transmitted across the blood-brain barrier. Even though it is kind of considered a bad guy, it is definitely necessary for proper function of the brain.
For example, we found that cholesterol also acts on TRKB and our results actually imply that antidepressants can bind to TRKB only because cholesterol supports this binding and it is required for the antidepressant effects.
Lukas: I have one final question for you: What comes next for you and your lab?
Eero: There are a number of things we are doing. One of these, which is quite natural now that we have found this binding site and have a model of it, is looking for drugs that can be designed for this particular site, with potentially higher affinity than common antidepressants. One result of this could be altered versions of classical antidepressants that act faster. The other thing that we are investigating are natural substances in the body, other than BDNF, that interact with TRKB, such as cholesterol. This is also something that we would like to investigate more in detail and understand better.
Lukas: Perfect! Thank you again for your time and all the best for the future.
Is microdosing LSD safe, and does it really have its alleged benefits? Answering this question requires understanding tolerance to LSD.
The public often runs off with a compelling story before the scientific results are in. This is equally true for the ego narrative as it is for the DMN narrative.
It has been three years since Michael Pollan’s How to Change Your Mind launched psychedelic science back into mainstream awareness. The book popularized the notion that the Default Mode Network (DMN), the brain network that becomes active when people are not engaged in a task and let their mind wander is the seat of the ego or self, and that psychedelics work primarily by “shutting it down.” In it Pollan writes:
“It appears that when activity in the default mode network falls off precipitously, the ego temporarily vanishes, and the usual boundaries we experience between self and world, subject and object, all melt away.”1
Since the book’s publication, the media has been flooded with stories framing ego death via DMN-silencing as the hallmark of the psychedelic experience.2 This framing has been so widely accepted as common knowledge among the psychedelic-minded general population that well-known psychedelic retreats now incorporate lines like the following into their mission statements: “[We] make the most of psilocybin’s effects on the DMN by helping participants explore the freedom from egoic control in a safe, comfortable, and guided environment.”3 By contrast, most psychedelic scientists, if pressed, will explain that the tie between the ego and the DMN is something of a myth, or at least an overblown narrative.
“I think that a lot of researchers are maybe barking up the wrong tree in terms of ego dissolution,” says David Yaden, PhD, a postdoctoral research fellow at Johns Hopkins Center for Psychedelic and Consciousness Research, in a 2020 interview with humanistic psychologist Dr. Scott Barry Kaufman. “The focus on the DMN is something that will probably not continue to be very helpful in terms of scientifically understanding why these experiences are so beneficial.”4
So, how did we get here, along with Pollan and others? And does it even matter that we’re here? What’s the harm, if any, in believing psychedelics shut down the DMN and dissolve the ego that is rumored to live there?
Interested in cutting-edge research on how psychedelics affect the brain and mind? Check out our INSIGHT 2021 conference in September, which includes presentations on such topics by Prof. Dr. Dr. Uwe Herwig, and Dr. Katrin Preller.
Handed down from Sufi Muslim and Buddhist traditions, ego death was adopted by Timothy Leary in the 1960s to describe the first stage, or “bardo” (Tibetan, intermediate or transitional state between death and rebirth) of drug-induced altered states of consciousness in his book The Psychedelic Experience: “complete transcendence—beyond words, beyond space-time, beyond self.”5 Leary describes subsequent stages as “periods of hallucinations” and finally “a rebirthing into routine reality.”5 Around the same time, although only indirectly related to psychedelics, the concept of “psychic death” was introduced by Carl Jung6 and comparative mythologist Joseph Campbell described the Hero’s Journey as a process of stripping one’s self in order to return changed to routine reality.7 In the 1970s, transpersonal psychologist Stanislav Grof offered the view that ego death should be the primary objective of psychedelic therapy.8 During the psychedelic research slump, spiritual author and speaker Eckhart Tolle continued to popularize ego death, equating it with freedom from suffering.
Sixty years after it was introduced to the West, ego death has become something of a competitive sport in certain circles, with entire online psychedelic forums devoted to comparing levels of its experience.2 As an anecdotal phenomenon during both psychedelic and non-psychedelic states, ego death is well-documented, but does current neuroscience research reflect our interpretation of this phenomenon as a “loss of self,” and is it really localized to one brain network?
Prof. Dr. Robin Carhart-Harris’s 2014 paper on the Entropic Brain (here our blog post on this) was the first to argue that the experience of psychedelic states arises from a disintegration of the DMN.9 Also, Carhart Harris’s research group at Imperial College London published the first major study tying decreased DMN connectivity under LSD to ego dissolution.10 Since then, many other psychedelic researchers have jumped on board, investigating these links.11, 12
In a 2020 study on ego dissolution after psilocybin, Natasha Mason et al. from Maastricht University further found that glutamate concentrations in the medial prefrontal cortex and the hippocampus, two brain regions belonging to the DMN, correlated with positive and negative experiences of ego death, respectively.12 However, in interpreting these results, they state that “these areas were chosen based on previous anatomical, functional, and behavioral evidence implicating them as potential key regions in modulating the psychedelic experience.” In other words, regions outside the DMN were not considered specifically because the running research narrative did not include them—an approach that may favor deduction over discovery.
Can the link between ego dissolution, psychedelics, and the DMN really be fortified by such studies? When examined more closely, there appear to be a few holes worth patching up.
First off, despite decreases in connectivity being reasonably consistent across the research literature, these decreases are often not “selective” to the DMN. This means they happen in other brain networks too, including the Salience Network, which plays a firmly established role in self-awareness.13 The effect sizes in these other networks are often larger than in the DMN. What’s more, since measuring DMN activity is essentially measuring mind wandering that researchers often face the problem of having insufficient data to extract significant patterns from.
“It’s an issue of small samples, where we’re looking at 10-15 subjects,” says Dr. Manoj Doss, a neuropsychopharmacologist at the Johns Hopkins Center for Psychedelic and Consciousness Research, referring to the limited scope of existing psychedelic studies in general. “What’s even worse is that it’s unconstrained cognition. If I’m on psychedelics, there’s going to be a handful of things [my brain] might be doing. [While in the MRI scanner,] I could be paranoid, wondering what the experimenter wants out of me, that they can read my mind or something with the fMRI. There are also situations in which you’re really going to enjoy the experience and be paying attention to the visuals you’re getting. Or you’re going to be really empathic thinking about your mom or whatever it is. So, if some sub-sample of the subjects is more likely to do any one of those things, that’s going to result in massively different findings. So even just getting a baseline ‘What do psychedelics do in resting state [fMRI]?’ is a bit of an ill-fated endeavor.”
What’s more, the primary target of psychedelics—5-HT2A receptors—are expressed across the whole brain, not just in DMN regions. “It is conceivable that the DMN contributes to the (subjective) effects induced by psychedelics,” says Dr. Katrin Preller, a psychedelics researcher at the University of Zurich, and member of MIND’s Scientific Advisory Board, “but most likely only in interaction with other brain areas and networks.”
With a whole brain to explore, and many regions seemingly impacted equally, there would seem to be a risk in perpetuating a narrative built on a shaky foundation, if only because it encourages a myopic focus on the DMN and draws attention away from other possibilities. “Unfortunately, Pollan’s book already came out,” Doss says, not in a way of denigrating Pollan’s work, but to lament the fact that the public often runs off with a compelling story before the scientific results are in. This is equally true for the ego narrative as it is for the DMN narrative. “’Ego dissolution’ is a very broad term that captures quite a few experiences related to the psychedelic state, from more focused changes in body perception to the complete feeling of unity or loss of self,” says Preller. “For it to be useful in research and/or clinical settings, we need a better, more fine-grained definition of what we mean exactly when we are talking about ego dissolution.”
To deepen the issue, consider that some substances that decrease DMN connectivity actually increase egoism, which is in direct opposition to the enhanced empathy reported under psychedelics: “Amphetamine can make people more egotistical, yet it decreases DMN connectivity,” Doss says. “Alcohol decreases DMN connectivity and can do the same thing. The idea of the DMN being strictly the self and decreases in DMN being involved with ego dissolution … I don’t know if that’s useful.”
If you’re not a scientist, however, what’s the danger in believing your ego sits on a throne in the DMN, presiding over your existence until usurped by psychedelics? If a perceived experience of self-loss translates to beneficial outcomes, why should it matter so much that we challenge this narrative? For one thing, this story leads us to two false beliefs: that the self is a singular entity in the brain, and that the DMN has a singular function. Both statements couldn’t be farther from the truth.
“One huge aspect of our selves is that we come from here [pointing to his body], not from the corner of the room,” Doss says. “Another aspect of who you are is what you do. And that’s going to be more involved with motor networks and Executive Control Networks. So, to narrow down the self to the DMN … I don’t know if that’s useful. Which is why a lot of us in cognitive neuroscience try to narrow down these networks and brain regions to functions of performance on certain tasks. Which then constrains the inferences you can make regarding what specific aspects of the self the DMN is involved in rather than just overall ‘self.’”
Perhaps most significantly, the DMN is now widely believed to direct social thought just as much, if not more than, self-referential thought.13 Kevin Tan, a PhD candidate at the Social Cognitive Neuroscience Lab at UCLA, shows in a preprint submitted to Nature that thinking about the self and thinking about others recruit a common neurocognitive pathway involving the DMN.14 “I think all the major brain networks are involved in social cognition, but the DMN plays the most crucial role,” Tan says. “The DMN supports computations that actually do abstract social cognition, rather than just providing antecedents for it.”
If we ignore this relationship, we ignore some compelling evidence for the fact that self-perception and social perception are interlinked, a finding which could change the way we approach mental health care beyond psychedelics. What we lose in pigeonholing brain networks isn’t just the elegant, nuanced functioning of the brain for the sake of understanding its mechanics; it’s also the philosophical, behavioral, and clinical significance of discovering which cognitive processes overlap with one another.
“We know it’s a sin at this point to call the amygdala the ‘emotion center,’” Doss adds. “Yet we still refer to these networks by how they were first described, in an easy way for all of us to understand. Even scientists like stories.”
Just because a theory becomes a paradigm doesn’t mean that the theory is accurately represented. When examined closely, Carhart-Harris’s own work does not conclusively identify the DMN as the main character in the story. For example, in a 2016 paper on ego dissolution and LSD, he and his colleagues propose that it may be the enhanced connectedness among networks, rather than the increased or decreased activity within one particular network, that leads to the experience of ego dissolution:
“LSD increased global integration by inflating the level of communication between normally distinct brain networks. The increase in global connectivity observed under LSD correlated with subjective reports of ‘ego dissolution.’ The present results provide the first evidence that LSD selectively expands global connectivity in the brain, compromising the brain’s modular and ‘rich-club’ organization and, simultaneously, the perceptual boundaries between the self and the environment.”15
It’s worth noting that experiences of ego dissolution often go hand-in-hand with feelings of connectedness and merging, perhaps mirroring what’s happening in the brain. Still, some might argue a distinct ego is needed to experience a loss of ego. These are fundamental questions of consciousness which can’t be neatly packaged into a single narrative. More books like Pollan’s will come and go as psychedelic science advances, but in order to stay grounded in that science, it’s important to keep the full story unwritten.
Is there DMT in the brain? What could it be doing there? These questions have been on the minds of psychedelic researchers for decades, and answering them was never going to be simple. New research goes beyond attempts to prove romantic ideas about DMT release from the pineal gland during near-death experiences. Through looking at individual neurons, this research indicates that DMT might have a role as a non-canonical neurotransmitter involved in protecting the brain from physical and psychological stress. A theme emerging from the research updates the original question: what if DMT is naturally neuroprotective?
Interested in cutting-edge research on the neural effects of DMT? Check out our INSIGHT 2021 conference in September, which includes presentations on this topic by Carla Pallavicini, Ph.D. and Christopher Timmermann, Ph.D.
Neurotransmitters are small molecules secreted in the nervous system to relay information between different neurons. Many of them – serotonin, dopamine, and adrenaline, to name a few – belong to the chemical class of monoamines. The most potent naturally occurring psychedelic, N,N-dimethyltryptamine (DMT), belongs to this same class of molecules. DMT can be found in trace amounts in animal nervous systems (including mammals), but it hasn’t been directly proven to act as an endogenous neurotransmitter.1 It is more common and better understood in plants, where it helps defend some species from herbivorous animals.2
Humans have been extracting DMT from plants for centuries. It isn’t orally active due to the presence of monoamine oxidase (MAO), an enzyme that degrades DMT, in the human digestive tract. Amazonian shamans have known how to circumvent this for centuries, combining a DMT-containing vine with plants containing MAOIs, or monoamine oxidase inhibitors, that stop the degradation of DMT. The psychedelic brew resulting from this mixture is known as ayahuasca, from aya (spirit) and waska (vine).3
Ayahuasca is inseparably intertwined with the mythogenesis and spirituality of South American indigenous tribes. Analogously, as DMT entered Western awareness, it easily found its place in literature and philosophy. Its biological properties have also intrigued scientists since its first synthesis in 1931. Because of DMT’s similarity with serotonin, it was tempting to hypothesise that it might naturally occur as a neurotransmitter in the human body. Where could such a peculiar neurotransmitter be found? Popular conjecture, borrowing concepts from both science and mythology, placed it in the pineal gland.
The primary role of the pineal gland is regulating sleep patterns by producing melatonin. But the history of this pea-sized structure in the forebrain is much more romantic. In ancient Egypt, it represented the eye of the sky god Horus, while in India it has been associated with the “third eye”, a mythical gate to higher consciousness. A modern incarnation of these stories originated from DMT: The Spirit Molecule, a book in which author and psychiatrist Rick Strassman, MD, postulates that large quantities of DMT may be secreted in the dying brain, enabling the transition of consciousness from one life to the next.4
Since the inception of Strassman’s theory, the presence and purpose of DMT in the pineal gland have been subjects of heated debate. While it hasn’t thus far been isolated directly from human brains, experiments in both humans and rats demonstrate that their brains – including the pineal gland – contain enzymes necessary for the synthesis of DMT.1
DMT’s potential involvement in near-death experiences is hard to either prove or disprove in humans, but attempts have been made in rats. Research has shown that rat brains contain DMT and that its concentration increases following induced cardiac arrest.1,5 Could this mean that these lab rats have gone through a near-death experience? Is this experience mediated by DMT, or is DMT just a metabolic waste product of a stressed organism?
Experimental results offer limited insight. If anything, DMT might be just one part of the veritable brainstorm of neurotransmitters (including serotonin, dopamine and, noradrenaline) that gets released in response to the severe stress of cardiac arrest.1 Moreover, even though the concentration of DMT increased, it was not possible to determine whether the increase corresponded to an exogenous psychedelic dose. While some researchers believe this to be the case, others point out it is unknown how low physiological quantities of endogenous DMT could be stored to be released en masse,6 as well as the biological reaction that such a release would trigger. Current scientific knowledge lacks the smoking gun needed to directly implicate DMT in near-death experiences: a well-characterised biochemical mechanism.
One-size-fits-all solutions are rare in biology. Neurotransmitters and psychedelic compounds alike act upon multiple brain regions, interact with different receptors with varying specificity, and trigger a wide spectrum of biochemical and genetic signalling cascades. DMT is no different, and while it was originally considered to exert its effects mainly via the serotonin 2A receptors, new targets for it have been found. One of these new targets, the sigma-1 receptor (Sig1R), is not the answer to the puzzle of DMT. It does, however, present us with several intriguing puzzle pieces.
Sig1R is unusual. Its origins are a mystery: In evolutionary terms, it is more closely related to a fungal enzyme called sterol isomerase than to any mammalian neurotransmitter receptor.7 Scientists are uncertain about how to interpret this finding, especially considering the fact that this particular fungal enzyme was first isolated from a fungus that produces alkaloids similar to LSD.
While many receptors specialise in relaying neurotransmitter signals either on the cell membrane, inside the cell, or in the nucleus, Sig1R is unusual because it can do all three. On the membrane, it can interact with other neurotransmitter receptors and change their function by forming complexes with them. When it’s inside the cell, it binds anti-stress proteins and aids them in performing their functions.8 In the nucleus, it recruits other proteins that bind to DNA and activate or deactivate different genes via epigenetic mechanisms.9
This multifunctional receptor is known as an ‘’orphan’’, which means scientists haven’t yet identified its main activating neurotransmitter. It was first suggested that Sig1R could be a subtype of opioid receptors, but scientists later found that other compounds bind to it as well, including cocaine and the sex hormone progesterone.10 More recently, evidence has mounted for speculations that DMT might activate this receptor.
The first indication that this might be the case came from cell culture research, where it was demonstrated that DMT can bind to Sig1R. Mouse research expanded on this finding and showed that mouse behaviour under the influence of DMT doesn’t change when serotonin and dopamine receptors were blocked. But after their Sig1R receptor had been deactivated, the mice stopped reacting to DMT. These results have led the researchers to conclude that Sig1R is one of DMT’s main targets.11 Another clue comes from the fact that in the synapses connecting different neurons, Sig1R is located close to an enzyme involved in DMT synthesis.12 This led some researchers to wonder whether Sig1R, rather than 5HT-2A, is the main mediator of DMT’s psychedelic effects.
What happens in the cell when DMT activates Sig1R? Some answers come from cell culture research. Recent studies have found a role for DMT in both the immune response and the anti-stress response of individual human cells. In immune cells, DMT was shown to activate the production of anti-inflammatory molecules.13
In a similar study, human neurons in cell culture were deprived of oxygen. Neurons quickly die when they don’t have enough oxygen, but treatment with DMT and the subsequent activation of Sig1R enabled more of them to survive.14 This finding offers a link back to Rick Strassman: If DMT helps stressed cells, could it also be helping whole organisms in states of stress – when close to death and severely oxygen-deprived? While it is tempting to speculate, it is important to keep in mind that neurons in the brain function in a complex, context-dependent way. Observing individual neurons in culture shows scientists what is happening inside them, but says little about how they interact with each other in a living, 3D brain.
Presently, this gap has not yet been bridged. Researchers have not tested Sig1R activity in intact brains undergoing hypoxia or other types of physiological stress. In a dying brain, DMT might be helping neurons to survive—but survival alone doesn’t tell us what those neurons are doing or how their activity might create the visions characteristic of near-death experiences. Lacking direct evidence, we may take some hints from brain imaging studies and attempt to connect them with known Sig1R mechanisms.
Looking at people’s brains on DMT and ayahuasca, researchers observe altered activity in the visual and auditory centres of the brain, as well as memory-related regions. These include centres for perception and processing of negative emotions and sad memories, memory retrieval centres, and the amygdala (a brain region commonly associated with social and emotional processing, including fear, anxiety and aggression).15,16
Dr. Antonio Inserra, a researcher from Flinders University in Adelaide, attempted to reconcile the molecular and whole-brain perspectives and formulated an intriguing hypothesis about the roles Sig1R could play in these brain activities.7 His analysis focuses specifically on the role of DMT in trauma processing, a phenomenon which garnered his interest due to anecdotal reports from PTSD patients whose symptoms were reduced after ayahuasca sessions. He speculates that Sig1R might form complexes with other receptors and boost signal transmission and synaptic plasticity in memory centres, which could help retrieve and reprocess traumatic memories. He further points out that Sig1R in the nucleus serves as an epigenetic regulator,9 meaning that it recruits enzymes that add different tags to DNA and histones (the proteins around which DNA is coiled in the cell) in order to turn genes on and off. It has long been understood that epigenetic mechanisms have an important role in all aspects of memory forming and remodelling. Because of this, Inserra suggests that some of the mechanisms through which ayahuasca treats trauma may be mediated by Sig1R epigenetics in the brain’s memory centres.
A new study from Dr. Simon Ruffell, a research associate at the King’s College London, also links DMT, Sig1R, and epigenetic regulation. His team, supervised by Prof. Celia Morgan (University of Exeter), followed participants in ayahuasca ceremonies in the Amazon to investigate how these experiences impacted their traumatic memories. The participants reported significant, long-lasting decreases in depression, anxiety, and general distress. In order to find out why, Ruffell’s team collected saliva samples from them and analysed changes in the epigenetic tags on their DNA. They discovered that the Sig1R gene is epigenetically changed in some participants (unpublished results presented at the ICPR2020 conference). Since we know the receptor itself is involved in epigenetic modulation, this might be just the beginning. Which other genes do we see epigenetically modified after ayahuasca sessions? Ruffell’s epigenetic research may offer more clues not only about how DMT works with Sig1R on an epigenetic level but also about the epigenetics of memory as such. No matter what other results come out of this study, it already serves as an important bridge between the lab and the ceremony; between the cell, the brain, and the experience.
The current state of DMT research resembles disjointed puzzle pieces. While there are several indicators that there might be naturally occurring DMT in the human brain, its locations and functions remain elusive. More data is available about how ayahuasca and exogenous DMT work, both in the cell and in the brain, but we can’t yet justify extrapolating the roles of endogenous DMT from these findings.
Nevertheless, a variety of speculative theories have recently surfaced. While some researchers are focusing on DMT’s potential anti-inflammatory and neuroprotective roles, others look at the brain imaging and trauma studies and point towards its possible effects on memory-remodelling. Both might prove to be true, and both can be placed in the context of Rick Strassman’s theory that DMT is present in human brains to alleviate the effects of massive physiological stress, such as in oxygen-deprived neurons during near-death experiences. Could the dying brain be releasing endogenous DMT to keep itself alive for as long as possible? If so, the commonly reported characteristics of near-death experiences—including visions and one’s “life flashing before one’s eyes” —might simply be side effects. In the cases of neuron survival and memory processing, research so far points towards the multifunctional, mysterious Sig1R receptor as a key actor in these processes.
While the intricacies of its molecular mechanisms have yet to be fully described, the multifunctional Sig1 receptor is now firmly established as a target of DMT, and this opens new lines of inquiry. Perhaps the most exciting new research will include investigations into how DMT and Sig1R affect epigenetic regulation. Information about which genes they activate or deactivate could put the findings from cell culture research into the context of whole organisms. Epigenetic mechanisms lie at the very foundation of our dynamic interactions with the world, and with our own minds. Understanding how these mechanisms help store and remodel memories may help us formulate a coherent biological model of the therapeutic effects of the psychedelic experience.
“Rather than having the MDMA-assisted psychotherapy and then sending them home with a journal and some happy thoughts, what we really ought to be saying is that the therapeutic window is actually for weeks, if not months after the acute psychedelic effects have worn off.”
At the Johns Hopkins University School of Medicine, Department of Neuroscience, neurobiologist and MIND’s scientific advisory board member Gül Dölen, MD-PhD, studies the mechanisms by which psychedelic drugs work to treat diseases of the social brain like PTSD, addiction, and severe forms of autism. Dölen spoke to me about her 2019 Nature paper,1 which showed that MDMA re-opens a “social critical period” in the mouse brain when it is sensitive to learning the reward value of social behaviors – but only if the mouse is in a social setting. Based on this research, Dölen and her colleagues believe two things are required for MDMA, and potentially all psychedelics, to be therapeutic in the context of social brain diseases: 1) the re-opening of the critical period and 2) the right social context for the memory to be reshaped. Not only does this view challenge current psychedelic therapy models; it also suggests a way forward for psychiatric treatments more generally.
Saga Briggs (SB): Based on your animal studies, how do you think psychedelic drugs might work in humans to treat social brain diseases like PTSD?
Gül Dölen (GD): When we think about what happens when someone has PTSD, what we’re dealing with is that during their childhood or youth [during this maximum sensitivity to the social environment, or “social critical period”], they were in a social environment and something bad happened to them, and in that moment, their response was very adaptive. They were protecting themselves by putting up walls, by guarding themselves from whatever was causing that injury.
But then the critical period closes, and over time, that adaptive response starts to become less and less adaptive until they reach adulthood and they’re unable to form intimate relationships. They’re unable to keep a job. They have a very negative view of themselves in terms of self-esteem, that they’re not deserving of love and being in the world. The memory becomes an extremely well-ingrained worldview, and it’s hard to dislodge it. And so the idea is that what we’re doing with MDMA is going back and allowing them to rewrite that memory in a way that’s adaptive, now that the traumatic event has been removed from their environment.
And so I think that in the end of the Nature paper1, we kind of ended with, “Oh, well, [psychedelic drugs] might be just making the therapeutic alliance stronger,” but based on other more recent data and thinking about it longer, I think that it’s more than just the therapeutic alliance. It’s about making available those memories to modification.
SB: How does this memory modification work exactly?
GD: The way I’m talking about it now is I call it “open state engram modification.” So you put the brain on MDMA in an open state where you’re going to be sensitive to your social environment again, and then –either through therapy or through processing your own memories or looking at photographs or journaling—what you’re doing is bringing back the memory engram that is relevant to the trauma in this state where you are available to manipulate it and make those memories malleable and rewrite them to respond to the realities of your current world.
SB: And do you think that has to happen in a social setting, per se? I think in your Nature paper you mention this phenomenon only happened when mice were with other mice. But of course, many people have transformational experiences taking psychedelics on their own.
GD: I actually think probably one of the most surprising and profound findings of the paper is the setting dependence, because every other explanation that has been made of how these psychedelic drugs work from literally everybody else has always overlooked the fact that these experiences are very much modified by the set and setting, that they’re context dependent. You know, it’s not like people who have PTSD are taking MDMA and going to raves and coming back cured. Yes, you can have profound experiences that are important in a therapeutic way outside of a doctor’s office. But you’re not going to have it if you spent the whole time just partying. In that case you’re not engaging those [traumatic] memories.
SB: Is this the same mechanism you believe could work to treat severe forms of autism?
GD: Before we can dive in on the human trials for autism, we kind of want to get a little bit more information about autism. One of the things that happened when I was a graduate student is that, my graduate advisor Mark Bear and I, we put forward this theory that if you turn down the signaling of a specific glutamate receptor [mGluR5], it balances out the exaggerated protein synthesis observed in autism.2 This theory had a lot of enthusiasm and excitement and seemed to be validated by animal research that was replicated by twenty-eight other labs. After those preclinical animal studies got so much press, the big pharmaceutical companies jumped on board and they thought they were going to cure autism with this mGluR modification. And then the clinical trials failed, and it was a big disappointment for the whole field of translational neuroscience. It was devastating because we all thought it was going to work, and then it didn’t. So in trying to think about why it didn’t work, there were a lot of different possible explanations. But I think it’s that every single one of the animal studies was carried out either from genesis [doing the manipulation genetically so they were born with the modified gene] or they were given [the modification] very early in development and just given it chronically for their whole lives. Whereas, in the human trials, the youngest recruited patients were sixteen years old, but most of them were adults—well past the age when their social critical period would be closed.
So, the idea that I would love to pursue is, well, maybe the reason that the clinical trials failed is because the mGluR therapy was right, but the critical period was closed. What we really needed to do is give a mGluR modulator, plus a psychedelic, to reopen the critical period. So that under the conditions of an open social critical period, the biochemical imbalance would be corrected and then you would get therapeutic efficacy.
SB: Would open state engram modification be a lasting treatment for these diseases? How long did the effect last for the mice in your study?
GD: Yeah, actually, I think that’s the second most important thing that we found in this study: Every other study trying to figure out the mechanisms of this has really focused on the acute effects of the drugs. And what we found is that after MDMA, the critical period starts to open about six hours after the acute dose. And then it kind of peaks out at 40 hours and stays up for at least two weeks, and then by a month it comes back down. So just to kind of put that into perspective, two weeks in a mouse is probably more like two months in a human.
I think that also informs how we might want to be doing these clinical trials. Rather than having the MDMA-assisted psychotherapy and then sending them home with a journal and some happy thoughts, what we really ought to be saying is that the therapeutic window here is actually for weeks, if not months after the acute psychedelic effects have worn off. We need to treat that period of time as precious and really make there be a lot of intensive focus and therapeutic activity happening during that window rather than just kind of setting them off and letting them be on their own.
SB: In what other ways could these findings influence treatment models?
GD: This speaks to a debate that’s going on right now in psychedelic therapy. The pharmaceutical companies are really wedded to this idea that if we can understand the mechanisms of these drugs, on a pharmacological level, then eventually we can design a drug that activates whatever mechanism is curing depression or PTSD or whatever it is, and then we can design out all of those nasty psychedelic side effects. The psychedelic journey can be gone, right? Like, that’s their dream.
And then you have on the other side the psychologists, who say, “No, that can’t be right because we know that we can achieve these psychedelic therapeutic effects even without the drug, as long as we can get them to this mystical place. We can do it with meditation, we can do it with a little bit of breath work, etc. And furthermore, the strength of that mystical experience correlates with the strength of the therapeutic effects.”
So these are the two sides of the debate. And I think our finding about the setting dependence of psychedelics in opening the critical period kind of offers a middle ground between these two worldviews. What it says is that the binding of the drug to the receptor opens a critical period—that’s the pharmacological effect that the drug companies have been so furiously searching for. Our hypothesis is that that is the mechanism. Any drug or any manipulation that can reopen the critical period has the potential for that therapeutic effect. But then on top of that, the setting dependence of it means to me that what the psychedelic journey is doing and the setting is doing is priming the brain so that the right memory and the right circuit is being brought into reactivation or made available for modification in this open state.
It’s a middle ground between these two different views of how the [drug] is working. And I think it really says, mechanistically when we are evaluating a potential hypothesis or a new compound or a new way of doing these clinical trials, we need to address this issue of “are we opening the critical period and are we effectively triggering the relevant engram?” Because if we’re not doing either of those things, it’s not going to work.
It remains to be seen whether critical period reopening will become a deliberate aim of psychedelic therapies, especially as other labs begin to claim therapeutic efficacy with trip-less synthetic versions3 of psychedelic drugs. Regardless, there appears to be significant, untapped therapeutic potential to be explored in the months following standard psychedelic treatment. In the case of PTSD, this window could prove invaluable. In the case of autism, which is not universally considered a disease, the conversation is more complex. While the notion of “curing” autism has been and should be challenged, for example by questioning the ethics of fundamentally changing core aspects of an individual’s personality, Dölen’s work stands as a pivotal contribution to the field for those who might seek treatment.
1. Nardou, R., Lewis, E., Rothhaas, R., Xu, R., Yang, A., Boyden, E. and Dölen, G., 2019. Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature, 569(7754), pp.116-120.
2. Dölen, G. and Bear, M., 2009. Fragile x syndrome and autism: from disease model to therapeutic targets. Journal of Neurodevelopmental Disorders, 1(2), pp.133-140.
3. Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2020;589(7842):474–9.
Results from the Interdisciplinary Conference of Psychedelic Research 2020
Here’s a thought-provoking question: Would you rather take a high dose of LSD or psilocybin sporadically to dissolve the boundaries between yourself and the universe, or just a tiny amount regularly to become more creative and excel at intellectually demanding tasks? The latter option has recently garnered the attention of biohacking communities, where it is popularized as microdosing. At the recent Interdisciplinary Conference of Psychedelic Research (ICPR2020), researchers investigating microdosing practices and effects shared their findings and suggested that microdosing might not actually be the right tool for performance enhancement.
Interested in cutting-edge research on this and related issues? Check out our INSIGHT 2021 conference in September, which includes presentations by Enzo Tagliazucchi, Ph.D., and by George Fejer, M.Sc. on research into microdosing.
The stimulant effects of low doses of LSD have been known since Albert Hofmann himself suggested it as an alternative to Ritalin.1 Today, microdosing enthusiasts may come to the practice with a far greater variety of motivations. One of their primary drivers is the promise that regularly using “sub-threshold” (“won’t get you high”) amounts of psychedelic substances – will enhance cognition and memory.2 Indeed, members of online microdosing hubs (e.g. Reddit, TheThirdWave) enthusiastically report positive effects related to their cognitive performance and creativity. Scientists refer to these benefits collectively as nootropic effects. Others are more focused on the mental health and well-being benefits: users with depression and anxiety claim microdosing helps with their symptoms, and healthy users report it helps put them in a more positive mood.
The true cognitive benefits of microdosing remain elusive, however, as microdosers worldwide turn a blind eye to the limited yet growing body of evidence against their claims. This lack of clarity is compounded by researchers who simultaneously emphasise the novelty and the limitations of their work. While there have been around a dozen published studies in the past couple of years that examine the many supposed benefits of microdosing,3 it is not uncommon for researchers to claim theirs is the first of its kind. They will also commonly state that while they find no difference between placebo pills and microdoses, these results are preliminary, and they need more research before they are certain that microdosing truly has no performance-enhancing effects. When will this moment of certainty come?
The recent virtual conference ICPR2020 provided important insights into the latest psychedelic research trends. With a variety of speakers covering topics ranging from philosophy to neuroscience to politics, the September conference provided participants with a holistic, level-headed view of all the newest research.
ICPR2020 proved once again how important microdosing has become in the psychedelic science community: the conference accorded it two whole sections and five separate lectures. True to the “interdisciplinary” tag in the conference title, these talks ranged from fundamental biological research examining the pharmacology of microdosing (Tobias Buchborn from Imperial College London) to psychology-based studies examining the influence of microdosing on artistic and aesthetic sensibilities (Michiel Van Elk, PhD, from Leiden University).
The remaining three speakers presenting microdosing-related work were Nadia Hutten, PhD, from Maastricht University, Neiloufar Family, PhD, from Eleusis Ltd, and Balazs Szigeti, PhD, from Imperial College London. All three of them showed results pertaining to the effects of microdosing on both well-being and cognition. Szigeti and his group have a paper in preparation, while the Eleusis and Maastricht studies were recently published. 4,5
In order to understand the results, it’s important to understand the methodology of these studies and the similarities and differences in their experimental setup. Importantly, the Maastricht University and Eleusis studies involved microdosing LSD in a clinical setting, while the Imperial study was surveying at-home microdosers (using any sort of psychedelic, but most commonly LSD and psilocybin), albeit with an innovative twist. Additionally, Maastricht researchers followed the acute effects of psilocybin microdoses for up to 8 hours after ingestion, while the other two studies followed participants for a month. In these month-long studies, microdosing schedules were based on the protocol that popularised microdosing in the first place, stemming from James Fadiman’s 2011 book “The Psychedelic Explorer’s Guide.”6 According to this protocol, microdoses of LSD or psilocybin are taken every 3 days for a month.
The laboratory setting imposes limitations on sample size, so the Maastricht and Eleusis studies were done with under 50 participants, while Szigeti’s remote, self-blinding study had no such limitations and included almost 200 microdosers. This would make it, with certain disclaimers, the largest placebo-controlled microdosing study to date.
Comparing these studies is further complicated by differences in setting, number and age of participants (20-somethings in Maastricht, 60-somethings at Eleusis), and the cognitive parameters that were measured. All three studies looked at participants’ attention spans and measured their reaction times, but Eleusis and Imperial added some visual and spatial memory tests. The Imperial study measured the most cognitive parameters, with additional tasks that tested deductive reasoning, spatial planning, and mental rotation.
“Set and setting” has been a traditionally important phrase in psychedelic science, referring to the phenomenon that the mindset and the circumstances in which people take psychedelic drugs will influence their effects. This is well-known and applied in high-dose psychedelic research: participants in the famous psilocybin cancer trials, for example, got to have their psychedelic experiences in a “lab” mimicking a cosy living room.7 This gives some assurance that the experience won’t be negatively affected by the subtle discomfort people often feel in overtly clinical atmospheres.
When it comes to microdosing, however, giving the lab a makeover may not suffice. Most of the anecdotally claimed benefits of microdosing become most apparent in the long run, as people are just living their lives. Will they get better at work and problem-solving? Will they start more creative endeavours? Will their relationships prosper? These are not things researchers are able to gauge when they have participants come to their lab. Spending the whole day in the lab, having taken only a “sub-threshold” dose of a drug, might even put people in a slightly agitated mood that could tamper with their well-being and cognition. Still, a double-blind, placebo-controlled trial is the gold standard for any pharmacological study, especially for those involving mind-altering substances. These studies allow us to distinguish the mind’s intrinsic suggestibility from the physiological effects of the drug and are, therefore, indispensable.
Before it was possible to conduct rigorous, placebo-controlled studies with psychedelics, the only way to find out about participants’ microdosing experiences was the humble questionnaire.3 In the Imperial self-blinding study, Szigeti and colleagues elevated the classic online survey to a placebo-controlled form. Instead of collecting data post-hoc, the researchers asked their at-home microdosing participants to carefully organise a month’s worth of microdoses in capsules and place the unlabeled capsules in envelopes marked only with QR codes. They also needed to prepare an equal number of QR code-labelled envelopes with empty, placebo capsules. They then had to shuffle all the envelopes, randomly pick out half of them for a month’s worth of use, and send the researchers the QR codes. This way the researchers knew, based on the QR codes, whether the participants were taking a microdose or a placebo, while the participants themselves were none the wiser.
The most prominent limitation of the self-blinding study is that it relies on the participants procuring their own LSD or psilocybin for the study, meaning there’s no way to tell what amount they’re actually taking and whether the substances are pure. The effects of this limitation, however, are largely alleviated by the large sample (191 participants completed the study, compared to 20-50 in the lab-based studies). Most importantly, the self-blinding study design has a major advantage, allowing us a glimpse into the effects of microdosing in a natural, everyday setting, while also providing a placebo control.
The reported nootropic effects of microdosing are manifold: improvements in concentration, creativity, spiritual awareness, productivity, language, and visual capabilities.8 So, did all these claims hold up when put to the test in the lab (in the Eleusis and Maastricht study) and in a placebo-controlled at-home setting (Imperial College)?
Two of the three placebo-controlled studies presented at the ICPR2020 conference found no significant differences in cognitive performance between the placebo control and the microdoses of LSD or psilocybin. Only the Maastricht study found positive effects of LSD on visual attention, yet the Eleusis study did not find effects on visual attention in a different task.
In the self-blinding study from Imperial, there was no difference in cognitive ability when participants took microdoses, neither acutely (2-5h after ingesting the pill), nor at the end of the four-week regimen. The researchers did, however, find a significant susceptibility to the placebo effect. They asked their microdosers an important question: “Do you think you’ve taken a microdose?”
When the participants thought they had taken a microdose, whether or not the pill was actually a placebo, they felt a greater sense of well-being, more mindful, and more satisfied with their lives. Presented with a placebo, the mind can “cheat” thoughts and moods, but it can’t cheat a cognitive test: whether or not they thought they had taken a performance-enhancing drug, and whether or not they’d actually taken one, the participants’ test scores remained the same.
But the scientists weren’t convinced. Balazs Szigeti, the lead researcher in the self-blinding study, suspects that if microdosing had such wide-ranging positive effects like people anecdotally claim, they should have been seen in such a large sample. Still, he doesn’t exclude the possibility that further research might uncover small, specific positive effects. For example, the researchers in Maastricht found that microdosing can be beneficial for sustained attention – though while this result is promising, the study from Eleusis showed no increase in performance on a similar attention test.
In another example of potential specific effects, the self-blinding study results show a slight, but statistically insignificant trend towards increased capability for mental rotation. “More studies should reproduce our findings before a firm conclusion could be reached, but in my opinion, the cognitive benefits of microdosing do not look promising”, concludes Szigeti.
Taken together, all the findings from ICPR2020 might lead recreational microdosers to ask themselves: “Am I performing better, or do I just think I am?”
The unglamorous truth is, research to date has shown that the best, most reliable nootropic is… cardiovascular exercise.9 Different drugs that supposedly boost your brain have come in and out of style. Modafinil, the most popular one, was even proven to be mildly effective at enhancing attention and memory, particularly in performing complex tasks.10 But none of the nootropics’ effects are even remotely close to “unlocking the full potential of the human brain” in the way depicted in the movie Limitless. Psychedelics are no exception.
While it may not significantly alter cognitive performance, microdosing might still be beneficial for the brain in other ways. Nadia Hutten’s research at Maastricht University demonstrated that microdosing does lead to acute increases in BDNF (Brain-Derived Neurotrophic Factor), a molecule important for neuroplasticity.11 And at Eleusis Ltd, Neiloufar Family researches how microdosing might prove helpful in treating early Alzheimer’s disease. Her clinical research is led by the hypothesis that low doses of LSD can increase BDNF signalling and thus increase neuroplasticity, which would help protect the ageing brain from decay.11
This is not even the only mechanism through which LSD microdoses could act as neuroprotectants. Drugs that act on the serotonin 5HT-2A receptor, including LSD, have proven anti-inflammatory effects, and neuroinflammation is strongly implicated in Alzheimer’s pathology.13 When asked to comment on performance-enhancing effects, Neiloufar Family says, “I am not concerned that LSD did not have a nootropic effect on healthy adults, because a nootropic effect in a healthy population is not necessary for a drug that otherwise has a therapeutic effect in a patient. If you look at other drugs that help with cognition, like atomoxetine for ADHD, it doesn’t have nootropic effects in healthy people but is effective in treating ADHD.”
As the popularity of microdosing increases, the psychedelic research community needs to prioritise conclusively answering one more question: is it safe in the long run? Research conducted thus far looked at participants’ health for brief periods of up to a month at a time, but people in internet microdosing hubs sometimes promote daily use of low doses of psychedelics over months and years. Acute adverse effects are rare and include occasional increases in anxiety and restlessness (common contraindications of stimulants), but long-term adverse effects are virtually unknown.
When thinking about long-term effects, it is wise to take note of the case of fen-phen (fenfluramine), a popular weight loss drug in the 90s that turned out to come with significant cardiac risks. Fen-phen can lead to heart disease by acting on its primary target, the 5HT-2B receptor.12 Most psychedelic drugs have the 5HT-2A receptor as their primary target, but they are not completely specific and can activate the 5HT-2B as well. Does that mean chronic microdosing over many months and years, can lead to negative cardiac outcomes? More research is needed.
We still don’t know if microdosing can significantly improve brain health, or if the reported emotional well-being benefits are based entirely on the placebo effect, or if doing it for months or years at a time can damage your heart. When it comes to the nootropic benefits, the evidence is rather inconclusive. While one study found improved sustained attention after LSD, another did not find this effect. And, after all, maybe the tasks used to measure cognitive performance are simply not capturing the effects microdosers are reporting – maybe we are yet looking in the wrong place.
Further research is in the works as Balazs Szigeti’s self-blinding study at Imperial enters its second phase, and the Beckley/Maastricht Research Programme starts a new study using neuroimaging tools to investigate the effects of repeated microdoses more closely and objectively.
These new studies could lead to establishing the mechanisms of how microdosing can make our brains healthier and more resilient to ageing. But from what we have seen so far, they could also strengthen the case against microdosing for superhuman cognitive abilities. In the scientific exploration of the benefits of psychedelics, wanting both a psychologically and neurologically transformative experience at a high dose and a biohack from a microdose might simply be too much to ask.
Disclaimer: This post was edited in April 2021. Before, the post stated that ‘none of the three studies on microdosing found positive effects on cognitive performance.’ However, as it is stated in the post, the Maastricht study found a positive effect on sustained attention in the Psychomotor Vigilance Task.
The Psychedelic Compendium is a series of curated lists of research articles introducing specific topics in a nutshell. Since psychedelic research is a rapidly growing field and new articles are published almost daily, we understand that it might be overwhelming to skim through a multitude of publications searching for the right one. To make it easier to find relevant research, we are introducing lists of article recommendations carefully selected by our team.
Comprised of both open and closed access articles, our lists of recommended readings aim to lay the foundations for understanding distinct aspects of psychedelic research. Starting from basic overviews and then diving deeper into specific research perspectives, the lists highlight the most important publications in the field.
To make the lists a handy tool for not only researchers and professionals but also journalists and the general public, we will provide a brief summary of each article. We believe that bridging the information flow between academia and society will significantly benefit both parties. High quality research combined with clear channels of communication with the public will facilitate responsible policy making and therefore result in sustainable development of the relations between science, governments, and the population.
This post will be continually updated – stay tuned for the incoming recommendation lists!
These ten articles will give you a solid foundation to start your psychedelic research journey. You will gain an overview of state-of-the-art of psychedelic research, the history of psychedelic exploration, the many applications of psychedelic substances in various fields, and most importantly, their therapeutic potential.
Psychedelic-assisted therapy has the potential to help improve global mental health. In this list, we will introduce the history and current state of the research on psychedelic-assisted therapy, as well as challenges and future perspectives.
Psychedelics offer a new avenue in the treatment of mood disorders. In this list, we will explore the advantages of psychedelics over mainstream antidepressants and summarize essential studies investigating the potential of psychedelics in the treatment of depression and anxiety.
This list of recommended readings explores the diversity among serotonin receptors, the history of their discovery, their relations with psychedelics, and their mechanisms of mediating subjective experiences and therapeutic effects.
In this list, we focus on general press articles about psilocybin research and therapy that were published mainly in larger international newspaper outlets.
This list of Top 10 Articles of 2020 will discuss a ground-breaking trial with psilocybin for major depressive disorder, long-term outcomes of MDMA-assisted psychotherapy for PTSD, how psychedelics work in the brain, and how to produce psychedelics at a larger scale.
This selection of research articles on ketamine for mental health will explore its promise in treating not only depression but also the positive effects on suicidal ideation, addiction, and further symptoms of mental health disorders.
This list presents press articles discussing the therapeutic use of ketamine in mental health treatments and its potential modes of action.
EDGE is a Berlin-based registered non-profit association. This post was written by the four core members: Tatiana Luphasina, Amelia Young, Corinna Kühnapfel, and Ian Erik StewartView full profile ››
Whether incidental or decisive, art in neuroscience is a tool for educating and inspiring, communicating and sharing, for artists and neuroscientists alike.
At the MIND Foundation’s Symposium “Progress on Bewusstseinskultur,” as well as the recent Members’ Convention, guests may have noticed various artworks in MIND’s new office space in Berlin Friedrichshain. Both in-person and online attendees also got to experience a meditative light and sound performance by OATS collective. In this blog post, we would like to share with you the motivation and story behind these, as well as our other work as EDGE.
EDGE came to life three years ago in Berlin, when all of us were pursuing neuroscience degrees (in neurobiology, medical neuroscience, and cognitive science). We soon realised that many of our fellow students were also talented artists, with no fitting platform to express themselves. “The greatest scientists are artists as well,” Albert Einstein once said. We believed that the study of the brain and all the beauty that neuroscience research produces is worth sharing.
Soon we decided to curate an exhibition, held in July 2018 at >topLab in the heart of Neukölln, Berlin, accompanied by tours, talks, and Q&As with the artists. We considered the exhibition an excellent way to communicate scientific knowledge in an alternative style, to provide insight into the scientific process, and to humanise and individualise researchers in the eyes of the public. For four days, we displayed a dense variety of works: a dance performance, photography in both black & white and colour, water-colour and oil paintings, projections, a sound-scape, a hologram, graphite sketches, light-boxes, and more. Scientific themes were evident in many pieces, with microscopy images, magnified blow-ups of biological tissue, and lab equipment—but there was also a lot that was personal and human in the works on display. Many depicted friends and colleagues at work, while others showed the human side of clinical neuroscience in artworks on mental diversity. Given the chance to express this through art, we opened up a space for communication between artists and visitors. What do the artists want to convey about neuroscience? Who are they? Why do they do research on? What is that like? What do they find beautiful about it?
During this exhibition, we received a lot of positive feedback from our fellow students about the chance to build on their creative expressions and connect with like-minded individuals. We had planted a seed: a demand for a community interested in the intersection of art and neuroscience, neuroscience communication, and the beauty of the brain. Thus, we continued and expanded the activities of the project. In 2019, we held our first workshop in our new series on “Neuroscience and Creativity” with the goal to evoke constructive synergies between artists and scientists, to share practical and conceptual knowledge, and to generate public outreach from academia. We are convinced that such an exchange of approaches and methods may benefit both the artistically and scientifically creative mind.
Later that year, we hosted our second summer exhibition. This time we set up an open call for artists, and we soon noticed how many artists out there are inspired by research in neuroscience, biology, and psychology. Their artworks depicted different topics in neuroscience, such as memory, mindfulness, and neurological diversity, and they even used neuroimaging techniques like EEG for interactive performances. For many of them art, too, is research: Artists are investigating similar questions to scientists and are also trying to understand themselves and the world around them. Art asks questions: how to communicate and conceptualise topics, and how to experience them.
Our exhibition travelled across two locations: the foyer of the CCO, Charité’s research facility in Berlin Mitte, and a decommissioned power plant in Berlin Steglitz. These contrasting locations attracted people from different fields and recontextualised the works for new perspectives. What emerged was new access to typically secluded neuroscientific work. Artist and neuroscientist Dr. Mateusz Ambrozkiewicz said, “I think this project offers deep insight into the work of a neuroscientist, explains the concept of developmental diseases, and attracts people to promote discussions and thought.” He continued: “I am thrilled that I can present my work in a different medium, reach a varied audience, and explain why basic research is of invaluable benefit to humankind.”1
This summer we also established our collaboration with the MIND Foundation. In the visual arts exhibition accompanying the INSIGHT conference 2019, we curated video installations and paintings (examples can be found on pages 30-34 in the conference report). One year later, we had the great opportunity to decorate MIND’s new office space in Berlin-Friedrichshain with artworks by eight different artists just before the start of the MIND Symposium on “Progress in Bewusstseinskultur.”2 The day was accompanied by an arts performance from OATS collective Amsterdam, offering a direct experience of the connection between art and consciousness.
Ever since, we have solidified our mission: to initiate interdisciplinary collaborations between artists and neuroscientists, to facilitate sharing contemporary conceptual and practical knowledge, to support the completion of art projects, and to give artists a platform for exhibitions in Berlin and beyond. We hope that members of the public who come to our exhibitions learn about neuroscience in an interactive way in order to enrich public knowledge and make science relatable. Furthermore, we want to offer scientists and research institutes a way to reach out and communicate their insights in an approachable way. We hope that this dialogue between artists and scientists will continue to form a community of individuals across disciplines to discuss and collaborate, combining perspectives to create works for the public good.
At this point, we are delighted to announce that this year, the MIND Foundation will host us for the first part of our 2020 multimedia exhibition. For four days (October 15-18), we will welcome the neuro-curious to this interdisciplinary showcase of the beauty of the brain by international artists and neuroscientists. People can book two-hour long time slots to comply with COVID-19 safety measures (tickets are available here).
Find some pictures from the exhibition here:
Psychedelics seem to have an unusually broad range of uses. Scientists want to know just how broad it really is.
When combing through new research on psychedelics, one trend sticks out immediately: expansion. More researchers are studying psychedelics than ever before.1 Not only are there more scientists, but they’re in more places, studying more substances, and testing psychedelic treatments on more disorders. This is the bleeding edge of psychedelic science, and it’s growing every day.
Psychedelics are winning scientists and clinicians over because of their potential for improving mental health.2 Most research these days is done with psilocybin, with some centers also focusing on LSD and other psychedelics, as well as MDMA for the treatment of PTSD. Psilocybin in particular is exciting because of its favorable safety profile and capacity to improve symptoms in multiple disorders.3 Not that this property is unique to psychedelics: SSRIs, for example, are used to treat both depression and anxiety.4 But psychedelics seem to have an unusually broad range of uses. Scientists want to know just how broad it really is.
So far, initial evidence from clinical trials supports psychedelic-assisted therapy for mood disorders, PTSD, and alcohol and nicotine dependence.5,6 Scientists are continuously building on this research, their sights set on getting the regulatory green light for psychedelic therapy in the next five years – if further trials confirm its efficacy. Worldwide, eighteen Phase 2 and 3 clinical trials for these diagnoses are currently ongoing, with several more in the works. The MIND Foundation, in collaboration with Charité Universitätsmedizin Berlin and the Central Institute for Mental Health Mannheim, will also conduct a large study on psilocybin therapy for depression beginning next year.
Meanwhile, research is expanding to other mental health conditions. At its Center for Psychedelic & Consciousness Research, Johns Hopkins University has expanded its studies with psilocybin to include eating disorders. Imperial College London, also boasting a Centre for Psychedelic Research, plans to do the same. Beyond that, research teams at Yale and the University of Arizona are testing whether psilocybin is effective against obsessive-compulsive disorder.
Scientists also hope that psychedelics might help people overpower addictions beyond alcohol and nicotine. The University of Alabama is finishing up a study investigating psilocybin for cocaine addiction, and the University of Wisconsin will soon do the same for opioid use disorder.
Clinical research is also taking some more surprising turns. One notable avenue is the treatment of cluster headaches and migraines, with clinical trials running at Yale, in Basel, and in Copenhagen. The Beckley Foundation has also sponsored a recent trial in which a low dose of LSD decreased pain perception.29 And researchers at Imperial College London have proposed using psilocybin as a last resort for chronic coma patients, although their theory has yet to be tested.7
Beyond knowing that psychedelics may treat certain disorders, it’s also important to know why.
Researchers have recently examined whether specific aspects of a trip make psychedelic therapy more likely to work. One crucial phenomenon appears to be the mystical experience (now an official scientific term!). Mystical experiences are characterized by feelings of ecstasy, oneness and unity, and transcendence of time and space. They are also known for being both saturated with meaning and difficult to put into words.8 Recent studies suggest that these kinds of experiences are important – perhaps even essential – for fruitful psychedelic therapy.9
At the physical level, psychedelics may promote neuroplasticity – that is, the brain’s ability to form new connections and restructure itself.10 In rats, most psychedelics promote several components of neuroplasticity in the pre-frontal cortex, and they’re more potent and quicker potent at it than nearly any other substance.11 In humans, scientists think augmented neuroplasticity may explain psychedelics’ long-term effects, and they’re busy trying to verify it.12,13 (If this sounds interesting, check out our blog post on neuroplasticity.)
Psychedelics may also work by counteracting inflammation in the brain, which is out of control in certain psychiatric disorders.14 According to Dr. Stephen Ross at NYU, reducing inflammation could also have uses beyond improving mental health. Drugs which enhance neuroplasticity and dampen neuroinflammation could be uniquely suited to treat Alzheimer’s disease and other neurodegenerative disorders. There is no evidence for this right now, but since Alzheimer’s can’t yet be cured or slowed down, it may be worth a try. Scientists at Johns Hopkins are conducting a study on psilocybin treatment for depression in Alzheimer’s disease, with plans to also measure changes in cognitive ability. And researchers at Yale have recently shown that LSD microdoses of up to 20µg are safe for older adults, opening the door for further clinical trials.14
Interested in learning more about the neural effects of psychedelics, and their therapeutic potential? Check out our INSIGHT 2021 conference in September, which includes presentations on these issues by Prof. Dr. med. Gerhard Gründer, and by Dr. Katrin Preller.
Some researchers wonder whether microdosing, or the use of sub-hallucinogenic doses of psychedelic substances, could have benefits too. Anecdotal reports on its effects abound, and science can help separate truth from hype. The newly minted Canadian Centre for Psychedelic Science studies microdoses of psilocybin, and other teams across three continents are researching microdosing in both patients and healthy subjects.
Due to regulatory limitations, much of this work has been done by surveying people who microdose privately. Although this study design has the advantage of taking place in a natural setting, its drawbacks loom large: True control groups and blinding are rare, many reports are retrospective and of questionable accuracy, and the study samples are likely skewed toward those with pro-psychedelic views. Nevertheless, researchers are doing their best. Several recent publications have explored self-reported effects of microdosing, finding both positive and unwanted outcomes.15–17 Another of these studies is taking place at Imperial College London right now.
Placebo-controlled trials with microdosing have also sprung up in the literature. A research team in Chicago administered microdoses of LSD to healthy volunteers, and like the survey studies, they found both positive and negative effects (as well as a big dollop of the placebo effect).18 Low doses of psilocybin are also being investigated for their ability to treat depression and migraines, since high doses may not always be feasible or desirable for patients. And a study on microdosing LSD with healthy subjects has just finished data collection , with another beginning in New Zealand. Some researchers hope microdosing will be an alternative to antidepressantsfor patients who experience unwanted side effects, or no effects at all. Others even hope for a safe way to enhance mood and cognitive performance in healthy subjects. But only time – and data – will tell.
DMT (N, N-dimethyltryptamine) has not been forgotten in the psychedelic renaissance, and its unique properties may earn it a niche in psychedelic therapy. DMT has a short duration of action which can be controlled intravenously, and unlike LSD and psilocybin, it doesn’t induce tolerance.19 Researchers in London have been studying DMT’s effects on brain activity using EEG,20 while scientists in Basel are conducting a clinical safety trial. DMT also has the distinction of being the only psychedelic substance found to be present naturally in a mammalian brain, and we are closer than ever to figuring out what it’s doing there.4,5
Research has also picked up on ayahuasca, the traditional Amazonian brew containing DMT. Much of ayahuasca research comes from Brazil, where researchers are testing its effects on mental health and brain functioning.21 Meanwhile, researchers in Switzerland are developing an ayahuasca pill. A synthetic pill would standardize the doses used in studies and could also temper some of ayahuasca’s unpleasant side effects, as well as protect Amazonian plants from over-harvesting.
DMT’s close cousin 5-MeO-DMT, traditionally obtained by milking live toads, has also appeared in the literature. Researchers from Maastricht University recently characterized 5-MeO-DMT’s effects on various measures of well-being,22 while a team at Johns Hopkins found that it might reduce symptoms of depression and anxiety.23 Similar to what is happening with ayahuasca, scientists are beginning to prefer synthetic sources of 5-MeO-DMT, in this case to avoid bothering any innocent toads.
Interested in cutting-edge research on the neural effects of DMT? Check out our INSIGHT 2021 conference in September, which includes presentations on this topic by Carla Pallavicini, Ph.D. and Christopher Timmermann, Ph.D.
Participants in psychedelic studies these days often end up in an MRI machine or wearing an EEG cap, allowing researchers to measure their brain activity while they trip. Using fMRI, one fascinating study from Maastricht University managed to capture which areas of the brain may cause the experience of ego dissolution.24 They’re currently using neuroimaging and behavioral methods to examine how psilocybin affects creative thinking, social cognition, and emotion.
Over in Switzerland, researchers have made enormous progress in identifying the receptors necessary for psychedelic effects.25 They are investigating how psychedelics affect brain activity, and recently characterized psilocybin’s effects on specific brain regions.26 In another line of research, scientists in Zürich and elsewhere are interested in the synergy between psychedelics and mindfulness meditation.27
These types of studies have allowed neuroscientists to develop theories to explain psychedelics’ peculiar effects. One of these is the entropic brain theory, developed by Dr. Carhart-Harris and his team in London.28 According to entropic brain theory, consciousness exists on a continuum between highly ordered and highly chaotic brain activity. While the brain’s activity is relatively orderly during normal consciousness, psychedelics push it into a more chaotic state. Carhart-Harris and his fellow scientists continue to test this theory with MRI and EEG experiments (Read more on the entropic brain theory in this blog post).
Psychedelic research is exploding in new and exciting directions – we are now at a point where fresh studies are published every single week. And every day, scientists all over the world are exploring different psychedelic substances, their effects on the brain, and how they might help improve mental health.
Summarizing the recent wave of science is a bit like trying to fit the ocean in a teacup. You can also check out the projects the MIND Foundation is working on right now.