From intoxicant to remedy

On a sunny day in 2015, Kirk Rutter took the Tube to Hammersmith Hospital in London, hoping to finally get rid of his depression. In the years before, he had struggled on and off with isolated episodes of illness. Since the death of his mother in 2011, the end of a relationship and a car accident the following year, it had become particularly bad. It felt like his brain was stuck in an endless loop, repeating the same negative thoughts over and over like a mantra: "'Everything I do turns to shit.' I really believed that," he recalls.

The visit to Hammersmith Hospital was initially just a preliminary discussion. The next day, Rutter would return to participate in a study. Led by psychologist and neuroscientist Robin Carhart-Harris of Imperial College London, he would ingest a powerful hallucinogen. After neither talk therapy nor medication could improve Rutter's condition in previous years, he was an ideal candidate for the trial.

"Everyone was super nice, especially Robin," Rutter says. Carhart-Harris led him into a room with a magnetic resonance imaging (MRI) scanner, which the researchers first used to record his brain activity in the normal state. Then Carhart-Harris showed Rutter where he would take the drug. He asked him to lie down and played him some of the music that would accompany the session. The psychologist also told him that he would have a drug with him that could neutralize the effects of the hallucinogen if necessary. They then practiced a relaxation technique that would help Rutter calm himself in case the intoxication overwhelmed him. Without warning, Rutter suddenly burst into tears. "I think I knew this was going to release some things in me. I was carrying quite a load on my shoulders at the time."

When Rutter returned the next day, one of the researchers handed him two pills containing a synthetic form of psilocybin, the psychoactive ingredient found in magic mushrooms, or "magic mushrooms." Rutter lay down on the bed, put on headphones and an eye mask. Soon, images of Sanskrit texts appeared before his eyes. Later, he saw golden, jeweled structures. Then his mind became preoccupied with his grief.

Psychedelics research is booming

The Imperial study is one of a growing number of clinical trials in which illicit psychedelic drugs have been used to treat mental disorders in recent years - usually under the close guidance of a psychiatrist or psychotherapist. While substances such as psilocybin, lysergic acid diethylamide (LSD), and MDMA (3,4-methylenedioxymethamphetamine, found in Molly and Ecstasy) were once considered dangerous narcotics, several U.S. states are now legalizing or at least decriminalizing their use for therapeutic or recreational purposes. Prestigious institutions such as Imperial College, Johns Hopkins University in Baltimore, the University of California at Berkeley, and the Icahn School of Medicine at Mount Sinai in New York City have opened centers dedicated to the study of psychedelics.

Several small studies now suggest that the drugs are safe to administer and can help people with intractable depression and other mental health problems such as post-traumatic stress disorder (PTSD), anorexia, or alcohol dependence. Psychedelic-assisted psychotherapy could thus potentially help prevent the deaths of many thousands of people and minimize the enormous costs that such disorders impose on society and the health care system.

According to some research, psychedelics can have a powerful positive effect on people with mental illness. For example, in a study published in November 2020, 71 percent of subjects who took psilocybin for a major depressive episode reported that their symptoms decreased by more than half. In half of the participants, the symptoms of the illness even disappeared altogether. Studies that followed the subjects over several months attested to the lasting benefits of the treatment - although they included only a few subjects.

Psychedelics are currently experiencing something of a renaissance in psychotherapy. In the 1950s and 1960s, research groups published more than 1000 scientific papers on the subject. In total, psychedelics were tested on around 40,000 people with mental illnesses at the time. However, with the increasing abuse of the substances as recreational drugs, they were banned - and their access was severely restricted, even for research purposes.

LSD and co. have a similar effect on the brain as antidepressants

In the meantime, neuroscientists and psychopharmacologists such as Carhart-Harris have the necessary technical means to also investigate how psychedelics affect the brain, and thus to fathom their therapeutic potential even more precisely. As early as the 1990s, researchers began using imaging techniques such as positron emission tomography (PET). They used these to examine the brains of participants before and after they used the drugs - or before and after they were administered an antagonist that blocked the drugs' effect. According to the studies, the brain responds similarly to psychedelics such as psilocybin and LSD, but also N,N-dimethyltryptamine (DMT), the active ingredient in ayahuasca, and to mescaline, a psychedelic compound from the peyote cactus. All of these substances act on the receptors for serotonin, a neurotransmitter that affects our mood.

Serotonin is also the target of a class of psychiatric drugs called selective serotonin reuptake inhibitors (SSRIs). It is now believed that these drugs, which are used primarily as antidepressants, do not work by simply flooding the brain with serotonin, as was originally thought. Rather, they appear to boost neuronal plasticity - the brain's ability to constantly reorganize itself and make new neuronal connections. There is evidence that psychedelic drugs such as psilocybin can also enhance plasticity. Animal studies, in particular, show this. Clinical studies also indicate that the biological effects are best brought to bear when patients are guided and accompanied by a trained therapist while taking the drug.

The substances "activate a therapeutic, dream-like state and intensify the sensory perception. Memories then emerge like little movies," explains Franz Vollenweider, a psychiatrist, and neurochemist at the Psychiatric University Hospital in Zurich. He believes this state of mind helps people break out of rigid thought patterns, such as those similar to Rutter's negative thought spiral. The receptive state into which psychedelics put patients thereby opens the door to new ideas about how to view one's past and future. A therapist can then pick up on and reinforce these insights.

Healing trips

The journey Rutter embarked on with Carhart-Harris was focused but flexible. When Rutter first took off his eye mask after the drug had begun to work, the therapist looked "fractured" to him. He also had a third eye in the middle of his forehead. "I would imagine I look pretty strange to you now," Carhart-Harris said in response. Rutter burst out laughing, and Carhart-Harris joined in. The two men then began to talk. Rutter wanted to talk about his resentment and bitterness, which led him to start thinking about the word "give in" and its etymology. Carhart-Harris researched it for him using his laptop. "That was a nice moment," Rutter says. He later returned to the clinic for a second session with a stronger dose of the drug. He also completed a second MRI scan and an "integration session," in which he talked with the therapist about his experiences during the drug binge. The treatment "made me look at my grief and sadness differently," Rutter says. "I came to the realization that neither was helping me and that letting go is not a betrayal."

Studying the therapeutic potential of drugs like psilocybin and ultimately deciding what treatment with it might look like is tricky. Currently, the world is looking at two studies in particular. One is a recently completed Phase III trial of MDMA, which has been tested against severe post-traumatic stress disorder. The substance is known, among other things, to boost mood and increase awareness of one's own feelings. A total of 90 subjects participated in the trial at 15 sites around the world. The Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit organization in San Jose, California, funded the study but has not yet published the results. On the other hand, COMPASS Pathways, a healthcare company in London, is currently conducting a Phase IIb trial testing different dosages of psilocybin for treatment-resistant depression.

Clinical trial phases

• When a new drug is developed, it goes through five clinical phases. To proceed to a higher phase trial, all previous phases must have been completed.
• Phase 0 trial: The first trials in healthy humans take place. About 10 to 15 people receive subtherapeutic doses, also called micro-dosing. The main aim is to investigate how the active substance behaves in the body.
• Phase I study: About 20 to 80 people receive a dose that could be relevant for later therapeutic use. It is tested how well the drug is tolerated and how safe it is.
• Phase II study: With about 50 to 200 people, the manufacturers check the therapy concept and determine an appropriate dose. At this point, the positive effects of the therapy should already be visible.
• Phase III study: Now it is decided whether the responsible authorities will approve a drug. The therapeutic efficacy of the drug must be demonstrated in 200 to 10,000 people. This also applies to its safety, appropriate pharmaceutical quality, and a suitable risk-benefit ratio.
• Phase IV study: These long-term observations begin after the drug has been approved. The aim is to detect, for example, very rare side effects that are only visible in very large patient collectives.

Evaluating the results will not be easy. This is partly because it is difficult to blind drug trials - that is, to ensure that neither the participants nor the doctors involved know who is receiving the real active ingredient and who is merely receiving a placebo. Most people who swallow a placebo pill will be able to guess that they have not received a powerful hallucinogen. Some research groups try to solve this problem by giving participants in the control group a pill containing niacin, which at least elicits certain physical responses.

Researchers also need to address the extent to which concomitant circumstances influence the success of drug-assisted psychotherapy. These include, for example, the participants' state of mind and the environment in which the trials take place. In the treatment rooms of the COMPASS study at the Utrecht University Medical Centre in the Netherlands, for example, the atmosphere is spa-like: a Mexican-style blanket adorns each of the large double beds on which the subjects sit for the treatment. Beanbags surround a palm tree in the corner, and a poster of van Gogh's "Almond Blossom" hangs on the wall.

Add to that the training and experience of the therapists who lead both the drug and drug-free integration sessions. COMPASS has specially developed a five-step training program for the professionals who accompany the patients in the study.

Strict rules would be needed for approval

The conditions from the studies would also have to be in place when the psychedelics are eventually widely introduced as new drugs, says psychobiologist Bertha Madras of Harvard Medical School. Exactly how such rules will ultimately be established, however, is still unclear. The U.S. Food and Drug Administration (FDA) has a mechanism in place to ensure that drugs are administered in a certain way: the so-called Risk Evaluation and Mitigation Strategies, or REMS. Through REMS, the agency can require doctors and pharmacists to obtain certification if they want to prescribe, dispense or use a particular drug - similar to the way opioids are prescribed, where medical professionals must demonstrate that they are taking steps to minimize the risk of addiction and abuse as much as possible.

That's because there are risks associated with taking psychedelics, too. In extremely rare cases, hallucinogens such as psilocybin and LSD can cause a lasting psychotic reaction. People with a family history of psychosis are at increased risk for this. People with schizophrenia, for example, are therefore excluded from studies with psychedelics. MDMA, as an amphetamine derivative, also has a certain potential for abuse.

REMS could also be used with psychedelics, says Walter Dunn, a psychiatrist at the University of California at Los Angeles who advises the FDA from time to time on the approval of psychiatric drugs. That would allow the use of the drugs to be tied to appropriate therapy components, preferably delivered by specially trained staff. This could mean that those therapists who have illegally "treated" patients with such substances over the past 30 years would soon be legitimized. However, caution is needed here: Some of them may not want to abide by the rules and requirements of a government that once drove them underground.

But there is still a long way to go before approval anyway. In late 2020, MAPS reported in a press release that it found statistically significant differences between the experimental and control groups in its ongoing Phase III trial of MDMA for severe post-traumatic stress disorder. However, the nonprofit won't say more about the results until the full data are published sometime during 2021. It is also currently recruiting participants for a second Phase III trial testing MDMA therapy in people with moderate-to-severe PTSD, which is expected to be completed before the end of 2021. COMPASS also expects to have resulted from its Phase IIb study of psilocybin by then. The company is also planning a Phase III study with the compound.

No miracle cure

Robert Malenka is researching the effects of MDMA in rodents. A psychiatrist and neuroscientist at Stanford University in California, he can well imagine that some psychedelic drugs will eventually be approved for the treatment of certain mental illnesses. "They have the potential to become part of our toolkit for treating patients," he says. But Malenka cautions against overzealousness and glorifying psychedelics, as some do who already offer psychedelic-assisted psychotherapy illegally. "I don't think they're going to turn out to be a miracle cure."

First, he said, more research needs to be done on the effects of the substances on the brain. In addition, there is the question of whether agents that have the same effect but do not cause hallucinations might not prove more useful in the long run. Others counter that SSRIs have also been used in psychiatry for a long time and help many people, although doctors still do not fully understand their mode of action.

"Subjects are already biased".

(Bertha Madras, psychobiologist)

Bertha Madras is particularly concerned about the design and sample size of many clinical trials. Numerous research groups deliberately recruit people for their trials who have taken psychedelics before. The groups justify this because it would minimize the risk of side effects and other adverse events. But people who are attracted to drugs might end up saying more positive things. And the consent forms that participants must sign before the trials also would generally already reveal what subjects should expect and what the expectations are. "So subjects are biased," Madras explains.

Despite everything, Rutter is convinced that the treatment he received in 2015 changed his life for the better. In the weeks following his sessions, he sometimes wondered if the negative thoughts his brain had always automatically reeled off before would return. "I was terrified," he says, "and I realized that I could control that a little bit after all." The thought had never occurred to him before.

A week later, he was out with friends at a mall and felt his openness and optimism slowly return. "It felt like someone opened the window in a stuffy room." Five years later, his depression still hasn't returned.