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Psychedelics reopen the social reward learning critical period

Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness1,2. These drugs have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies3,4,5,6,7,8,9. Nevertheless, a unifying mechanism that can account for these shared phenomenological and therapeutic properties remains unknown. Here we demonstrate in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelic drugs. Notably, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Finally, identification of differentially expressed genes in the ‘open state’ versus the ‘closed state’ provides evidence that reorganization of the extracellular matrix is a common downstream mechanism underlying psychedelic drug-mediated critical period reopening. Together these results have important implications for the implementation of psychedelics in clinical practice, as well as the design of novel compounds for the treatment of neuropsychiatric disease.

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Classically, psychedelics have been defined to include drugs such as lysergic acid diethylamide (LSD), mescaline, phenylcyclohexyl piperidine (PCP), ibogaine, 3,4-methylenedioxymethamphetamine (MDMA), psylocibin and ketamine, because each of these compounds produces alterations to sensory, self, time and space perception that are “so alien to everyday experience that they shed new light on the workings of these everyday mental functions”1. Although more recent attempts have been made to subcategorize psychedelics10 on the basis of the subjective character of the altered state that they induce (for example, hallucinogenic, empathogenic, oneirogenic or dissociative), their chemical structure (for example, tryptamines, phenethylamines or arylcyclohexamines), or their principal binding target (for example, serotonin receptor 2A (5-HT2AR), monoamine transporter, κ-opioid receptor (KOR) or N-methyl-D-aspartate receptor (NMDAR)), the importance of these categories for therapeutic applications remains unclear, since psychedelics that span the diversity of classification systems have shown remarkable promise for the treatment of addiction4,5, post-traumatic stress disorder6,7 (PTSD) and depression3,8,9. Thus, identification of a common neurobiological mechanism that can account for the shared therapeutic effects of psychedelics is an obvious priority for translational neuroscience.

During specific periods of brain development, the nervous system exhibits heightened sensitivity to ethologically relevant stimuli, as well as increased malleability for synaptic, circuit and behavioural modifications. These mechanistically constrained windows of time are called critical periods and neuroscientists have long sought methods to reopen them for therapeutic benefit. Recently, we have discovered a novel critical period for social reward learning and shown that the empathogenic psychedelic MDMA is able to reopen this critical period11. This mechanism shares a number of features with the therapeutic effects of MDMA-assisted psychotherapy for the treatment of PTSD, including rapid onset, durability and context dependence6,7. At the same time, cocaine does not reopen the social reward learning critical period11, and since cocaine does not share the psychedelics’ therapeutic profile12, these results lend further support for the view that the reinstatement of social reward learning in adulthood underlies the therapeutic efficacy of MDMA.

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Do psychedelics really work to treat depression and PTSD? Here’s what the evidence says

As of July 1, authorised psychiatrists have been allowed to prescribe MDMA (the chemical found in “ecstasy”) to treat post-traumatic stress disorder (PTSD), and psilocybin (found in “magic mushrooms”) to treat depression that hasn’t responded to other treatment.

Psychedelic therapies have researchers excited because evidence suggests they might have lasting beneficial effects on factors that cause psychological distress beyond the treatment period. These include feeling disconnected from other peoplefear of death, and rigid ways of thinking.

This stands in contrast to most medications for psychological issues, which only directly help while people keep taking them regularly.

But how strong is the evidence for psychedelic therapy?

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Early promise

Early results from studies around the world have found psychedelic therapy might be effective for treating a range of psychological issues.

For instance, most studies (but not all) have found patients tend to report fewer depression symptoms for periods ranging from several weeks to several months after psilocybin therapy.

Similarly, studies have found reductions in PTSD symptoms three weeks after MDMA therapy.

Not so fast

However, as psychedelic research has grown, limitations of the research have been identified by researchers both within and outside the psychedelic field.

One issue is that we aren’t sure whether findings might be due to a placebo effect, which occurs when a treatment works because people expect it to work.

In clinical trials, participants are often given either a medication or a placebo (inactive) drug – and it’s important they don’t know which they have been given. However, due to the strong effects, it is difficult to prevent participants from knowing whether they have been given a psychedelic drug.

Researchers have tried to use a range of different drugs (such as Ritalin) as a placebo in order to “trick” those participants not given a psychedelic into thinking they have received one. But this can be difficult to achieve.

In 2021, researchers reviewed clinical trials involving psychedelics such as LSD, psilocybin, and dimethyltryptamine (found in animals and plants) for mood and anxiety disorders. They found trials either had not assessed whether participants guessed correctly which drug they had been given, or that this had been tested and participants tended to guess correctly.

More recent trials either don’t measure this or find participants have a pretty good idea of whether they’ve had a placebo or a psychedelic drug.

Given the publicity and excitement around psychedelic research in recent years, it is likely most participants have strong beliefs such therapies work. This could lead to a significant placebo effect for participants given a psychedelic dose. Additionally, participants who realise they have received a placebo could experience disappointment and frustration, resulting in worse symptoms. The benefits of a psychedelic may seem even greater when they are compared to the experiences of disappointed participants.


Read more: The TGA has approved certain psychedelic treatments: the response from experts is mixed


Translating trials to practice

Anecdotally, patients might be motivated to report they have gotten better, even when they haven’t.

On a 2021 podcast, one clinical trial participant described how, in hindsight, the information they provided to the trial did not accurately capture the worsening of their symptoms. Trial participants are likely aware their results might affect whether treatments are legalised. They may not want to “ruin” the research by admitting the treatment didn’t work for them.

There is also uncertainty about whether the findings from clinical trials mean treatments will work in private practice. There may be a lack of clarity around how trial participants are recruited and selected. Therefore participants may not represent the typical person with PTSD or treatment-resistant depression.

And while the safety of psychedelics within controlled contexts is often emphasised by advocates, less is known about safety of psychedelic therapy outside clinical trials.

Resolving issues

These issues do not mean the promising psychedelic research conducted over the past several decades is worthless. Nevertheless, a recent review of the effects of MDMA and psilocybin on mental, behavioural or developmental disorders by Australian researchers concluded the “overall certainty of evidence was low or very low”.

Dutch researchers recently drafted a roadmap for psychedelic science with a checklist for future research to help avoid these pitfalls. When more research is done, it might turn out psychedelic treatments help patients and don’t come with unacceptable harms – we simply don’t know that yet.

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MDMA: Australia begins world-first psychedelic therapy

Earlier this year, researchers raised eyebrows when Australia’s traditionally conservative medicines regulator approved the use of psychedelics to assist therapy sessions.

The decision will see psilocybin, found in magic mushrooms, used for treatment-resistant depression. It will also allow MDMA, known as ecstasy in tablet form, for post-traumatic stress disorder (PTSD).

The changes come into effect on Saturday, making Australia the first country to classify psychedelics as medicines at a national level.

While initial access to the drugs will be limited and costly, many experts and patients are hailing it as a landmark moment.

But major health organisations have also urged caution.

‘Shining again’

Marjane Beaugeois was diagnosed with severe depression in 2017. “Within two months, I lost my mother, grandmother, beloved pet dog and my romantic relationship,” she recalls.

She couldn’t eat, shower, or leave her house in Melbourne – but says prescription antidepressants left her “zombie-like, unable to cry, self-soothe or feel better”.

“I’d still go to bed praying not to wake up,” the 49-year-old says.

When her research for alternative therapies led her to a psilocybin clinic in Amsterdam, she was hesitant.

“I have no history of drug or alcohol use. As an addiction counsellor, I was always very against it,” she says.

Marjane Beaugeois stands in the middle of two friends
Image caption,Marjane Beaugeois (centre) says psilocybin helped her treat depression

But she was also desperate to escape her treatment-resistant depression, so in 2018, she booked herself in.

The psilocybin was taken in a tea. “Colours became more vivid. I felt powerfully reconnected to the world; warm and fuzzy. I’m getting emotional just talking about it… it was a massive, beautiful experience of unconditional love.”

Three sessions later, she felt healed. “I could smile, feel joy, go about my daily routine with clarity,” she says. “When I got home, friends said they saw my eyes shining again.”

When Glen Boyes suggested microdosing psychedelics to treat his crippling depression, his therapist was sceptical.

“He explained it wasn’t something he does, but he couldn’t stop me, and would do brain scans to track my progress,” he says.

The 33-year-old veteran says he began experiencing “lingering PTSD” from his time in the army, during Covid-19 lockdowns in Sydney.

But after 10 weeks of microdosing and therapy sessions, red areas on his initial brain scans showing blockages had cleared. “My brain fog evaporated. I could think clearly again.”

Due to no other country rescheduling these substances for clinical use on a national level, the cohort who’ve experienced psychedelic therapy is small.

Professor David Nutt, Head of Neuropsychopharmacology at the UK’s Imperial College, congratulated Australia on “leading the world in this vital treatment innovation”.

Psychedelic researcher and psychiatrist Dr Ben Sessa described the approval as pioneering. “This is where the global psychedelic spotlight now shines,” he told the BBC.

Dr Sessa has resigned from his job running the UK’s primary psychedelic clinical organisation and will spend the next 18 months travelling to Australia to deliver a bespoke psychedelic prescribing training programme.

Glen Boys smiling in pictures
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New FDA Guidance on Psychedelics Could Open Minds, Funding Sources

New FDA guidance on psychedelics changes little for researchers but could open minds and funding sources.

This story was reprinted with permission from Crain’s New York and written by Amanda D’Ambrosio.

Last month, federal regulators released research guidance for classic psychedelics, marking the first time the government has offered suggestions for studying medicines like LSD, MDMA and psilocybin to treat mental illness. The draft guidance signals a shift in the medical community’s perception of psychedelic medicine—a field that has previously been deemed fringe.

Local researchers and biotech companies say it doesn’t impact them much.

“In that guidance document, there’s nothing surprising,” said Rob Barrow, chief executive of MindMed, a Midtown-based biotech company investigating psychedelic drugs, especially for companies that have been in conversation with the FDA about their research.

While researchers say the guidance will not drastically change how they study the substances, it does have an impact on two major hurdles facing the burgeoning industry: public perception and funding.

“I think one of the biggest potential upsides is that it communicates (the FDA’s understanding of this research) to the broader world—whether that’s providers, patients, investors, researchers,” Barrow said.

The organization’s engagement with previously taboo substances signals a shift that the FDA is engaged in legitimate conversations about clinical trials for these medicines, also opening more doors for potential funding.

The FDA’s proposed guidance comes as general interest in psychedelics has increased, and industry experts estimate the drugs will grow into a multibillion-dollar industry. While interest in the field has grown, most of the funding for research has come from donors and biotech companies.

Dr. Michael Bogenschutz, director of NYU’s Center for Psychedelic Medicine, said that most funding came from philanthropy organizations until around five years ago, when private funders and biotech companies began entering the space. The Center for Psychedelic Medicine, which launched in 2021, received $5 million in funding from MindMed to train researchers.

Public funding, which supports critical research that can bring treatments from clinical settings to the real world, has been sparse. But despite limited funding from the government, the field has published research showing the promising potential of these therapies.

In recent years a few randomized clinical trials, the gold standard in medical research, have shown that psilocybin-assisted psychotherapy might improve major depressive disorder or alcohol use disorder.

“The very early small studies that were done on limited funding were extremely promising,” Bogenschutz said of psilocybin, noting that evidence is still lacking on whether the drug is safe and effective.

But in order to conduct the studies that further investigate the safety and efficacy of psilocybin and other psychedelic drugs, researchers need funding from a key source—the government.

“This is something that needs the kind of investment that all potential therapeutics get—government funding,” said Dr. Rachel Yehuda, director of Mount Sinai’s Center for Psychedelic Psychotherapy and Trauma Research. Currently, trials of MDMA and psilocybin led by Mount Sinai researchers are funded by philanthropy.

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Berkeley says ‘yes’ to psychedelics — with limits

Berkeley’s City Council effectively legalized a range of psychedelic substances within city limits Tuesday, unanimously voting to de-prioritize enforcement of state and federal laws against entheogenic and psychedelic plants and fungi.

The measure was designed, in part, for users of certain psychedelics to be able to access health resources within the city without fear of legal repercussions, similar to other harm-reduction measures like needle exchanges, according to the text of the resolution. It also opens Berkeley’s doors to researchers looking into ways of using psychedelics to treat mental health issues.

The final version of the resolution still forbids “giving away, sharing, distributing, transferring, dispensing, or administering” psychedelics.