Exactly. It lends weight to the idea that we might need help of hormones to remove our inhibitions. But those hormones can be created in a number of ways. Here is a study on humans:

We are not, but we do share many basic biological traits, so that learning about rats can help us learn more about ourselves. In fact, in the previous days, by reading about rodent experiments, I learned more about myself than by reading many psychological books.

i'm aware of the study you quoted but to me exogenous oxytocin does nothing, well if dosed high enough it facilitates bowel movement it seems..

they were researching it on autistic spectrum disorder right?
i'm aware of the study you quoted but to me exogenous oxytocin does nothing, well if dosed high enough it facilitates bowel movement it seems..

Yes, there is some controversy about the mode of delivery. But perhaps a roundabout way to oxytocin could be more useful.

they were researching it on autistic spectrum disorder right?

No, not in that research. They were researching the fear extinction.
Here is a very nice summation of many scientific studies about things which can increase oxytocin levels:

And here is one about essential oils: The Effects of Essential Oil on Salivary Oxytocin Concentration in Postmenopausal Women - PubMed

When it comes to probiotics, I will have to try them again. They are also a controversial topic.
Vitamin A seems to be another thing that can help with the production of oxytocin.

Here is another thing that might help increase oxytocin levels.

If you chose to supplement with choline, the best types for increasing the brain levels are Citicoline (CDP choline) and Alpha GPC.

but that could be an erro crasso my fren, your body is smarter than you and would desensitize you even further probably
but that could be an erro crasso my fren, your body is smarter than you and would desensitize you even further probably

Desentitization is a common problem for many hormones, but not for oxytocin, it seems, because oxytocin has a positive feedback loop. Which means that, once you jump-start the oxytocin production, your body will continue to produce oxytocin on your own, at least for some period of time.

Oxytocin is one of a few hormones that have a positive feedback loop. This means that the release of oxytocin leads to actions that stimulate your pituitary gland to release even more of it.

Most hormones create negative feedback loops after they’re released, meaning your body releases less of the hormone after it has its effect on your body.

Oxytocin can also open some parts of our brain which are locked in adults.

MDMA Reopens Child-like “Critical Periods”​

Psychedelics have been used for thousands of years in both cultural and medicinal settings. Over the past few years, a renaissance in psychedelic research has provided new insights into psychedelic drugs as a treatment for serious mental health conditions, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), when combined with psychotherapy.

The biological mechanisms behind these therapeutic advancements are still poorly understood at present. But some aspects are being uncovered.

In a recent Analytical Cannabis webinar, Gül Dölen, an associate professor of neuroscience at Johns Hopkins University, explained one such recent discovery. Her presentation delved into research from her lab that shone a light on how the effectiveness of MDMA-assisted psychotherapy may be linked to the psychedelic’s ability to reopen a “critical period” in the brain for social reward learning.

What is a critical period?​

As the brain develops in infancy and through childhood, it has to adapt to vast amounts of external information and stimuli. To make sense of these stimuli, the young brain will go through certain “critical periods” of learning, which can create a significant impact on later behavior as the brain matures.

“Critical periods are periods of time, usually during development, where the brain is extremely sensitive to the outside world and the ecologically relevant cues that it needs to learn from,” Dölen explained. “And this sensitivity to the world is coupled to a heightened period of malleability and plasticity that allows synaptic circuit and behavioral modifications to occur.”

The term critical period was first coined by the zoologist Konrad Lorenz to describe the first 24-48 hours after snow geese hatch and imprint onto the first moving object they saw as a mother figure. This is ordinarily their actual mother, but during Lorenz’s research, it was himself. If no suitable mother figure is shown to the geese until after this critical period, they will fail to form a strong attachment.

Scientists have long recognized that our inability to cure certain diseases comes from the fact that, by the time we get around to identifying the disease process or making a treatment available for the disease process, the relevant critical period is closed,” Dölen said.

Once the critical period is closed, even if the disorder process that is responsible for the disease is reversed or ameliorated, because the brain is no longer able to reorganize itself and induce these synaptic and circuit modifications, that rebalancing is ineffective.”

This is most famously seen in cases where people are born with bilateral cataracts, Dölen added. If the cataracts are not removed until adulthood, then the person will still remain blind as the brain’s visual system is not able to adapt to this new, corrected visual space. If there were a way for scientists to reopen these critical periods, then it could open the door to new treatments for conditions involving the brain and its plasticity.

Oxytocin and serotonin control critical periods for social reward learning​

The Dölen lab at Johns Hopkins University is interested in the brain mechanisms that control social behavior, and so the team has postulated that there could be some critical period for social reward learning involved in this process. To test this, the lab used a social conditioned place preference assay with laboratory mice at different age gaps to determine if social reward learning is conditioned by a critical period in mice.

The mice were raised in a home cage with a neutral bedding material inside of it. Pre-trial, the mouse subject was placed into a new cage with two areas, each containing a novel bedding material for the cage, and the time the mouse spent in each area was measured. The mouse would then be subject to social conditioning by being introduced to a cage with other mice that also contained one of the two novel bedding choices. They would then undergo isolated conditioning by spending time alone in a cage with the second bedding choice. Post-trial, the mouse was reintroduced to the split-area cage and the amount of time spent in each half was remeasured to assess the effects of the social conditioning.

“The social reward learning – the ability to learn from these social cues – peaked around postnatal day 35 to 42. Then it declines, and by mature adulthood it’s closed,” said Dölen.

With a critical period identified, the focus turned to the brain mechanisms that might regulate this social reward learning behavior in juveniles. From her postdoctoral training, Dölen was aware that synaptic plasticity induced by the hormone oxytocin might be a candidate for this. And so the team used an electrophysiology experiment to invoke synaptic responses from brain slices taken from the lab mice and compared the synaptic plasticity of the mice at different ages.

They found that the application of oxytocin in the juvenile mice brain slices induced robust plasticity, but that this plasticity was not observed when the same experiment was done on adult mice brains.

This suggests that the magnitude of oxytocin-induced synaptic plasticity in the nucleus accumbens is developmentally downregulated and corresponds to the developmental downregulation of the behavioral plasticity that we saw,” Dölen explained.

“Interestingly, we have also shown that serotonin and oxytocin are working in coordination to encode this social reward learning, but serotonin plasticity is not developmentally downregulated. So what this tells us is that while the two mechanisms work together, they are regulated differently across development.”

Reopening the critical period with MDMA​

With this new insight into oxytocin playing a role in the opening and closing of the social reward learning critical period, theoretically, it would then be possible for researchers to leverage this knowledge and reopen such critical periods for therapeutic benefit. However, oxytocin cannot directly cross the blood-brain barrier, making it an unreliable therapeutic avenue for further development.

“So, we decided to turn our attention to MDMA,” Dölen said. “We knew that it had these prosocial effects, and we thought, ‘Wouldn’t it be interesting if somehow this prosocial psychedelic could trigger the reopening of the critical period?’”

“We knew that MDMA, from previous literature, binds to the serotonin transporter, and when it does [...] it reverses the direction of the transporter. So, instead of taking up the serotonin from the synapse, it’s actually injecting it into the synapse. And so you’re getting this massive influx of serotonin in response to MDMA.”

“But there was also anecdotal evidence and some circumstantial evidence that MDMA might be triggering oxytocin neurons to release oxytocin.”

And so the researchers repeated the mouse experiment, but this time they gave the mice a single dose of MDMA up to 48 hours before the place preference assay began.

They found that the MDMA dose did indeed reopen the critical period for social reward learning in the adult mice, beginning around 6 to 48 hours after the dose. The reopening of the critical period lasted at least two weeks, up to around 4 weeks before returning to baseline.

“We were really excited about these results, because we knew about the human clinical trials that have been looking at MDMA-assisted psychotherapy for the treatment of PTSD,” Dölen said. “To our knowledge, this is the first time anybody has been able to match a sub-acute or chronic effect of MDMA to the behavioral readout that we’re using.”

According to Dölen, this idea of MDMA reopening critical periods in the brain accounts for many of the observations coming out of MDMA-assisted psychotherapy trials, observations that other theories simply cannot explain.

“MDMA’s therapeutic effects are context-dependent,” explained Dölen. “If you take MDMA and go to a rave party, you don’t come back automatically cured of PTSD, or addiction, or depression. You have to have used MDMA in a therapeutic setting.”

“This context-dependence of MDMA’s therapeutic effects does not hold for the proposal that maybe MDMA is working as sort of a next-generation anxiolytic. Whatever anxiolytic properties MDMA has or not, these are context independent. Whereas the MDMA-dependent reopening of the critical period for social reward learning is dependent on giving the MDMA in the social context. I think that this is very interesting, and it differentiates this explanation from other explanations.”

Building on their discoveries in the area of MDMA and critical periods, Dölen’s team recently initiated the PHATHOM project (Psychedelic Healing: Adjunct Therapy Harnessing Opened Malleability). This initiative aims to investigate the hypothesis that psychedelic drugs as a wider drug class can reopen other distinct critical periods in the brain and that these effects can be further harnessed for therapeutic benefit.

Beyond the Therapeutic Alliance​

How MDMA and Classic Psychedelics Modify Social Learning – An interview with Gül Dölen

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, 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.

Priming the brain for psychedelics​

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?

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.

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.

Going beyond the acute effects​

SB: Is this the same mechanism you believe could work to treat severe forms of autism?

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. 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?

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.

Where therapy meets big pharma​

SB: In what other ways could these findings influence treatment models?

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.

are you not inverting things? i.e body releases more because your receptor desensitizes

Yes, that could happen in some cases, such as after using the Pitocin to induce the labor in pregnant women.

The risk of Pitocin as a cause of autism attributable to oxytocin receptor desensitization in the brain of the fetus is evaluated in terms of a mathematical model. A composite unit, D, for oxytocin receptor desensitization levels is established with the form ((IU-h)/ml)E-3, where IU is the international unit for oxytocin. The desensitization values for oxytocin receptor desensitization at a concentration of 10 nmol of oxytocin per liter for 3, 4.2 and 6h corresponding to 0%, 50% and 100% desensitization are calculated to be 15 D, 21 D, and 30 D, respectively. The permeability of the blood-brain barrier in the fetus to oxytocin is discussed, and the upper limit of the concentration of Pitocin in the placenta, and its possible diffusion into the blood and brain of the fetus, is calculated for a routine dose of 6 milli U per minute of Pitocin over a 12h labor. This dose of Pitocin is shown to result in a desensitization value in units of D that is more than a factor of 10 below the 0% desensitization value of 15 D. This indicates that routine doses of Pitocin are not a significant cause of autism attributable to oxytocin receptor desensitization. This is consistent with the findings of a major epidemiological study of the association of Pitocin with autism in Denmark entitled, "Oxytocin-augmented labor and risk for males", Behavioral Brain Research, May 1, 2015; 284:207-212, which found no association between the use of Pitocin during labor and the incidence of autism for females, and a modest association for males.

The use of synthetic oxytocin (OT) to induce and/or augment labor and delivery is on the rise. Maternal exposure to OT during birth may have adverse effects on the infant's development, including increased risk for autism. Yet, studies that test this biologically plausible association and whether it is modified by sex are limited and show inconsistent findings. To this end, we conducted an epidemiological analysis, including all singleton live births in Denmark between 2000 and 2009 (N = 557,040), with a follow-up through 2012. A total of 2110 children in this cohort were subsequently diagnosed with autistic disorder according to the ICD-10-DCR. Augmentation of labor with OT was modestly associated with an increased risk for autism in males (HR 1.13; 95% CI, 1.00-1.26; P = 0.04), but not in females (0.99; 0.77-1.27; P=0.95). Among males exposed to OT augmentation, 560 were subsequently diagnosed with autistic disorder, and among those not exposed, 1177 met criteria for autism (incidence rate 103.2 and 81.4 per 100,000 person-years, respectively). Our findings suggest a modest association between OT-augmented labor and risk for autism in males. However, given the known benefits of using synthetic OT during labor and delivery caution is warranted when interpreting the findings. Future studies should also investigate dose-dependent effect of OT on infant's development.

Results: Compared with children born to mothers who received neither labor induction nor augmentation, children born to mothers who were induced and augmented, induced only, or augmented only experienced increased odds of autism after controlling for potential confounders related to socioeconomic status, maternal health, pregnancy-related events and conditions, and birth year. The observed associations between labor induction/augmentation were particularly pronounced in male children.

Conclusions and relevance: Our work suggests that induction/augmentation during childbirth is associated with increased odds of autism diagnosis in childhood. While these results are interesting, further investigation is needed to differentiate among potential explanations of the association including underlying pregnancy conditions requiring the eventual need to induce/augment, the events of labor and delivery associated with induction/augmentation, and the specific treatments and dosing used to induce/augment labor (e.g., exogenous oxytocin and prostaglandins).

In such cases, the repair of oxytocin receptors would probably be the proper solution.
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