Last week, I introduced my key takeaways from a virtual Q&A last month with Gül Dölen MD PhD. Hosted by Jayne Gumpel LCSW and Carl Spitzer MD of Big Tent Ketamine or BTK, Dr Dölen summarized findings from her research on critical learning periods and the implications for psychedelic-assisted therapy including ketamine therapy.
In this post, I will summarize Dr Dölen’s latest research from 2023 and describe what it means for ketamine therapy.
Starting in 2019, scientists demonstrated that it was possible to reopen the critical period for social reward learning with a single dose of MDMA or 3,4-methylendioxymethamphetamine. Because some conditions like PTSD may be harder to treat once this critical period has closed by adulthood, this discovery implied that new therapies could be developed that reopen the critical period for social reward learning. In turn, it would be easier for behavioral health professionals to help their patients modify their memories, thoughts, and behaviors in positive ways.
The next question begged to be answered: Was there something unique about MDMA or might other psychedelics work too?
In May 2023, Dr Dölen and her colleagues pointed to an answer in their paper titled, “Psychedelics reopen the social reward learning critical period.” They found that instead of its prosocial or empathogenic effects, MDMA reopened the critical period for social reward learning because of its ability to produce acute subjective effects. In other words, it is precisely the psychoactive altered state of consciousness which one experiences on MDMA that helps reopen the critical period for social reward learning.
The most recent Nature paper extended earlier research on MDMA to other psychedelics. Dr Dölen and her team, including Romain Nardou, found that in addition to MDMA, psilocybin, ketamine, LSD, and ibogaine, also reopen critical periods. During the Q&A, Dr Dölen suggested that basically all psychedelics, regardless of whether they are social, reopen this critical period for social reward learning.
This discovery also challenged existing ideas that substances like LSD, DMT, psilocybin, and mescaline (which act on a specific subtype of 5-HT receptor called 5-HT2AR or simply 2A) were meaningfully different from MDMA and ketamine, at least in a therapeutic context. Importantly, this also meant that substances that broadly influence serotonin receptors or 5-HT receptors, like many psychedelic compounds, may be the key to reopening critical learning periods. As such, Dr Dölen is an advocate for a more inclusive understanding of psychedelics beyond just hallucinogenic properties. She likened the variety of psychedelics to different types of alcohol (wine, vodka, beer), each offering different experiences but ultimately having a similar underlying effect.
These findings strongly indicate that psychedelics have a significant role in the treatment of mental health conditions like PTSD, depression, and anxiety. (I can attest. This is something I often see firsthand at Innerbloom Ketamine Therapy.) Because of their ability to produce an altered state of consciousness and therefore reopen critical periods, psychoactive substances like MDMA and ketamine, in effect, enable the rewiring of neural pathways. Also known as neuroplasticity and neurogeneration, these types of changes in the brain have been shown to facilitate learning and adaptation in adults, who traditionally have less neural plasticity compared to younger people.
If all psychedelics help rewire neural pathways by way of reopening critical periods, why do we limit our treatment to ketamine therapy? In short, because it’s safe, effective, and legal when administered by licensed healthcare providers. There’s also relatively lots of research—23 years’ worth—demonstrating ketamine’s antidepressant effects. This is because ketamine has never been subject to the most strict limits (Schedule I of the Controlled Substances Act), compared with other psychedelic compounds.
Dr Dölen’s latest research also uncovered another significant finding: The duration of time that the critical period was reopened correlated with the duration of time that the subjects (mice) felt acute subjective effects of the psychedelic. That is, the longer the trip, the longer the critical period was reopened.
Of the psychedelics examined, Dr Dölen noted that ketamine has the shortest acute subjective effect, lasting 30 minutes to two hours in humans. She observed that other substances like psilocybin, MDMA, and LSD have longer durations. Ibogaine appears to have the longest effect tested. This indicates that relative to psilocybin, for example, ketamine reopens a critical period for less time, in this case up to 48 hours (but this time in mice), all else equal.
Two excerpted histograms from Dr Dölen's research paper
Based on the correlations they observed, Dr Dölen suggested that extending the duration of ketamine infusion beyond the common 40 to 60-minute session could potentially lengthen the window of time that critical periods remain open. However, it’s important to note that there are several factors that determine the optimum infusion duration. The cost-to-benefit ratio is the most relevant for many. Further, Dr Dölen offered the following considerations related to ketamine therapy.
The amount administered is a crucial factor in any pharmacologic therapy. For ketamine and other psychedelics, the dose needs to be within the psychedelic range for the treatment to be effective. Dr Dölen shared her belief that a significant, overwhelming experience is necessary to trigger the synaptic changes required for critical period reopening. In other words, the patient must experience acute subjective effects, even if inconvenient or challenging.
And with ketamine, there is an upper limit. Anesthetic doses of ketamine are ineffective in reopening critical periods. Dr Dölen noted that this may be due to the lack of social context at such high doses, where mice and humans would be essentially non-responsive.
The idea is to maintain a prolonged, continuous state of wandering or introspection without direct intervention from psychotherapy, allowing patients to explore and identify memories that need reconfiguration. Longer ketamine sessions, similar in duration to MDMA-assisted psychotherapy trials (which are eight to ten hours), might significantly increase the duration of the therapeutic window. Like I mentioned earlier however, the appropriate ketamine infusion duration depends on the person and condition, among other important factors.
Unrelated to her work, Dr Dölen cited a study where researchers found that ketamine reopened a critical period for ocular dominance plasticity in mice. In order to keep the critical period open for longer, the researchers spaced a series of ketamine doses days apart. They found that with each subsequent dose, the critical period remained open.
If this technique were adapted for humans, one might see how it could be beneficial to space ketamine infusions far enough apart to keep the critical period open while allowing for adequate psychotherapy between infusions. However, Dr Dölen noted a caveat regarding extending the critical period with multiple doses: For complex conditions like severe PTSD, it might be beneficial to wait several months between sessions. This would allow for the proper integration of experiences from the first session before attempting another.
Dr Dölen and her research team determined that the longer the acute subjective effects were felt, the longer the critical period was reopened. While a longer critical period offers new opportunities to develop novel therapeutic approaches, longer does not necessarily mean desirable. There are at least two reasons why.
First, there is danger of exposure to harmful influences during the critical period following psychedelic therapy. After the acute subjective effects disappear and the critical period has reopened, people are in a heightened state of vulnerability and sensitivity which is similar to that experienced in childhood. This is when proper integration psychotherapy should be performed because people will be more susceptible to influence and learning. While this has significant potential upside, it can be harmful.
As an example, Dr Dölen warned of the potential for negative indoctrination during this vulnerable period by citing Charles Manson who used LSD to manipulate and indoctrinate people. She also described the risk of returning patients to harmful environments (such as chaotic lifestyles or abusive situations) after treatment. This can potentially cause new damage, as the patients are more impressionable and can be adversely affected by negative experiences during this sensitive period.
Dr Dölen compares this vulnerable period to the recovery phase after major physical surgeries, like open heart surgery, where the body is more susceptible to injury and requires rest and protection. Similarly, after psychedelic therapy, the 'mental tissue' is delicate and needs a protective and nurturing environment.
These considerations underscore the necessity of ensuring a safe, supportive, and therapeutic environment post-psychedelic treatment. This is crucial to avoid negative influences and maximize the positive outcomes of the therapy.
Second, there may be a huge opportunity to tailor individual therapeutic approaches by taking advantage of the different proprieties of various psychedelics. This is analogous to selecting the right tool and technique for the job.
Dr Dölen entertained the idea of using different psychedelics together (stacking) or choosing specific ones based on their unique effects and responses in individual patients. She also suggested that the subjective experiences induced by different psychedelics (cognition-forward, emotion-forward, dissociation-forward) could be matched to the needs of individual patients. Interestingly, Dr Dölen noted that there could even be potential for selecting specific psychedelics based on a patient's physiological state or condition, such as anorexia or veganism, where certain mechanisms of action might be more effective.
Reflecting on this Q&A session, I was surprised that so much breadth and depth were covered in just 90 minutes. While there were many takeaways, here are a few concluding remarks that Dr Dölen emphasized.
While psychedelics may help people who are seeking healing or behavior change get unstuck or accelerate their positive outcomes, they are powerful substances that have a potential to result in worse patient outcomes. Dr Dölen emphasized that the therapeutic effects of psychedelics are not solely due to the drugs themselves but the combination of the drug with therapy. This is particularly evident in reports from war veterans who describe the healing process beginning after the psychedelic experience, highlighting the learning and integration that occur post-treatment.
Psychedelics are unique among other pharmacological interventions because their outcome, positive or negative, depends on the context or the setting. One key benefit of this may help avoid what Dr Dölen calls the "melty brain problem” whereby potential adverse effects like amnesia, seizure, or loss of structural integrity could occur. Because psychedelics are context dependent, therapeutic approaches which take advantage of psychedelics may be able to target specific parts of the brain, avoiding widespread disruption.
While Dr Dölen shared lots of intriguing information that might benefit my patients today, she also acknowledged that the science lacks definitive answers to most questions asked. Further, she encouraged ketamine clinicians to experiment with different approaches to find what works best. Especially because conclusions from animal studies may not readily apply to humans, health care providers who work with psychedelics like ketamine should experiment, publish results, and share practices in order to contribute to our broader understanding of psychedelics and their use in therapy.
If reopening critical periods is akin to surgery, Dr Dölen emphasized that psychedelic therapy could completely transform our current pharmaceutical approach to mental health. Rather than lifelong medication regimens with debatable therapeutic effectiveness, she likens psychedelic therapy to a one-time “open mind surgery” with lasting results.
As someone who performed surgery for over a decade before starting Innerbloom Ketamine Therapy, I tend to agree with Dr Dölen when she advocates for a more definitive, cure-oriented approach to mental health. Unlike long-term medicalization, psychedelics may provide lasting solutions rather than temporary alleviations.
This post and my post from last week are my own interpretation of the Q&A session which was hosted by BTK. While I always stive for accuracy and completeness, my writing has not been reviewed or approved by Dr Dölen or BTK. However, I am grateful to both.
I encourage you to watch the Q&A session here as well as other videos which feature this prominent researcher. Alternatively, I recommend Dr Dölen’s appearance on the Tim Ferris Show in April 2023. You can listen or read. Be well.
Gül Dölen MD PhD is an associate professor of neuroscience at the Johns Hopkins University School of Medicine. Some of her most important discoveries relate to how we learn and form memories during critical periods in our development. Her work is featured at www.dolenlab.org.
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