Hallucinogenic drugs may have therapeutic potential, but can regulation keep up| Long article of nature

Source: & nbsp; Nature Portfolio

Original author: Paul Tullis

Some regulators will need to work on how to safely use powerful hallucinogens to treat depression and post-traumatic stress disorder.

In 2015, on a sunny day in London, Kirk Rutter took the subway to Hammersmith Hospital, hoping to finally cure his depression.

Rutter’s depression has been good and bad over the past few years. But since his mother died in 2011 and experienced breakup and car accident in the same year, Rutter’s condition has become more and more serious. He felt that his brain had entered what he called an “automatic circuit” and repeated the same negative thoughts like a spell – “I couldn’t do anything well.” I was so sure, “he recalled.

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The visit to Hammersmith was just a pre inspection. He will return the next day to participate in a study in which he will take a powerful hallucinogen under the guidance of Robin Carhart Harris, a psychologist and neuroscientist at Imperial College London. Years of talk therapy and various anti anxiety drugs have failed to improve Rutter’s condition, so he is qualified to participate in this clinical trial.

“Everyone was very nice and lovely, especially Robin,” Rutter recalled. Carhart Harris took him to a room equipped with a magnetic resonance imaging machine (MRI) so that researchers could know what his basic level of brain activity was. Then he told Rutter where he would stay after taking the medicine. Carhart Harris told him to lie down and played him some music that would accompany the whole process of the experiment. He also explained that if necessary, a drug was ready to neutralize the effects of hallucinogens. Then they practiced an emotional landing technique together, which could help Rutter calm down in case he felt overwhelmed. Rutter burst into tears without warning.

“I think I knew it would be a relief – I was really struggling,” Rutter said.

When Rutter came back the next day, a researcher handed him two tablets containing synthetic naked mushroom element, a psychoactive ingredient found in magic mushroom. Rutter lay in bed, wearing headphones and goggles. Soon Sanskrit appeared in front of him and saw the magnificent structure. Then his heart began to deal with his sadness.

In the past few years, a series of clinical trials have been launched to treat psychosomatic diseases with illegal hallucinogens such as naked mushroom, LSD (ergoyl diethylamine) and MDMA (3,4-subunit dioxymethamphetamine, also known as Molly or ecstasy). Such studies are generally closely guided by a psychiatrist or psychotherapist. The idea of hallucinogens for the treatment of mental disorders has existed for decades – and even centuries in some cultures – but its momentum has developed rapidly in the past few years as investors and scientists refocus on this method (see “hallucinogenic drug development”).

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Once considered a dangerous plaything against mainstream culture, these drugs are now being accepted by the mainstream. Several States and cities in the United States are legalizing or decriminalizing naked mushroom for therapeutic or recreational purposes. In addition, respected institutions, including Imperial College of technology, Johns Hopkins University, University of California Berkeley and Icahn School of medicine in Mount Sinai, New York City, have also opened centers specializing in hallucinogens. Some small studies have shown that this drug can be used safely and may be beneficial to people with refractory depression and other psychological problems (such as post-traumatic stress disorder, PTSD). A clinical trial involving MDMA has recently been completed and the results are expected to be published soon. Regulators will then consider whether to allow such treatment through prescription.

Hallucinogen assisted psychotherapy may provide necessary treatment for patients suffering from mental disorders, including post-traumatic stress disorder (PTSD), major depression, alcohol dependence disease, anorexia nervosa, etc. these diseases cause thousands of deaths in the United States and billions of dollars of productivity loss in the world every year.

But these are new areas for regulators. “This area has not been explored in terms of formal assessment interventions for mental disorders,” said Walter Dunn, a psychiatrist at the University of California, Los Angeles. Dunn sometimes advises the U.S. Food and Drug Administration (FDA) on psychotropic drugs. Most drugs for depression and anxiety are available at community pharmacies. In contrast, these new methods need to use powerful substances in the treatment environment under the close care of trained psychotherapists. Regulators and treatment providers will need to work hard to solve the problem of how to implement them safely.

Bertha Madras, a psychiatrist at Harvard Medical School at McLean Hospital, said: “the clinical trials on depression reported at present are carried out under highly limited and controlled conditions.” this will make it difficult to explain the results. A treatment may be shown to be beneficial to patients in the trial, but it may be because the trial process is carefully coordinated and everyone involved is well trained. At the same time, how to set up a placebo control group for such experiments poses another challenge because these drugs are too effective.

Besides, there are risks. In extremely rare cases, hallucinogens (such as psychedelic drugs and LSD) can cause sustained psychiatric reactions, which is more common in people with a family history of psychosis. Then, people with schizophrenia, for example, will be excluded from trials involving hallucinogens. Moreover, MDMA is a derivative of amphetamine, so it is at risk of drug abuse.

But many researchers are excited about the prospect of such experiments. Some trials showed obvious results: for example, in a study published in November 2020, 71% of people taking psychedelic drugs to treat major depression reduced their symptoms by more than 50% after four weeks, and half of the participants achieved remission. After treatment, some small-scale follow-up studies showed sustained benefits.

“Sometimes you look at the data of a therapy and think, ‘it worked a little bit,’” said neurologist Jennifer Mitchell. She worked at the Weill Institute of Neuroscience at the University of California, San Francisco and participated in the recently completed MDMA trial. “Then when you see MDMA related experiments, you think, ‘forget that.’ the effect is not at the same level.” Rutter was deeply touched by his experience in hallucinogen experiments, and he has provided advice to a company sponsoring this compound experiment.

Carnival new world

The current wave of interest in the therapeutic potential of hallucinogens is an old revival. In the 1950s and 1960s, scientists published more than 1000 articles on the use of hallucinogens as psychotherapy; In total, these drugs were tested on about 40000 people. Then, as the recreational uses of these drugs spread, the law banned their use, and the FDA restricted the supply of their research uses. Until recently, neuroscientists and psychopharmacologists like Carhart Harris had the technology to begin to interpret the effects of these drugs in the brain. This gives them some insight into how these compounds help treat mental illness.

Researchers began to explore hallucinogens in the late 1990s. Before and after volunteers used these drugs, or together with antagonists that inhibited some of their effects, they observed them using neuroimaging techniques such as positron emission tomography (PET). These studies show that the brain’s responses to hallucinogens (such as naked Pleurotus and LSD), N, n-dimethyltryptamine (DMT), the active component of dead rattan water, and mescaline (a hallucinogenic compound extracted from Perot cactus) are similar. They all act on serotonin receptors, a neurotransmitter that affects mood.

Serotonin is also SSRI & nbsp; (selective serotonin reuptake inhibitor) is the target of this important psychiatric drug. It is now believed that the effects of these antidepressants are different from the initial hypothesis – not by filling the brain with neurotransmitters, but by stimulating neural plasticity, the brain’s ability to form new neuronal connections. There is some evidence that hallucinogens (such as naked Pleurotus) can enhance neural plasticity in animal experiments. In addition, there is limited evidence that the same situation may also occur in human brain. Clinical studies also show that the biological effects of these drugs are the best under the guidance of human beings.

裸盖菇素疗程设置(如模型图示)须谨慎重复以应用于临床试验。来源:COMPASS Pathways the course of treatment of naked Pleurotus ostreatus (as shown in the model diagram) should be carefully repeated for clinical trials. Source: Compass pathways

Franz Vollenweider, a psychiatrist and neurochemist at Zurich psychiatric university hospital, said that these drugs “activated a therapeutic, dream like state, strengthened sensory perception, and memory jumped out like a small film”. He is one of the contemporary pioneers in the research of hallucinogenic drugs. He believes that this receptive mental state provides an opportunity to help people get rid of stereotyped thinking patterns, such as Rutter’s automatic circuit in depression.

“People are trapped in diseases like depression because they form this efficient but wrong thinking system,” said David Nutt, a psychopharmacologist at Imperial College London, who bluntly supports the government’s evidence-based reform of illegal drug policies. Psychiatry has a term for this kind of thinking: “rumination”. The idea behind hallucinogenic therapy is that the receptive psychological state brought by drugs opens the door to new ideas about the past and the future, which can then be strengthened by therapists. Carhart Harris, who trained with Nutt, said: “there is increasing evidence that this is largely a synergistic effect of drug-induced superplasticity and treatment support.”

Rutter said his treatment experience with Carhart Harris was focused and flexible. When Rutter took off his eye mask for the first time after the drug took effect, the therapist looked “fragmented”, as if there was another eye in the middle of his forehead. “I can imagine that you look strange to me now,” Carhart Harris said. Rutter burst into laughter, and Carhart Harris laughed with him. When the laughter stopped, the two began to talk. Rutter wants to discuss his resentment, which leads to thinking about the word “resent” and its etymology. Carhart Harris looked up the word for Rutter on his laptop. “It was really a wonderful moment,” Rutter said. He later went back for a second treatment and used a larger dose of drugs, followed by a second MRI and “integration” course to discuss these experiences.

Treatment “makes me look at sadness in a different way,” Rutter said. “It makes me realize that sadness doesn’t help, and letting go is not a betrayal.”

Clinical dilemma

However, it will be very difficult to effectively test these drugs and translate clinical research into practical therapy. Two of the most watched studies are trying to solve these problems. One is the recently completed MDMA clinical trial, which tested the method in patients with severe post-traumatic stress disorder. This is a phase III clinical trial, usually the final stage before the drug regulatory authority decides whether to approve a treatment. The experiment involved 90 participants in 15 locations around the world. The multidisciplinary Association for hallucinogen Research (maps), a non-profit organization in San Jose, California, sponsored the study, but the results have not been published so far. (translation note: the results have been published by the time this push is published. Https://www.nature.com/articles/s41591-021-01336-3)

Meanwhile, compass pathways, a London based mental health care company, is conducting a phase IIB trial to test the treatment of refractory depression with different doses of hallucinogens.

The evaluation of the results is not easy. One concern revolves around control. Most people who get a placebo will know that they don’t get a powerful hallucinogen. Some studies evaluating hallucinogenic drugs have tried to solve this problem by giving people in the control group tablets containing niacin, which causes a physical sensation, usually a flushing reaction of the skin. Mitchell said that in her MDMA study, some participants who were given the drug thought they received a placebo, while others who received a placebo thought they received a drug.

The designer of the study also has to solve the problem of how important the non drug aspects of the trial are to the results, including the mentality of individuals entering the experience and the environment in which the experience occurs.

In the treatment room set up by the medical center of Utrecht University in the Netherlands for compass research, the atmosphere is like a hotel spa. At the foot of a double bed, a Mexican style blanket is folded. A palm tree is planted in the corner next to the bean bag chair. On one wall was a poster of Van Gogh’s apricot flower. All 24 treatment sites in the study had similar decorative styles.

合成裸盖菇素,这是裸盖菇中发现的精神活性成分。来源:Paul Taggart/Bloomberg/Getty synthesized pleurotin, which is a psychoactive component found in Pleurotus ostreatus. Source: Paul Taggart / Bloomberg / Getty

The next step is to provide training and experience for therapists who need to guide the drug administration and drug-free integration. Compass, which went public in September with a market value of more than $1 billion, has developed a five-level training program for therapists in its clinical trials. Ekaterina malievskaia, co-founder and chief Innovation Officer of the company, said that if the company wants to win the approval of regulators, the site investigators must strictly abide by the training content.

Madras further pointed out that all test conditions need to be replicated in order to promote these drugs in any larger environment. “The approval of these drugs must be based on the strict conditions of their clinical investigation,” she said. However, the method of authorizing such conditions is not clear. For FDA, there is a mechanism to ensure that drug treatment is managed in a specific way: risk evaluation and mitigation strategies, or REMS. Through REMs, the agency can require prescribing doctors and pharmacists to obtain corresponding certification aimed at reducing drug-related risks (such as addiction and dependence on opiate prescriptions). Dunn said that the REMS strategy can also be used for hallucinogens. This ensures that the drug supply is bound to clinical treatment and may certify practitioners. A person engaged in one of the clinical trials said that he was discussing with the FDA whether therapists managing drugs should be trained, what should be included in the training, and whether therapists need some certification.

Certification may mean legalizing therapists who have been illegally “treated” for up to 30 years. But some of these therapists may resist the advice or participation of the government that drove them underground.

There is still a long way to go before it is approved. By the end of 2020, maps reported in a press release that there was a statistically significant difference in the treatment effect between the MDMA trial control group and the placebo group (see go. Nature. COM / 362xsvp). The company will release complete data sometime this year and will not explain the results before. It is also recruiting personnel for the second phase III clinical trial, which will use MDMA therapy to treat patients with moderate to severe post-traumatic stress disorder, with the goal of completing by the end of this year. Compass expects to get the results of its phase IIB study at that time, and is planning to carry out phase III study.

Robert malenk, a psychiatrist and neuroscientist at Stanford University in California, has studied the effects of MDMA on rodents. He believes that some hallucinogens can eventually be approved as drugs for specific diseases. “They have the potential to be – I want to use the right Metaphor – part of our toolkit for treating patients”, but he also warned against excessive enthusiasm, especially in some advocates of underground hallucinogen assisted psychotherapy. “I don’t think they can be magic drugs,” he said

He believes that further research is needed to explore the hypothesis of how these drugs work in the brain, and in the long run, some equally effective compounds that do not produce hallucinations may actually be worth exploring. Others pointed out that although clinicians have not fully understood its mechanism, SSRI drugs are also effective for many people.

But when it comes to clinical research, Madras says she is concerned about the scale and design of these studies. She pointed out that many of the people recruited in the study had taken hallucinogens. She believes that people who have been attracted to have such experience may be more likely to say positive words about drugs. Nutt once said that working with people who have used hallucinogens can reduce the chance of adverse events. But Madras says there are other potential confounding factors. “The informed consent form of these experiments tells you the possible expectation of the experimental results, so there will be bias on the subject,” she said

Rutter said, however, that he was convinced that the treatment he received in 2015 had changed his life. In the weeks after treatment, he found himself wondering whether the previous “automatic circuit” would come back. “I was scared,” he said, “but I also realized that I began to have a little control over it, didn’t I?” he had never thought of it before.

After a week or so, he went to a shopping mall with his friends and felt the return of optimism and openness in his heart. “It’s like someone opened a window in a stuffy room.” five years later, his depression never recurred.