Psychedelic psilocybin therapy for depression granted Breakthrough Therapy status by FDA

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Psychedelic psilocybin therapy for depression granted Breakthrough Therapy status by FDA

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Psychedelic psilocybin therapy for depression granted Breakthrough Therapy status by FDA

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Rich Haridy
October 24th, 2018


Granting of Breakthrough Therapy status allows the FDA to expedite research and review of psilocybin-based treatments...


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Granting of Breakthrough Therapy status allows the FDA to expedite research and review of psilocybin-based treatments to move them into clinical use sooner
(Credit: Vox19/Depositphotos)


In an extraordinary step forward for the psychedelic drug research community, the US Food and Drug Administration (FDA) has just given psilocybin therapy for treatment-resistant depression a Breakthrough Therapy designation. This classification suggests the treatment has demonstrated significant potential in early clinical evidence, allowing the FDA to assist and expedite subsequent development and review processes.

The FDA's Breakthrough Therapy designation was created in 2012 as a way of presenting a faster pathway to approval for drugs that display treatment advantages over current options for serious or life-threatening conditions. While not all Breakthrough Therapy treatments may ultimately prove efficacious and make it to market, the designation is generally a positive thumbs-up from the FDA that it's potentially useful and should be expedited.

The specific designation in this instance is directed at a phase IIb trial currently underway across Europe and North America. The research is investigating the optimal dose range for psilocybin in regards to severe treatment-resistant depression. Prior research has found that one to two doses of the psychedelic agent, administered in controlled settings, can markedly reduce a person's depressive symptoms. The safety of these treatments has also been established through earlier research.

The multi-center clinical trial now underway is being run by life sciences company COMPASS Pathways and expands on decades of work by researchers around the world who toiled to push this previously taboo drug into the light of legitimate medical research. Robin Carhart-Harris, head of the Psychedelic Research Group at Imperial College London, has been working for several years to establish the efficacy of psilocybin treatment for depression, and notes that this new FDA designation is a positive sign for the future of psychedelic drug therapy.

"The Breakthrough Therapy designation is a strong endorsement for the potential of psilocybin therapy," says Carhart-Harris. "We look forward to learning more as further clinical studies are carried out, by our team at Imperial College as well as in COMPASS's multi-center trial."

One of the interesting looming implications of psilocybin's acceleration towards legitimate medical use is that if it passes phase III clinical trials the FDA will be forced to recommend a change to the drug's restrictive Schedule 1 control. Schedule 1 is the most restrictive category of drug control in the United States, essentially establishing the substance as highly addictive and having no medical benefit. This kind of oppressive classification limits the breadth of research into potential beneficial uses for specific drugs.

Marijuana has been the drug under the most scrutiny in recent times regarding its strict scheduling. Following the landmark approval of Epidiolex, the first ever medicine approved in the United States from a marijuana-derived compound, the FDA was challenged to recommend rescheduling marijuana, or at the very least cannabidiol (CBD), the primary compound derived from the plant. While the DEA is the US government agency ultimately in control of scheduling drugs, it generally acts on recommendations from the FDA once a certain compound reaches general approval stages. Ultimately the DEA refused to drop either marijuana or CBD from its restrictive Schedule 1 classification, instead contorting itself to limit the rescheduling to Epidiolex specifically and not anything broader.

This psilocybin therapy, on the other hand, poses a more complicated scenario for the FDA, and other relevant United States authorities. Much like the pathway being forged with MDMA for PTSD, the demonstrable clinical benefits of the substance make it impossible to keep it restricted to Schedule 1, especially if it successfully moves through phase III clinical trials.

Researchers working with psilocybin from Johns Hopkins recently penned a comprehensive article suggesting the drug needs to be rescheduled down to Schedule IV. The article outlined a raft of evidence highlighting the potential therapeutic benefits of the drug, as well as its proven low rates of abuse, and demonstrable lack of physical dependence potential.

"We should be clear that psilocybin is not without risks of harm, which are greater in recreational than medical settings," says Matthew Johnson from Johns Hopkins, "but relatively speaking, looking at other drugs both legal and illegal, it comes off as being the least harmful in different surveys and across different countries."

This latest step from the FDA, to offer psilocybin a Breakthrough Therapy designation, is a quietly extraordinary move from the federal agency, implicitly suggesting this previously stigmatized drug may have beneficial clinical uses. And, if all continues along the same path, within the next five years a significant psychedelic drug, that has been restricted for decades, may become more available for clinicians and medical researchers to work with.



newatlas

Editor's note (October 25, 2018): This article was edited to clarify the relationship between the DEA and the FDA in regards to how a drug can be reclassified.


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'Magic mushroom' ingredient could work as mental health treatment

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from https://www.cnn.com/2020/11/07/health/d ... index.html

While magic mushrooms are known for their hallucinogenic effects, they may also have a role to play in the treatment of some mental health treatment.

Or they might, if they weren't illegal in most states.
Oregon has become the first US state to make psilocybin, the hallucinogenic compound in magic mushrooms, legal for mental health treatment in supervised settings.
They have more evidence for their case with a new small study of 24 adults with major depression that published this week in the journal JAMA Psychiatry, which found that two doses of psilocybin led to a large reduction in depressive symptoms.

"The magnitude of the effect we saw was about four times larger than what clinical trials have shown for traditional antidepressants on the market," said Alan Davis, an adjunct assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, in a news statement.
"Because most other depression treatments take weeks or months to work and may have undesirable effects, this could be a game changer if these findings hold up in future 'gold-standard' placebo-controlled clinical trials."

While not without limitations, the study is the latest research to explore how psilocybin could help ease mental health problems. Other studies have suggested that the compound may help in the treatment of anorexia, obsessive-compulsive disorder and addictions.
The participants in the John Hopkins study had experienced depression for around two years before being recruited and had to give up existing antidepressants. Thirteen participants received the psilocybin treatment immediately after being enrolled, and 11 participants were put on a waiting list and received the same treatment after an eight-week delay.

The study offered more evidence of psilocybin's "rapid and powerful effect," said David Nutt, a professor and director of the neuropsychopharmacology unit in the division of brain sciences at Imperial College London. The results could have been skewed by the fact that patients knew they were going to get the drug, with expectations potentially increasing the size of the effect, said Nutt, who wasn't involved with the research.
A 2016 study conducted by some of the same John Hopkins researchers found that psilocybin could ease depression and anxiety in patients who had life-threatening cancer.

"Because there are several types of major depressive disorders that may result in variation in how people respond to treatment, I was surprised that most of our study participants found the psilocybin treatment to be effective," said Roland Griffiths, an author of the new study and the 2016 paper, and a professor at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Center for Psychedelic and Consciousness Research.
Psilocybins can produce visual and auditory hallucinations and profound changes in consciousness over a few hours after ingestion, the study said.
In the United States, possession of the compound is a felony, as they are classified as a Schedule I substance.
The vote in Oregon requires the Oregon Health Authority to allow licensed, regulated production and possession of psilocybin, exclusively for administration by licensed facilitators to clients.

How it might affect the brain
How psilocybin affects the brain still isn't completely understood, but Nutt at Imperial College said that it appeared the compound disrupted negative thinking circuits through the 5HT2Z receptor in the brain.
"Standard anti-depressants protect against the stressors that lead to and perpetuate depression but don't directly access and remedy underlying biopsychosocial causes," he wrote in a paper he coauthored and published earlier this year.

"In contrast, psychedelic therapy harnesses a therapeutic window opened up by the brain via the effects of drugs to facilitate insight and emotional release."
He said that the substance tended to work with "internalizing disorders" like depression or obsessive-compulsive disorder whereby individuals ruminate on failings or intrusive thoughts.

Another explanation could be more straighforwardly pharmacological, said Guy Goodwin, a professor emeritus of psychiatry at the University of Oxford -- that psilocybin "is just a kick up the backside" of the serotonin system. Serotonin is a chemical and neurotransmitter in the digestive system, brain and blood system that regulates mood, social behavior, appetite, sleep, memory and sexual function.
Goodwin, who wasn't involved with the research, said the main limitation of the John Hopkins study was the absence of longer-term follow-up -- the team followed up with the participants only four weeks after the treatment. Depression for many people is a long-term condition, and determining if the treatment had lasting effects is a key missing factor.

What's more, with studies like these, it can be hard to tease out the effects of the drug from the process of administering it, Goodwin said.
The study participants received about 11 hours of psychotherapy and received the drug under the care of trained professionals and in a setting designed to put the patient at ease.
"You get an effect irrespective of whether the treatment works because everyone is caring for you and looking out for you and measuring things. People like that and feel better for that. In a real comparison you'd do everything the same but the actual drugs."

However, he said that larger studies were underway that should address the questions raised by early proof of concept studies like this one.
"This is a nice, small preliminary study with a lot of weaknesses but equally the positive results promise better things."
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Re: Psychedelic psilocybin therapy for depression granted Breakthrough Therapy status by FDA

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from https://www.cnn.com/2020/12/20/opinions ... index.html

(CNN) It's said that science progresses "one gravestone at a time," since major changes in theoretical perspective usually require a new generation or more to take hold.

Psychiatry, in contrast, is in the midst of a massive shift: We're experiencing a veritable psychedelic revolution, as drugs like MDMA, psilocybin and ketamine offer new hope for treating severe mental anguish.

I've been a psychiatrist for 15 years, and I have long recognized that there is a significant percentage of patients for whom we have never been able to offer meaningful relief. In my experience, these are largely patients with extensive trauma histories, such as childhood abuse and neglect. Trauma, as the root of so much psychological distress, is the great imitator: It can present as depression; suicidal thinking; self-harm; dissociation or numbing; substance abuse; panic; an eating disorder; or even impulsive aggression.

Psychiatry and mental health treatment have traditionally focused on talk therapy and medications, interventions which are often quite helpful at relieving many types of psychological distress. Yet I never truly understood why we couldn't successfully talk or medicate some of our patients out of their trauma until I began to work with psychedelics in 2017. I'm finding that my entire perspective on healing trauma is rapidly changing, one psychedelic session at a time.

Psychedelics, which include a broad range of substances that tweak the dials of consciousness in very different ways, initially suggested great promise as medicinal treatments for mental health disorders in the 1950s and '60s. Drug prohibition in the following decades pushed them underground, and these drugs were then largely ignored by the psychiatric establishment until a resurgence in exploration in the 1990s.
The psychedelic treatment revolution taking place today arguably started in 2006, with Carlos Zarate's JAMA paper suggesting the unexpected efficacy of the anesthetic ketamine for depressed and suicidal patients.

Now ketamine -- which you may know by the street name "Special K" -- is widely available across the United States for medicinal use, and it's becoming an indispensable part of depression treatment. Two other psychedelics, MDMA and psilocybin, are in Phase 3 and Phase 2 clinical trials, and could be approved within the next couple of years for treatment of PTSD and depression.

I have always been a materialist -- a "show me the evidence" sort of person. I've been deeply curious about an energetic or spiritual element that would affect a person's overall health, but it always seemed a little woo-woo and unscientific to merit much attention. In my residency program, for example, we never considered that trauma might be held in the body, much less in the spirit. Yet it is now becoming clear through psychedelic psychotherapy research that trauma is held both in the body and in a person's spirit -- or life energy, or primary consciousness, whatever one might label it.

Herein lies the reason why so many people suffering from depression and anxiety, addiction, and/or profound psychological despair have found their mental health struggles to be so resistant to treatment: I believe these disorders are more often than not tied to a deep, and largely untouchable, river of trauma that lies beneath our reach in the unconscious mind.
Somatic trauma therapists, who primarily focus on feelings and perceptions in the body, have long used this knowledge to bypass the verbal, analytical ego and access stored trauma in the tissues. But the process of somatic therapy can be slow, arduous and even painful, as therapist and patient struggle to reach that which is deepest and most hidden in our body and psyche.

Psychedelic treatment, meanwhile, appears to be a less painful portal to accessing the interface of the unconscious and the body. This is profoundly difficult to explain but easy to witness in the treatment room, as people are able to open up and explore previously unreachable wounds, perceptions and insights.
I discovered this during my first experience with using psychedelics to treat deep-seated trauma, when I joined a MAPS-sponsored study of MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD). As a co-therapist in those sessions, I observed patients being able to mentally return to the source of the trauma and begin to rework and reframe their experience without fear. Using pharmaceutical-grade doses of MDMA alongside psychotherapy sessions, they were able to process what happened with the warm light of compassion, pushing away the toxic sludge of shame that surrounded the trauma.
MDMA, better known by its street names of "Ecstasy" or "Molly," is a Schedule 1 illegal drug that, prior to its prohibition in 1985, was used by some psychotherapists to help their clients work through trauma and other psychological issues. The nonprofit MAPS -- which stands for Multidisciplinary Association for Psychedelic Studies -- was founded shortly after MDMA's criminalization, with the goal of making MDMA again available for research and treatment.

So far, the work has shown promise: 68% of participants in the Phase 2 MAPS clinical trials no longer met the criteria for PTSD a full year after receiving treatment. In 2017, the FDA gave MDMA a breakthrough therapy designation, meaning the results of early clinical research indicated potential for a substantially improved treatment for severe PTSD.
We don't fully understand why MDMA is so effective at fostering trust and empathy while also dialing down fear, but one mechanism might involve the inhibition of specific circuits in the amygdala, the fear node of the brain. There's more research to be done, and MDMA is not yet available for patients outside of research studies.

The psychedelic ketamine, however, is available now, and I use it extensively within my own practice -- it's hard for me to remember how I even practiced without it. A 50-year-old general anesthetic, ketamine has been successfully repurposed over the past few years to treat depression and PTSD. Although low -- as in non-psychedelic -- doses of ketamine appear helpful for depression, I and many other physicians are finding that the fully dissociative psychedelic doses of ketamine appear to be the most powerfully effective. While the lower doses do improve mood and energy for many, they typically don't touch the somatic-spiritual, or unconscious, interface where we've found trauma to lurk.

In these higher psychedelic dosage treatments, I often see hidden rivers of trauma come to the surface, where the patient and I can begin to explore the heretofore unspeakable and unknowable. Most of who we are lies in the unconscious, and with severe trauma the unconscious is where the healing needs to start.

Psychedelics including MDMA, psilocybin, THC (yes, THC!), ayahuasca and ketamine, when prescribed under the care of a medical professional in combination with psychotherapy, are opening up rapid access to these realms that have been so difficult to reach and understand. And once this access has been established, we are finding that patients are healing with intermittent treatments, often spaced over months or longer, in contrast with standard psychiatric medications, which are dosed daily or even multiple times a day. Psilocybin, a compound found in "magic mushrooms," has been found to reduce symptoms for depression, anxiety and obsessive compulsive disorder, while the South American brew ayahuasca has been shown to be effective as a treatment for severe depression.
Psychiatry might be moving to a model where many patients do intermittent psychedelic treatments, interspersed by both talk and somatic therapies, and thus moving away from daily medications for symptom management. At the least, psychedelics are finally giving us a chance to help traumatized patients and their treatment resistant mood and anxiety symptoms.
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