End of Year Psychedelic Research Review: Study #3
End of Year Psychedelic Research Review #3
Continuing our Year-End Psychedelic Research Review, we think it’s fair to say there are clear standouts, milestones, and dare we also say, favorites. Often these end of year countdown lists work there way towards their top ranked object/accomplishment of “Best in show/First Place”, but I prefer to think of this as creating an immersive panorama that illustrates a broadly detailed picture of the current theoretical ecosystem. Where are we and what do we now believe we know better? Standouts can be within subcategories; clinical practice vs laboratory results, so to say one is more important than the other is a bit of a false comparison. Each achievement in their subfield is contributing to the whole sphere of study and raising the foundational knowledge we all need to move forward.
But everyone has a favorite, either in terms of creating foundational landmarks/milestones or creating a new theoretical framework that has greater facility in explaining universal mechanisms of action. So our first pick with Imperial’s study of psilocybin vs escitalopram for depression would be a great example of a clinical study where we get to see real world effects on actual patients finally being validated. Imperial’s study design was excellent with an extremely thorough accessory data set. Zeus Tipado’s pick of the year was Ling-Xiao Shao’s confirmation of psychelic-induced spinogenesis; increased spinal density and trunk growth in vivo, a major mechanism of action that had been suspected for years but never directly observed, a great example of hardcore lab work in neurology also showing direct reductions in depression.
And then you have work when you look at the scope of it, your breath just leaves as you reel at the possibilities for application and practice, so as promised last night I’m going to offer up the work of Dr. Gül Dölen of John Hopkins for some of the most consequential work on offer this year. She presented unpublished work at the beginning of this month at the Horizons Conference in NYC. it was building on previously released work from her lab and proposes a radical new universal mechanism of action that explains a multitude of lateral and downstream effects. If you haven’t seen her in action, you could revisit her very pointed panel discussion with Drs. Charles Nichols and David Olson on Psytech Global, with panel moderator Kyle Bueler of Psychedelics Today. Dr. Gölen’s fierce intellect is a thing of wonder in action and her presentation at Horizons did not disappoint.
As we discussed yesterday, there has been a growing trend line of evidence developing in support of a transdiagnostic effect across multiple conditions, showing a universal mechanism of action underlying all psychedelics. So her presentation was based around new unreleased evidence in support of a previous paper from dolenlab.org, “Oxytocin-dependent reopening of a social reward learning critical period with MDMA”, by lead author Romain Nardou et al. Apparently neuroscientists have been obsessed with neuroloplastic states knows as critical (or sensitive) period openings. During this developmental period, an organism’s neurology is especially malleable to outside influences before settling in to a fixed configuration. Over 100 years ago, it was first noticed in snow geese imprinting behavior, but it occurs in many areas like song learning in birds, mapping of the somatosensory cortex, ocular dominance plasticity, language learning in early childhood, motor learning after stroke, etc. After a certain time, these periods then close, with their peak occurring in juvenile adolescence, so there is a limited window after strokes to recover and in childhood to acquire languages. Neuroscientist have focused on whether it’s possible to reopen these critical periods in order to make alterations in plasticity in order to change the course of neurological conditions or diseases, or for therapeutic benefit.
It turns out Dr. Dôlen’s lab discovered a new type of critical period called social reward learning, based in part on her earlier work with the etiology of autism. Social reward learning can be seen in teenagers when they are especially responsive/suceptible to peer pressure and why it may be challenging to navigate foreign cultures once that period closes as those were not the social cues you were imprinted with during this opening. This particular type of plasticity is mediated by oxytocin and is somewhat limited to a brain structure called the nucleus accumbens. “Oxytocin is a hormone and a neurotransmitter that is involved in childbirth and breast-feeding. It is also associated with empathy, trust, sexual activity, and relationship-building. It is sometimes referred to as the “love hormone,” because levels of oxytocin increase during hugging and orgasm.” The nucleus accumbens plays a “significant role in the cognitive processing of motivation, aversion, reward, and reinforcement learning; hence, it has a significant role in addiction. In addition, part of the nucleus accumbens core is centrally involved in the induction of slow-wave sleep. The nucleus accumbens plays a lesser role in processing fear (a form of aversion), impulsivity, and the placebo effect. It is involved in the encoding of new motor programs as well”. But this specific plasticity becomes unavailable to adults but is still present in children and juveniles.
This ability to induce plasticity is known as metaplasticy, the plasticity of plasticy, if you will. This type of plasticity is available for oxytocin but not serotonergic pathways in juveniles. But it’s important to differentiate this type of plasticity from hyperpalsticty. Hyperplasticity is a result we can expect from cocaine use, which operates in the dopaminergic pathway (deeply implicated in reward and addiction), and strongly creates non-specific snynaptic plasticity throughout the cortex and lacks the therapeutic effects for neuropsychiatric diseases that we see in psychedelics. Crucially, this cocaine mediated hyperplasticity doesn’t re-open the social reward critical period, so she cautions those that are just seeking a medicinal approach in psychedelic drug development that the reason psychedelics are exciting for researchers is that they are context dependent; they don’t want to end up with a modified ibogaine with the duration of ketamine due to potential loss of critical periods or runaway hyperplasticity. “And that’s why you can’t just go to a rave, take MDMA, and be cured of PTSD”. Cocaine lacks the therapeutic effect that occurs with psychedelics during social reward learning critical period reopening. This is state dependent conditioning to a degree and set and setting profoundly makes a difference here.
So how do we reopen it? MDMA creates profound “pro-social” acute subjective effects and to make sure that it was not just the acute effects, her lab waited until 48 hours after before measuring if the critical period was open to see if this juvenile oxytocin-mediated metaplasticity was operating and it was, so they knew it wasn’t just due to the acute effects of the MDMA. It begins reopening within 6 hours and continues strongly for at least two more weeks with MDMA; by one month it’s returned to baseline. But to her and her teams knowledge, this is the first time it's been established that MDMA can reopen this critical period window in an animal model and that it is dependent on the social context. And like much of what has been occurring during this psychedelic research renaissance, their “medicinal properties have been known for millennia”, but the underlying mechanisms was unknown and the critical period reopening is very strong candidate.
There was skepticism that MDMA could cause this because other psychedelics aren’t as pro-social in the same way, more of an abstract realization of the oneness of humanity than the overwhelming need to get into a very intimate group hug that is a stereotype of MDMA users. Her lab had strong suspicion that there was a mechanism underlying all psychedelics for reopening critical periods and while they were context dependent, they didn’t relying on the acute pro-social effects that are limited to MDMA, so they tested ketamine, psilocybin, LSD, and ibogaine also. All of them reopened social reward critical period after 48 hours as well, but then the story began to take a deeper turn. Within popular discussion of psychedelics, the period of the afterglow between different compounds are known colloquially to have varying durations; ketamine is generally agreed to have a fairly narrow afterglow while LSD and Ibogaine are regaled for their persisting afterglow windows and that “the time course of the acute subjective effects is proportional to the durability of their therapeutic effects”. So Dölen’s lab suspected there was a very tight dependence between the acute subjective effects of a specific compound and the duration of their critical period reopening and they were correct.
So the durations for the critical periods are as follows;
ketamine – 1 week
psilocybin and MDMA – 2 weeks
LSD – 3 weeks
and Ibogaine – 4+ weeks (they stopped testing at 4 weeks).
She emphasized that rather than just the acute pro-social effects, an altered state of consciousness shares similar characteristics to the critical period opening at an experiential level and we see that clearly open at 48 hours, well after the acute effects are done. She also warned that the search for a universal mechanism at the receptor level was likely to be a potential dead-end as critical period opening was shown across multiple psychedelic compounds despite them not all sharing the same receptor activation. A lot of focus has been in towards the 5HT2A receptors and in fact they were able to demonstrate its necessity in reopening the critical period window with both LSD and psilocybin, but it was not a necessary receptor for either ketamine or MDMA in order to reopen the critical period. The theme held true for Beta arestin receptor where in using Beta arestin knockout mice, they were able to show that LSD was unable to open the critical period, but when the beta arestin receptor was present both LSD and MDMA were able to reopen the critical period, but not for ketamine or ibogaine. So neither Beta arestin or 5HT2A are universal mechanisms for the critical period reopening.
So she and her team believe that any universal mechanism for critical period reopening is downstream of the receptor level and secondary messenger cascade level, all the way down at the level of DNA transcription regulation and a good portion of that belief was due to the persistent duration of the therapeutic affect; it's very long. Apparently the transcription is happening with Immediate Early Genes (IEG) and Extracellular Matrixes (ECM). IEGs are deeply involved in formation, storage, and recall of memories, more specifically working, episodic, recognition, and fear memories. Those types of memories likely become maladaptive in certain psychiatric conditions like schizophrenia, PTSD, and depression. IEGs are also crucially involved in Long Term Potentiation (LTP), another type of memory consolidation but more important for associative memory like motor learning. Both types of memory/conditioning have deep implications for pain processing and formation. ECM is the surrounding supporting tissues and structures supporting cells throughout the animal and plant kingdom; blood plasma is the extracellular matrix for blood cells, for one notable example.
So IEGs and ECMs are changing in this critical period reopening in response to social reward learning, giving strong support to context dependence (set & setting), and by extension, that the value of psychedelics lies in large part that they are drug-mediated experiences. This is fairly strong support for members of the psychedelic research community that emphasize the nature of the experience beyond just the induction of nuroplasticity mediated by dendritic regrowth. It doesn't obviate it, they are both crucial aspects of the therapeutic model but it shows the experiences themselves, in the right social context, are inducing direct neurological, deeply structural changes as well.
In close, private discussions over the last 18 months, REMAP Therapeutics has been repeatedly asserting that in order for psychedelics to be most effective, particularly against conditions like chronic pain, there is an acute need to recognize the “active versus passive care dilemma” that many clinicians and therapists within the pain field face. Treatment for pain conditions cannot be just the passive receipt of that activity; there has to be an active participation in the rehabilitation process in order to re-condition and re-educate the nervous system. The classic example is someone goes in for physiotherapy, the therapist makes an adjustment to the patient, who then leaves feeling better but once they are back to their normal day-to-day activities and movement patterns as they walk to the parking lot, the pain returns, once again a type of state-dependent conditioning we see in the bio-psycho-social model for pain. So the neurological re-education and re-organization has to happen within an active, dynamic context where the pain is more likely to be provoked and elicited to a degree before it can be resolved with contextually-specific “remapping”.
Psychedelics treating chronic pain can't be taken only passively; preparation and especially integration afterwards are vitally necessary. We experienced this directly after our participation in the NYU trial when suddenly all of our interventions that had hit a wall prior to our dosing session suddenly rapidly regained traction in their therapeutic magnitude. We made significant progress with pain and performance that had stalled for literally years. So having this vital framework from Dr. Gölen and her team feels like a major breakthrough for everyone in this field. We think it's safe to go as far as putting it on a similar level to Robin Carhart-Harris’ REBUS model in terms of its broad application and ability to make predictions. You can also see hints of this in Dr. Joel Castellanos’ paper from May 2020, who presented later the same afternoon at Horizons earlier this month.