Reclassification recommendations for drug in 'magic mushrooms'

Reclassification recommendations for drug in 'magic mushrooms'

If phase III clinical trials are successful, researchers suggest categorizing the drug as schedule IV

September 26, 2018

Science Daily/Johns Hopkins Medicine

In an evaluation of the safety and abuse research on the drug in hallucinogenic mushrooms, Johns Hopkins researchers suggest that if it clears phase III clinical trials, psilocybin should be re-categorized from a schedule I drug -- one with no known medical potential -- to a schedule IV drug such as prescription sleep aids, but with tighter control.

 The researchers summarize their analysis in the October print issue of Neuropharmacology.

 "We want to initiate the conversation now as to how to classify psilocybin to facilitate its path to the clinic and minimize logistical hurdles in the future," says Matthew W. Johnson, Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "We expect these final clearance trials to take place in the next five years or so."

Following the Controlled Substances Act of 1970, any drug with the potential for abuse is categorized based on criteria that take into account whether the drug has accepted medical use, and its safety and the potential for abuse. Although preliminary research studies suggest that psilocybin may be effective for smoking cessation and for disorders such as cancer-specific depression and anxiety, it must clear phase III clinical trials before the Food and Drug Administration can be petitioned to reclassify it.

Studies in animals and humans both show low potential for abuse, the researchers say. When rats push a lever to receive psilocybin, they don't keep pushing the lever like they do for drugs such as cocaine, alcohol or heroin. When it comes to human studies, people who have used psilocybin typically report using it a few times across their lifetime.

As for safety, studies show it frequently falls at the end of the scales with the least harm to users and society, say the researchers. Psilocybin also is lowest in the potential for lethal overdose as there is no known overdose level.

"We should be clear that psilocybin is not without risks of harm, which are greater in recreational than medical settings, 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," says Johnson.

That being said, although psilocybin is relatively less harmful than other drugs and not prone to compulsive abuse, the researchers don't recommend releasing psilocybin into patients' hands even with a prescription. "We believe that the conditions should be tightly controlled and that when taken for a clinical reason, it should be administered in a health care setting monitored by a person trained for that situation," says Johnson. The researchers foresee that the process for psilocybin use in the clinic would be similar to how an anesthesiologist prescribes and administers a drug, minimizing the potential for abuse or harm.

https://www.sciencedaily.com/releases/2018/09/180926082159.htm

'Magic mushrooms' may 'reset' the brains of depressed patients

October 13, 2017

Science Daily/Imperial College London

Patients taking psilocybin to treat depression show reduced symptoms weeks after treatment following a 'reset' of their brain activity.

The findings come from a study in which researchers from Imperial College London used psilocybin -- the psychoactive compound that occurs naturally in magic mushrooms -- to treat a small number of patients with depression in whom conventional treatment had failed.

In a paper, published today in the journal Scientific Reports, the researchers describe patient-reported benefits lasting up to five weeks after treatment, and believe the psychedelic compound may effectively reset the activity of key brain circuits known to play a role in depression.

Comparison of images of patients' brains before and one day after they received the drug treatment revealed changes in brain activity that were associated with marked and lasting reductions in depressive symptoms.

The authors note that while the initial results of the experimental therapy are exciting, they are limited by the small sample size as well as the absence of a control group -- such as a placebo group -- to directly contrast with the patients.

Dr Robin Carhart-Harris, Head of Psychedelic Research at Imperial, who led the study, said: "We have shown for the first time clear changes in brain activity in depressed people treated with psilocybin after failing to respond to conventional treatments.

"Several of our patients described feeling 'reset' after the treatment and often used computer analogies. For example, one said he felt like his brain had been 'defragged' like a computer hard drive, and another said he felt 'rebooted'. Psilocybin may be giving these individuals the temporary 'kick start' they need to break out of their depressive states and these imaging results do tentatively support a 'reset' analogy. Similar brain effects to these have been seen with electroconvulsive therapy."

Over the last decade or so, a number of clinical trials have been conducted into the safety and effectiveness of psychedelics in patients with conditions such as depression and addictions, yielding promising results.

In the recent Imperial trial, the first with psilocybin in depression, 20 patients with treatment-resistant form of the disorder were given two doses of psilocybin (10 mg and 25 mg), with the second dose a week after the first.

Nineteen of these underwent initial brain imaging and then a second scan one day after the high dose treatment. Carhart-Harris and team used two main brain imaging methods to measure changes in blood flow and the crosstalk between brain regions, with patients reporting their depressive symptoms through completing clinical questionnaires.

Immediately following treatment with psilocybin, patients reported a decrease in depressive symptoms -- corresponding with anecdotal reports of an 'after-glow' effect characterised by improvements in mood and stress relief.

Functional MRI imaging revealed reduced blood flow in areas of the brain, including the amygdala, a small, almond-shaped region of the brain known to be involved in processing emotional responses, stress and fear. They also found increased stability in another brain network, previously linked to psilocybin's immediate effects as well as to depression itself.

These findings provide a new window into what happens in the brains of people after they have 'come down' from a psychedelic, where an initial disintegration of brain networks during the drug 'trip', is followed by a re-integration afterwards.

Dr Carhart-Harris explained: "Through collecting these imaging data we have been able to provide a window into the after effects of psilocybin treatment in the brains of patients with chronic depression. Based on what we know from various brain imaging studies with psychedelics, as well as taking heed of what people say about their experiences, it may be that psychedelics do indeed 'reset' the brain networks associated with depression, effectively enabling them to be lifted from the depressed state.

The authors warn that while the initial findings are encouraging, the research is at an early stage and that patients with depression should not attempt to self-medicate, as the team provided a special therapeutic context for the drug experience and things may go awry if the extensive psychological component of the treatment is neglected. They add that future studies will include more robust designs and currently plan to test psilocybin against a leading antidepressant in a trial set to start early next year.

Professor David Nutt, Edmond J. Safra Professor of Neuropsychopharmacology and director of the Neuropsychopharmacology Unit in the Division of Brain Sciences, and senior author of the paper, added: "Larger studies are needed to see if this positive effect can be reproduced in more patients. But these initial findings are exciting and provide another treatment avenue to explore."

https://www.sciencedaily.com/releases/2017/10/171013091018.htm

Active ingredient in magic mushrooms reduces anxiety, depression in cancer patients

December 10, 2015

Science Daily/American College of Neuropsychopharmacology

Psilocybin, found in magic mushrooms, decreased anxiety and depression in patients diagnosed with life-threatening cancer. New research shows that patients who received a psilocybin dose that altered perception and produced mystical-type experiences reported significantly less anxiety and depression compared with patients who received a low dose of the drug. The positive effects lasted 6 months.

A single dose of psilocybin, the major hallucinogenic component in magic mushrooms, induces long-lasting decreases in anxiety and depression in patients diagnosed with life-threatening cancer according to a new study presented at the annual meeting of the American College of Neuropsychopharmacology.

Patients who receive a cancer diagnosis often develop debilitating symptoms of anxiety and depression. Reports from the 1960s and 1970s suggest that hallucinogenic drugs such as LSD may alleviate such symptoms in cancer patients, but the clinical value of hallucinogenic drugs for the treatment of mood disturbances in cancer patients remains unclear. In this new study, Roland Griffiths and colleagues from the Johns Hopkins University School of Medicine investigated the effects of psilocybin on symptoms of anxiety and depression in individuals diagnosed with life-threatening cancer. Five weeks after receiving a dose of psilocybin sufficiently high to induce changes in perception and mystical-type experiences, patients reported significantly lower levels of anxiety and depression compared with patients that received a low dose of the drug. The positive effects on mood persisted in the patients at 6 month follow-up.

The authors suggest that a single dose of psilocybin may be sufficient to produce enduring decreases in negative mood in patients with a life-threatening cancer.

https://www.sciencedaily.com/releases/2015/12/151210181635.htm

First trial to investigate magic mushrooms as a treatment for depression delayed by UK and EU regulations

April 7, 2013

Science Daily/British Neuroscience Association

The world's first clinical trial to explore the use of the hallucinogenic ingredient in magic mushrooms to treat depression is being delayed due to the UK and EU rules on the use of illegal drugs in research.

Professor David Nutt, president of the British Neuroscience Association and Professor of Neuropsychopharmacology at Imperial College London (UK), will tell the BNA's Festival of Neuroscience today (Sunday) that although the UK's Medical Research Council has awarded a grant for the trial, the Government's regulations controlling the licensing of illegal drugs in research and the EU's guidelines on Good Manufacturing Practice (GMP) have stalled the start of the trial, which was expected to start this year. He is calling for a change to the regulations.

He will tell the meeting at the Barbican in London, that his research has shown that psilocybin, the psychedelic ingredient in magic mushrooms, has the potential to alleviate severe forms of depression in people who have failed to respond fully to other anti-depressant treatments. However, psilocybin is illegal in the UK; the United Nations 1971 Convention on Psychotropic Substances classifies it as a Schedule 1 drug, one that has a high potential for abuse with no recognised medical use, and the UK has classified it as a Class A drug, the classification used for the most dangerous drugs. This means that a special licence has to be obtained to use magic mushrooms in research in the UK, and the manufacture of a synthetic form of psilocybin for use in patients is tightly controlled by EU regulations.

Prof Nutt will say: "The law for the control of drugs like psilocybin as a Schedule 1 Class A drug makes it almost impossible to use them for research and the reason we haven't started the study is because finding companies who could manufacture the drug and who are prepared to go through the regulatory hoops to get the licence, which can take up to a year and triple the price, is proving very difficult. The whole situation is bedevilled by this primitive, old-fashioned attitude that Schedule 1 drugs could never have therapeutic potential, and so they have to be made impossible to access."

"The knock-on effect is this profound impairment of research. We are the first people ever to have done a psilocybin study in the UK, but we are still hunting for a company that can manufacture the drug to GMP standards for the clinical trial, even though we've been trying for a year to find one. We live in a world of insanity in terms of regulating drugs at present. The whole field is so bogged down by these intransient regulations, so that even if you have a good idea, you may never get it into the clinic."

He will say that the regulations need to be changed. "Even if I do this study and I show it's a really useful treatment for some people with depression, there's only four hospitals in this country that have a licence to hold this drug, so you couldn't roll out the treatment if it worked because the regulations would make it difficult to use," he said.

Prof Nutt and his team at Imperial College London (UK) have shown that when healthy volunteers are injected with psilocybin, the drug switched off a front part of the brain called the anterior cingulate cortex, which is known from previous imaging studies to be over-active in depression. "We found that, even in normal people, the more that part of the brain was switched off under the influence of the drug, the better they felt two weeks later. So there was a relationship between that transient switching off of the brain circuit and their subsequent mood," he will explain. "This is the basis on which we want to run the trial, because this is what you want to do in depression: you want to switch off that over-active part of the brain.

"The other thing we discovered is that the major site of action of the magic mushrooms is to turn down a circuit in the brain called the 'default mode network', which the anterior cingulate cortex is part of. The default mode network is a part of the brain between the front and back. It is active when you are thinking about you; it coordinates the thinking and emotional aspects of you."

The researchers discovered that the 'default mode network' had the highest density of 5HT2A receptors in the brain. These are known to be involved in depression and are the targets for a number of existing anti-depressive drugs that aim to improve levels of serotonin -- the neurotransmitter [1] that gives people a sense of well-being and happiness. Psilocybin also acts on these receptors.

"We have found that people with depression have over-active default mode networks, and they are continually locked into a mode of thinking about themselves. So they ruminate on themselves, on their incompetencies, on their badness, that they're worthless, that they've failed; these things are not true, and sometimes they reach delusional levels. This negative rumination may be due to a lack of serotonin and what psilocybin is doing is going in and rapidly replacing the missing serotonin, switching them back into a mind state where they are less ruminating and less depressed," Prof Nutt will say.

The proposed trial will be for patients with depression who have failed two previous treatments for the condition. Thirty patients will be given a synthetic form of psilocybin and 30 patients will be given a placebo. The drug (or placebo) will be given during two, possibly three, carefully controlled and prepared 30-60 minute sessions. The first session will be a low dose to check there are no adverse responses, the second session will give a higher, therapeutic dose, and then patients can have a third, booster dose in a later session if it's considered necessary. While they are under the influence of the drug, the patients will have guided talking therapy to enable them to explore their negative thinking and issues that are troubling them. The doctors will follow up the patients for at least a year.

"What we are trying to do is to tap into the reservoir of under-researched 'illegal' drugs to see if we can find new and beneficial uses for them in people whose lives are often severely affected by illnesses such as depression. The current legislation is stopping the benefits of these drugs being explored and for the last 40 years we have missed really interesting opportunities to help patients."

Ethical approval for the trial was granted in March and Prof Nutt says he hopes to be able to start the trial within the next six months -- so long as he can find a manufacturer for the drug.

[1] Neurotransmitters are chemicals that transmit signals from neurons (nerve cells) to target cells.

[2] Funding: The Beckley Foundation has funded part of Prof Nutt's research, and the Medical Research Council has agreed a grant for the proposed clinical trial.

Abstract title: "Can we use psychedelic drugs to treat depressions?" Symposium: "Treating depression with antidepressants: where are we now and where are we going?"

https://www.sciencedaily.com/releases/2013/04/130407090832.htm