The hippie drugs are coming in from the cold. First, it was marijuana and its CBD derivative that were given a guarded welcome as pain relievers – and now it’s the psychedelics that are being given a second look. Fifty years after they were banned, LSD, “magic” mushrooms and ecstasy are being tested on a range of psychiatric disorders, the conditions for which they were originally intended.

The US Food and Drug Administration (FDA) has already heralded the psychedelics MDMA (ecstasy) and psilocybin (magic mushrooms) as “breakthrough therapies” to treat post-traumatic stress disorder (PTSD) and depression that isn’t helped by standard drug therapies like SSRIs (selective serotonin reuptake inhibitors).

Last year, the agency approved Spravato (esketamine), made by drug giant Johnson & Johnson, for treatment-resistant depression – and its active ingredient esketamine is derived from ketamine. More psychedelics are in the pipeline, including a psilocybin-based antidepressant by biotech start-up Brightminds Biosciences.

In a major review of the published evidence, researchers from New York University School of Medicine found that MDMA and psilocybin were supported by the most positive research, and the evidence was also “promising” that LSD and ayahuasca, a traditional decoction of plants from the Amazon Basin, could help treat a range of psychiatric disorders.1

But it hasn’t been all one happy trip. Adverse reactions such as heart problems have been reported, and most of the patients taking a hallucinogenic drug will need constant care and monitoring for up to four hours. Researchers are busy dialing down the effects and investigating just how “micro” a micro-dose can be before it loses its effectiveness.

Despite these problems, the psychedelics are the only new show in town for treating psychiatric disorders. Big Pharma’s last great hurrah was Prozac, which was launched in the late 1980s – and doctors are quietly tip-toeing away from the drug and others in the SSRI family because they work only occasionally, if at all.

We spend $15 billion on SSRIs every year, but researchers who headed up one of the first independent studies into the drugs said they were left “shocked and surprised” by the drugs’ ineffectiveness.2

The irony is there’s nothing new about these hallucinogens. Many have been around far longer than antidepressants and were used to treat psychiatric problems for a decade or more before the 1960s counterculture discovered them.

In the UK alone, around 5,000 people took part in more than 40,000 LSD “sessions” in the 1950s and ’60s to treat a range of psychiatric problems, including anxiety, and hundreds of scientific papers monitored the success of the new therapy.

But illicit supplies were getting into the hands of healthy people who were taking them to get “high” and have spiritual experiences. LSD guru Timothy Leary’s exhortations that we “turn on, tune in and drop out” fell on deaf ears at the White House, and in 1970, President Nixon had the drugs reclassified as “Schedule I” controlled substances having no valid medical use.

Hello, again
That reclassification, coupled with negative press about “bad trips,” effectively put an end to their use as therapeutics – and anyhow the SSRI antidepressants were becoming the new kids on the block. But after 20 years in the medical wilderness, interest in hallucinogens started to pick up.

In 1992, German scientists tested mescaline, a hallucinogenic from the peyote cactus, on healthy people.3 Eight years later, the Center for Psychedelic and Consciousness Research at Johns Hopkins University became the first facility in the US to get the green light to test psychedelics on healthy people.

That center has published more than 60 research papers to date, including a 2006 report in which psilocybin was given to 30 people who all reported having experiences of “a spiritual significance,” that is still seen as groundbreaking.4 Now, a new generation of researchers has been inspired to rediscover the hallucinogenic drugs and their therapeutic benefits.

Psilocybin. Certain so-called “magic” mushrooms produce this plant alkaloid, which has been used to treat a range of psychiatric disorders. In 2016, Johns Hopkins researchers tested it on 51 people with advanced cancer who suffered from depression; 92 percent reported some or complete reversal of their symptoms following an eight-hour session with the drug, and 75 percent said their anxiety had also lifted.5

Similar success was reported in a group of 12 people whose severe depression had not been helped by SSRIs. After two sessions of psilocybin, all the participants has some improvement, and eight of them (67 percent) reported a complete reversal. Seven of the participants were still experiencing a significant improvement in their depression three months later.6

Improvements in people with obsessive-compulsive disorder (OCD) weren’t quite so long-lasting, but symptoms improved for a week in one small trial of nine people who hadn’t been helped by SSRIs.7

Psilocybin can also help people quit smoking. In one study of 15 heavy smokers who had three sessions with the drug, 12 of them (80 percent) quit and remained ex-smokers six months later. 8

LSD. Lysergic acid diethylamide (LSD) is perhaps the most famous of the hallucinogens. It was discovered by accident by Albert Hoffman, a chemist at Sandoz drug company, in 1943. Hoffman went on to discover psilocybin in 1958.
Sandoz marketed LSD as Delysid and psilocybin as Indocybin as treatments for neurological and psychiatric disorders, but stopped all manufacturing in 1965.

Although it’s one of the most potent hallucinogens, LSD is one of the least researched. One of its biggest successes is as a treatment for alcoholism.

An analysis of all the studies to date, including a total of 536 people, found that, on average, 59 percent of those who had just one LSD session reduced their alcohol misuse, compared to 38 percent of those given a placebo. Many stopped binge-drinking and some were not drinking at all even three months later. 9

MDMA. Better known as ecstasy, MDMA was first synthesized in 1912 by Merck, and has been used for various disorders, including anxiety, OCD and post-traumatic stress disorder (PTSD) – but unlike most hallucinogens, it can cause serious reactions, especially at high doses.

Only two SSRIs have been approved to treat PTSD, and one of these, paroxetine, has been described as “the antidepressant from hell.” So, researchers have been looking for alternatives, and the first trial using MDMA was completed in 2010.
Twenty participants were given two sessions of MDMA, and after two months, 83 percent of them reported major improvements, compared to 25 percent in the placebo group.10

Ayahuasca. This brew, used by indigenous people of the Amazon Basin for spiritual ceremonies, has also been used to treat depression. In 2016, 29 patients with depression were treated with either ayahuasca or a placebo, and 64 percent in the ayahuasca group reported a major improvement in symptoms after seven days, compared to 27 percent in the placebo group.11

More to come
The psychedelics represent a new way to treat psychiatric problems, and plenty more hallucinogen-based therapies are in the pipeline.

A psilocybin-based drug for depression, developed by the biotech start-up Brightminds Biosciences, has already reached phase 2 drug trials. Once more funds are in the coffers, the company will move on to trials in more people, and a drug could be available within the next year.

As chief executive Ian MacDonald explained, the key to developing the new generation of psychede
lic therapeutics is in dialing down the side-effects. But even with its own compound, he says, a person taking it will still need around four hours of nursing care after they take a dose.

On the plus side, the benefits can be seen almost immediately, even after just one session. “They are not for everyone, but I reckon that between 80 to 90 percent of people with depression are seeing some improvement,” he said.

“The tide is definitely turning. We’ve been engineering out a lot of the side-effects seen with the early psychedelics, and now they are much safer.”

But with any turning tide, there are always others looking to ride the surf. One is Compass Pathways, whose own psilocybin product earned the “breakthrough therapy” accolade of the FDA.

Backed by PayPal cofounder Peter Thiel, it is looking to dominate the psychedelic environment, including monopoly over the research.This early jockeying for position is already setting the scene for what could come, with narrow supply chains controlling the price of the therapies.

It’s a danger that seems a million miles away from the original hippie dream. But there are other threats on the horizon, too, and the most significant is also the most familiar – politics. It’s politicians who criminalized psychedelics in 1965, and a president who made them a Schedule I controlled substance.

Much of that fallout was a response to media that feared what was happening to the young, who truly were going through different experiences from their parents. That threat hasn’t necessarily gone away, although with CBD and mindfulness meditation going mainstream, there is a warmer current of acceptance circulating in the air today.

But the psychedelics will always be just one misstep away from another shutdown. A few negative stories about “bad trips” could be enough to stop the latest generation of psychedelic psychotherapies in their tracks.

High hopes
Research into psychedelic drugs has been scant since their highly politicized criminalization as Schedule I drugs in 1965. However, a new generation of scientists and doctors have picked up the torch, and the results they’ve reported so far, albeit in small numbers of patients, are incredibly promising – especially since most of these drugs have a low risk of side-effects.

References
1 Am J Psychiatry, 2020;appiajp201919010035
2 Lancet Psychiatry, 2019; 6: 903-14
3 Biol Psychiatry, 1992; 32: 976-91
4 Psychopharmacology, 2006; 187: 268-83
5 J Psychopharmacol, 2016; 30: 1181-97
6 Lancet Psychiatry, 2016; 3: 619-27
7 J Clin Psychiatry, 2006; 67: 1735-40
8 J Psychopharmacol, 2014; 28: 983-92
9 J Psychopharmacol, 2012; 26: 994-1002
10 J Psychopharmacol, 2011; 25: 439-52
11 Psychol Med, 2019; 49: 655-63

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