People have been blowing their minds with hallucinatory substances for millennia -- at least since the ancient Greeks drank a psychoactive brew thought to contain a barley fungus, ergot, in one of their sacred rituals. Today, many researchers are convinced that trippers are onto something good -- that the alteration of consciousness induced by psychedelics can be a tonic for mental health. Though these substances are largely outlawed, dozens of startups betting on legal changes are seeking to develop treatments based on them for illnesses like depression and anxiety. Not everyone is sold on the idea, and there are risks that come from manipulating the brain’s chemistry.

1. What are psychedelics?

They are a subset of mind-altering drugs distinguished, in the words of researcher J.H. Jaffe, by their ability to induce “states of altered perception, thought and feeling that are not experienced otherwise except in dreams or at times of religious exaltation.” Those with a history of use for spiritual purposes are called “entheogens,” from Greek roots meaning “to generate,” and “God within.” Psilocybin or “magic” mushrooms were used in Mesoamerican civilizations and possibly even prehistoric Europe. Ayahuasca is a brew of vines and shrubs native to the Amazon basin, while peyote is a small cactus that grows in the U.S. southwest and northern Mexico. LSD, which stands for lysergic acid diethylamide, is synthesized from a chemical present in ergot. These so-called classic psychedelics do not include the party drugs ketamine and MDMA (also known as ecstasy or Molly), nor the herb salvia, which is common in southern Mexico and Central America, nor ibogaine, which is extracted from the root of the iboga tree native to Africa; these are sometimes referred to as hallucinogens but have different mechanisms of action on the brain. Regardless, they are all being talked about as a new scientific and investment frontier.

2. Why is there renewed interest?

Researchers in the 1950s and 1960s produced hundreds of scientific reports on the use of LSD and psilocybin as therapeutic drugs, including studies showing improvements in patients with various mental disorders. But when the substances became associated with the counterculture movement of the time, they were strictly regulated in most countries, complicating research. Still, some scientists persisted, amid growing interest in alternatives to the pharmaceutical drugs that have so far been used to treat mental health disorders. In recent years, researchers produced groundbreaking studies on the promise of psychedelics to relieve emotional suffering in people nearing death followed by a growing body of work suggesting the substances can help with depression, post-traumatic stress disorder, addiction and anxiety. One theory is that by inducing an eroded sense of ego and feelings of universal connectedness, psychedelics can produce a shift in perspective that’s less fixated on the individual’s struggles and more appreciative of life.

3. How are they used therapeutically?

In many proposed therapeutic uses, people have a series of trips overseen by a clinician or guide of some sort. Ayahuasca tourism, with shamans leading psychedelic ceremonies, has become an industry in the Amazon. So-called microdosing involves ingesting, over an extended period of time, amounts so small there’s little or no perception of an altered state. There’s lots of anecdotal reporting of people using this practice to improve their mood or cognition but little scientific research.

4. Are they legal?

Mostly no, with exceptions. A 1971 treaty requires its 184 signatories to prohibit the use of LSD, psilocybin, mescaline (the hallucinogenic compound in peyote) and dimethyltryptamine (or DMT, the agent in ayahuasca). However, scientific and limited medical uses are exempted, and countries can, and do, make exceptions for indigenous, wild plants that contain psychotropic substances and are traditionally used in rites. Ayahuasca is permitted in such contexts in Brazil, the U.S., Canada and Peru. In the U.S., psilocybin mushrooms are outlawed under federal law, but the states of Oregon and a handful of cities have decriminalized them, making arrests for possession the lowest priority for police. Washington D.C. also decriminalized plants containing DMT, mescaline and ibogaine, and Oregon legalized psilocybin mushrooms for therapeutic use in supervised, licensed facilities. A loophole in the law in the Netherlands permits psilocybin truffles, the mushroom’s root-like filaments. Many psychedelic users continue to rely on a robust black market, often making purchases on the so-called dark web.

5. Are they risky?

Psychedelics can produce intense, confusing trips, which is one reason having a guide can be beneficial. Ayahuasca famously provokes vomiting and diarrhea. Drugs purchased on the black market may be tainted or come in unpredictable doses. Classic psychedelics aren’t associated with fatal overdoses, but they can impair the judgment of users, leading to deaths. Although it happens rarely, some users have recurrent hallucinations, called flashbacks, long after taking a psychedelic. Classic psychedelics are not addictive. Research into long-term effects is just getting started, but a number of studies have found either no association between lifetime use and rates of mental health problems, or an inverse relationship between the two. But there have been rare reports of use triggering psychotic episodes, especially among people with a family history of serious mental illness.

6. How are people investing?

A surge of startups are experimenting with different ways to profit from psychedelics, offering clinics or retreats, formulating novel molecules that behave in ways similar to classic psychedelics, and synthesizing plant-based substances, perhaps to create more predictable or side-effect-free trips. Venture capitalist Peter Thiel is backing a German startup, Atai Life Sciences AG, that acquires biotech companies, most of them developing psychedelic or hallucinogenic drug candidates. Shares of more than two dozen psychedelics companies trade on the Canadian Stock Exchange, and there’s a related exchange-traded fund, the Horizons Psychedelic Stock Index.

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