Show Me the Evidence, where we go beyond the frenzy of daily headlines to take a deeper look at the state of science around the most pressing health questions of the day. Welcome towhere we go beyond the frenzy of daily headlines to take a deeper look at the state of science around the most pressing health questions of the day.

After years of struggling with treatments for his worsening cancer, Roy was miserable — anxious, depressed, hopeless. Traditional cancer treatments had left him debilitated, and it was unclear whether they would save his life.

But then Roy secured a spot in a clinical trial to test an exotic drug. The drug was not meant to cure his cancer; it was meant to cure his terror. And it worked. A few hours after taking a little pill, Roy declared to researchers, "Cancer is not important, the important stuff is love." His concerns about his imminent death had suddenly vanished — and the effects lasted for at least months, according to researchers.

It was not a traditional antidepressant, like Zoloft, or anti-anxiety medication, like Xanax, that led Roy to reevaluate his life. It was a drug that has been illegal for decades but is now at the center of a renaissance in research: psilocybin, from hallucinogenic magic mushrooms.

Psychologists and psychiatrists have been studying hallucinogens for decades — as treatment for things like alcoholism and depression, and to stimulate creativity. But support for studies dried up in the 1970s, after the federal government listed many psychedelics as Schedule 1 drugs. But now researchers are giving the drugs another look.

While stories like Roy’s are promising, we’d need​ hundreds, perhaps thousands, more examples — rigorously tested, preferably in large randomized, controlled experiments — to know the effects claimed in the study are real and unbiased.

But that research is worth doing. Psychedelics show promise in alleviating some of the conditions that have proven hardest to treat — addiction, obsessive compulsive disorder, end-of-life anxiety, and, in some cases, depression are notorious for their resistance to treatment. Smoking relapse rates, for instance, have been estimated at 60 to 90 percent within one year, even as smoking kills hundreds of thousands each year.

"These are among the most debilitating and costly disorders known to humankind," Matthew Johnson, one of the psychedelics researchers at Johns Hopkins University, said. "We have some things that help, but for some people they’re barely scratching the surface, [and] for some people there’s nothing that helps at all."

Psychedelics may help. But the mechanism through which they appear to help people has left doctors scratching their heads and some scientists deeply uncomfortable with their findings: These drugs appear to use chemical pathways to trigger often deeply spiritual experiences that seemingly lead to tangible, measurable, long-term changes in behavior. That is not, to say the least, how traditional medicines typically function.

There’s still a lot we don't know and are just learning. So to understand what we know so far about psychedelic drugs and psychedelic-assisted psychotherapy for treating some of the most stubborn psychological conditions, I read more than 50 studies analyzing their safety and efficacy and talked to researchers involved in the work.

(Note: I looked only at the studies and research on classic psychedelics, such as LSD, psilocybin from magic mushrooms, and DMT. These drugs have broadly similar effects, activating certain serotonin receptors in the brain. Although MDMA — known as ecstasy or Molly — also shows promise for some conditions, like post-traumatic stress disorder, and is commonly included with psychedelics, its effects and use in therapeutic settings are too different to evaluate it alongside classic psychedelics. So I left it out of this review.)

Here’s what I learned from my look at the research.

1) The idea of using psychedelics for medicine isn't new

The idea of using psychedelic drugs as medicine is not new at all.

In 1943, Albert Hofmann serendipitously discovered the effects of LSD by, well, ingesting it in his lab in Switzerland. The discovery triggered a rush of research into LSD and similar substances in the 1950s and '60s.

Perhaps the best-known researcher of the time was Timothy Leary. Leary experimented with drugs in college, developing a particular fascination with psychedelics. His interest propelled him, after he became a young teacher at Harvard University, to begin more formally researching the drugs. This led to the creation of the Harvard Psilocybin Project, which administered psilocybin (commonly found in magic mushrooms) to graduate students and several prominent artists of the time in a set of experiments to reveal the drug’s effects on human consciousness.

Despite the odd origins, the research of the time was hopeful: Dozens and dozens of studies — not just in Leary’s lab but in many others across the country — had promising findings, suggesting psychedelics could be used in therapeutic settings to treat some of the most treatment-resistant conditions, such as addiction, anxiety, and depression.

But public concern, particularly over psychedelics slipping out of the research world and into widespread recreational use (see: Woodstock), led to a crackdown. And the research into psychedelic drugs was effectively shut down.

After a few decades, the restrictions on psychedelic drugs began to thaw. Starting in the 1990s, some researchers pushed for again treating psychedelic drugs as potential medical tools. Backed by privately funded groups like MAPS, the Beckley Foundation, and the Heffter Research Institute, researchers have overcome regulatory and funding hurdles to get some small preliminary studies done.

In part due to the hurdles to studying these drugs, the new research is preliminary and limited. The sample sizes are so small that it’s hard to say for certain whether the findings will hold for bigger, generalized populations. And several of the studies don’t include control groups or placebos — gold standards in science to ensure noted effects aren’t caused by something else.

But the findings are promising and challenging. To the extent that these drugs may work, they appear to do so through a very unusual mechanism: by eliciting a mystical, spiritual experience.

2) The mystical dimension of psychedelics is part of what may make them therapeutic

Here is a small sampling of how some participants in several studies since the 2000s described psychedelic experiences:

"Feelings of gratefulness, a great (powerful) remembrance of humility … of my experience of being, the experience of my being in and within the infinite."

"Not at all religious but significant in motivating me to nurture my spiritual life."

"I believe I channeled the power of the Goddess and that I hold that power in me. I believe she exists everywhere and I look for her to add spark, life, and joy to everyday ordinary situations."

"The experience expanded my conscious awareness permanently. It allows me to let go of negative ideas faster. I accept ‘what is’ easier."

"My conversation with God (golden streams of light) assuring me that everything on this plane is perfect; but I do not have the physical body/mind to fully understand."

It may be easy to dismiss these experiences. What do gods and golden streams of light have to do with medicine?

But the findings from many studies, which can involve months or years of follow-up, are promising — albeit not definitive. One very small study of 15 smokers found 12 (80 percent) managed to abstain from smoking for six months after a psilocybin treatment. A review of previous randomized controlled trials found that LSD helped alcoholics cut back on their drinking, while a much smaller study found psilocybin treatment helped people diagnosed with alcohol dependence cut back on their drinking days. Another study found that psilocybin may have helped treat depression for patients who had proven resistant to other treatments.

So how exactly are psychedelics achieving this? Researchers readily admit that they don’t have all the answers — or even total certainty that it’s solely the psychedelics at work. But drawing on the current studies and the research from the '50s and '60s, they have a theory: When people are faced with debilitating mental conditions, psychedelics — used, researchers emphasize, in controlled and supervised clinical settings — can trigger a powerful mystical experience. The experience can then provide a psychological context that makes positive behavioral change easier.

"They have profound, meaningful experiences that can sometimes help them make new insights into their own behaviors and also to reconnect with their values and priorities in terms of what’s important to them in the grander scheme of things," Albert Garcia-Romeu, another Johns Hopkins researcher, said. "When they have those kinds of experiences, it seems to be helpful for people to be able to make behavior changes down the line, like quitting smoking."

And here’s what really remarkable: In the studies, it only seemed to take one or two doses to produce months of benefits. Unlike psychiatric medications that require regular, often daily doses, psilocybin treatment — if it really works — appears to require just one or two sessions with one dose of the drug to have a months-long impact.

Michael Pollan wrote of some participants’ powerful experiences in an illuminating look at the research for the New Yorker:

Death looms large in the journeys taken by the cancer patients. A woman I'll call Deborah Ames, a breast-cancer survivor in her sixties (she asked not to be identified), described zipping through space as if in a video game until she arrived at the wall of a crematorium and realized, with a fright, "I’ve died and now I’m going to be cremated. The next thing I know, I’m below the ground in this gorgeous forest, deep woods, loamy and brown. There are roots all around me and I’m seeing the trees growing, and I’m part of them. It didn’t feel sad or happy, just natural, contented, peaceful. I wasn’t gone. I was part of the earth." Several patients described edging up to the precipice of death and looking over to the other side. Tammy Burgess, given a diagnosis of ovarian cancer at fifty-five, found herself gazing across "the great plain of consciousness. It was very serene and beautiful. I felt alone but I could reach out and touch anyone I’d ever known. When my time came, that’s where my life would go once it left me and that was O.K."

It might sound pseudoscientific. But drug policy experts and researchers say that if the experience helps people, even if it’s not founded on the most logical grounds, it should be taken seriously.

Spiritual experiences "have been part of humanity for thousands and thousands of years," Sameet Kumar, a doctor who follows the research closely, said. "Instead of blowing them off, let’s try to understand them. What’s going on here? This is part of the human experience — a very relevant and meaningful part of the human experience. And now we have these tools to study how certain sacramental elements that are found in nature and that can be synthesized … can be used for good."

A new set of studies, published in The Journal of Psychopharmacology, which had some of the largest sample sizes in the psychedelic research so far, showed the potential. The patients, which totaled 80 in both studies combined, all had advanced cancer and end-of-life anxiety or depression, driven in large part by their looming deaths. After a psilocybin treatment session, most of the patients — as many as 80 percent — generally showed improvements on metrics used to evaluate mood, depression, and anxiety.

While the studies couldn’t verify due to their small sample sizes and methodology whether psilocybin alone led to the gains, the studies found that the depth of the mystical experience — measured through widely accepted scientific metrics for these types of experiences — closely correlated with how strong the patients’ gains were. One of the studies also found that the strength of the dose produced bigger benefits.

These newer, larger studies validated the findings of previous pilot studies, which followed a similar model but had smaller sample sizes and were therefore less reliable for drawing more generalized conclusions.

Charles Grob, a psychedelics researcher at UCLA and author of one of the previous pilot studies, also pointed to Canadian research done in the 1950s with alcoholics as proof that the mystical experience triggered by psychedelics is key: Among patients in the Canadian research, the best predictor of who had the best outcomes (sobriety) "was that during the course of their many-hour one-psychedelic session, they had a powerful mystical-level experience."

Johnson of Johns Hopkins concurred, citing his studies: "For either [cancer-related end-of-life anxiety] or smoking cessation treatment, we found that the degree of mystical experience … is predictive of long-term beneficial effects — of reductions in anxiety and depression [and] reductions in cigarette smoking."

One way of understanding the effect is by looking at it as the opposite of a traumatic experience, as the smoking study explained it:

It is our contention that in a similar fashion, the psychedelic-occasioned peak experience may function as a salient, discrete event producing inverse PTSD-like effects-that is, persisting changes in behavior (and presumably the brain) associated with lasting benefit. By "PTSD-like" we are not presuming that these experiences necessarily share common biological mechanisms with PTSD. Rather, we are proposing that these experiences are "PTSD-like" in the sense that a single discrete event can cause lasting behavioral (and likely biological) changes, and "inverse" in the sense that these lasting changes are beneficial in nature, as opposed to deleterious.

"What it represents in the brain, we’re not really sure," James Rucker, a clinical lecturer at King's College London who worked on the depression study, said. "The way they describe it is often symbolic of what’s going on in their head. Take the goddess leading you through. Maybe it’s the goddess leading you through your depression and out the other side — if you take the metaphor like that."

3) We don’t really know why psychedelics trigger such powerful mystical experiences

In a recent study, British researchers used brain imaging techniques to gauge how the brain looks on LSD versus a placebo. They found big differences between LSD and the placebo, with the images of the brain on LSD showing much more connectivity between different sections of the mind.

This can help explain visual hallucinations, because it means various parts of the brain — not just the visual cortex at the back of the mind — are communicating during an LSD trip.

This, researchers argued, may show not just why psychedelic drugs trigger hallucinogenic experiences but also why they may be able to help people. "In many psychiatric disorders, the brain may be viewed as having become entrenched in pathology, such that core behaviors become automated and rigid," the researchers wrote. "Consistent with their ‘entropic’ effect on cortical activity, psychedelics may work to break down such disorders by dismantling the patterns of activity on which they rest."

"The idea with the psychedelics is to essentially try to shake the brain up a bit," Rucker, who didn’t take part in the brain imaging study, explained. "To try and lend the person who’s suffering a new perspective and try to change their behavior."

This is one of the few studies so far that analyzed how the mechanical, physical effects of psychedelics on the brain may help patients. Other research is unclear on the exact mechanisms, but it suggests that the classic psychedelics affect serotonin and, in the case of LSD, dopamine receptors in a way that may help elevate people’s moods.

According to Garcia-Romeu of Johns Hopkins, it’s likely these physical factors work with the spiritual experience to help people. "They all co-occur," he said. "It’s not like right now as I’m talking to you, there’s not activity in the temporal lobe in your brain, which is both chemical and electrical. All of this stuff is happening at the same time. But what we experience obviously is primary. You’re hearing my voice, so your subjective experience is focused in on what is happening in your field of consciousness, as opposed to the electrical … and neurochemical signals in your brain."

4) One reason psychedelics may work: They treat the person’s context, not just their illness

"My personal opinion is that the reason these kinds of conditions are so hard to treat from a standard medical perspective is that there’s something more to them than just the illness," Garcia-Romeu said, pointing to addiction as an example.

"Oftentimes we have to do actual therapy," he added. "We can’t just give them a pill to make their problems go away. We have to really delve into things like childhood trauma and current life situations and relationships and whether those relationships are healthy or toxic and how people feel about themselves."

Kumar works closely with cancer patients as a psychologist in a South Florida cancer center. He thinks psychedelic-assisted treatments could be a great boon to his line of work with late-term cancer patients, who struggle with crippling end-of-life anxiety that’s frequently impossible to treat.

"Patients with advanced cancer oftentimes don’t have the healthy coping tools that often take a lifetime of practice to get — healthy stress management, a set of spiritual beliefs that can be comforting, or an understanding or sense of purpose and meaning in their lives," Kumar said. As a late-term cancer patient, "you are suddenly faced with a situation in which you don’t have a lot of time, your physical health is in jeopardy, your cognition is dicey, and there just isn’t a whole lot of time to get a lot of stuff in place. Psychedelics are a very rapid way to induce very meaningful change in people."

5) The research is extremely early, with small sample sizes, so it’s hard to say if psychedelic drugs really are effective

Still, as promising as the research is now, it’s still fairly preliminary. The big issue with the studies done so far is they tend to have fairly small sample sizes, with generally fewer than 60 participants. There are also other methodological issues — for one, some studies don’t test a drug’s efficacy compared with a placebo or have a strong control group.

For example, the Johns Hopkins smoking study found that 80 percent of participants kept from smoking for six months after psilocybin treatment — an astounding result. But it had a mere 15 participants, 14 of whom were white. And there was no control group or placebo, so it’s unclear if the psilocybin or some other variable — the psychotherapy that accompanied the psilocybin, for example — produced the results.

These tiny sample sizes are a huge hole in the research so far. As Michael Slezak writes, small studies can be very deceptive: They can exaggerate the benefits of a treatment or perhaps suggest benefits that aren’t really there. So once the psychedelic research scales up to bigger sample sizes, the positive findings for these drugs could get much less striking — or even vanish entirely. We just don’t know yet.

"I don’t know if it will reach 80 percent. That’s awfully high," Grob, the UCLA researcher, said of the smoking study. "But my expectation is they should be able to demonstrate favorable efficacy and safety."

Then there are all sorts of other questions researchers would like to tackle: How would different doses of different psychedelic drugs work for different conditions? How long do the benefits last — is it weeks, months, years, decades? Are there other mental health conditions, such as eating disorders, that may benefit from psychedelic-assisted treatments? Are some of the benefits reduced or eliminated for people who aren’t spiritual or religious?

Perhaps the biggest of those questions is how long the effects of psychedelic-assisted psychotherapy last. For example, one review of the research on LSD-assisted psychotherapy and alcoholism found no statistically significant effect after 12 months. The recent study on psilocybin and depression concluded that the benefits seemed to significantly drop off in three months, although there some gains remained.

The latest set of studies on psilocybin-assisted treatment’s effects on cancer-related end-of-life anxiety and depression had more promising results, showing significant gains in measures of anxiety, depression, and well-being at least six months out. And since the sample sizes were bigger — one study had 51 participants, the other 29 — they are a little more reliable, although the sample sizes are still fairly small.

Perhaps the most promising study looking at duration is a 1991 follow-up by Rick Doblin to a study done in 1962. The 1962 study, dubbed the "Good Friday experiment," gave half of participants a placebo and the other half psilocybin as they watched a Good Friday sermon. Doblin followed up on these participants decades later, finding that those who received psilocybin all reported the experiment "made a uniquely valuable contribution to their spiritual lives," while none of those who received a placebo did.

But the follow-up evaluation was based on self-reports from the original participants, which were a small sample size of 20, only 16 of whom participated in the follow-up. Again, more rigorous standards and larger sample sizes are needed to know if the findings will hold.

Another tricky aspect of the research is ensuring double blindness, a research technique that ensures both the researchers and the participants don’t know what drugs are administered. (The idea is that knowing could influence the results if participants act differently or researchers treat participants differently based on the drug they get.) Obviously, this is difficult when the effects of psychedelic drugs are so obvious.

Rucker of King's College London said that ensuring double blindness is a big challenge. But he expects that researchers will figure out ways around this — like using placebos that are psychoactive but known to not produce certain benefits — and replicate the findings enough through different methodologies to make up for a lack of pure double blindness.

6) There are some big risks to psychedelic drugs

Although hallucinogens are fairly safe for patients who have been prescreened and take them in a supervised clinical setting, they are not without risks.

A review of the research on classic psychedelics found, for example, stories of people trying to fly and falling out of tall buildings. And there’s always the risk, researchers say, of people trying to wander around streets with cars, trying to drive, and putting themselves in all sorts of other dangerous situations when they’re too high to know any better.

There’s also the risk of people, particularly those predisposed to psychotic conditions, having a traumatic experience that permanently damages them psychologically. That’s particularly a concern with classic psychedelic drugs, which activate receptors linked to schizophrenia, psychosis, and other psychotic conditions.

"Certain people probably should not be taking these drugs at all," Garcia-Romeu of Johns Hopkins said. "We do a very careful job to screen those people out of our studies. And that’s why even though we’ve given the drugs — pretty high doses of psilocybin — to people here in the lab, we’ve never really had any major events where people have ongoing psychotic illness after the fact."

Beyond those two big risks, psychedelic drugs actually aren’t especially dangerous. They’re not addictive, and LSD and psilocybin in particular carry no significant risk of overdose.

A review of the research in 1999 found they don’t appear to cause personality changes or other chronic psychological issues. A study in 2005 found the long-term religious use of peyote seemed to have no negative cognitive or psychological effects on Native Americans. One study on psilocybin and a review of the psychedelic research found no major physical effects besides dizziness, headaches, and exhaustion for a few days after use of the drugs.

Still, the existing risks are why researchers emphasize that these drugs should only be used in supervised clinical settings. So far, the studies to date have only found benefits to psychedelic drugs in these settings, where trained experts oversee the experience to make sure nothing goes wrong. And researchers expect that if the drugs eventually make it out of research settings and into the real world, limiting their use to a supervised clinical environment will be crucial to their success.

"Above and beyond anything else, it’s essential to preserve strong safety parameters," Grob of UCLA said. "Without that, the work really cannot proceed."

7) Still, psychedelic use may eventually benefit more than the gravely ill

Currently, psychedelic research is focused on the truly ill. But there’s no obvious reason to believe the benefits are solely limited to that group. After all, almost everyone deals with some anxiety related to death. Psychedelics could help relieve that anxiety.

As Mark Kleiman, a drug policy expert at the New York University’s Marron Institute, previously told me, "The obvious application [of psychedelics] is people who are currently dying with a terminal diagnosis. But being born is a terminal diagnosis. And people’s lives might be better if they live out of the valley of the shadow of death."

Some of the studies on psychedelics have validated this idea. One 2011 study by Johns Hopkins researchers found, for instance, that people who reported psilocybin-induced mystical experiences showed more openness in personality tests. Other Johns Hopkins studies in 2008 and 2011 found that participants in psilocybin sessions reported higher life satisfaction and positive effects on mood, particularly among those who described the most powerful mystical experiences.

Again, researchers emphasize that these studies are preliminary and don’t support unsupervised personal use. But they do suggest that many people could potentially benefit from psychedelic-assisted therapy, even if they don’t have a severe, diagnosed disorder or condition.

"Most of psychology and medicine are, believe it or not, focused on the negative. The only time you go see a psychologist is if you have a mental illness, or the only time you go see a doctor is because you’re sick," Garcia-Romeu said. "But that’s 50 percent of the spectrum. The other 50 percent of the spectrum [is] people who are well or are even optimal, functioning at a higher than average level. And I think those people who are just fine … can certainly benefit from these types of experiences."

8) Medical psychedelic research exposes a big flaw in drug policy and funding

The early research in this field is promising enough that many researchers and experts are taking it very seriously and aggressively pursuing additional studies.

But much of the work has been snared by regulatory barriers.

The classic psychedelics are Schedule 1 substances, meaning the federal government deems them to have no medical use and high potential for abuse. With that schedule comes unique restrictions, so psychedelic studies have to, on top of getting approval from the Food and Drug Administration like other clinical trials, meet standards set by the Drug Enforcement Administration. This can all add months or years — which come with higher financial costs — to a study.

Another major hurdle is funding. "In the '50s and '60s, the federal government was spending a good amount of money to fund research with psychedelics," Garcia-Romeu said. "So LSD was something that you could be a psychiatrist in the 1950s and submit a grant to the government and get plenty of money to do research to see what are the effects of this drug or how can it be used therapeutically and clinically."

The story is different today. After widespread psychedelic abuse in the 1960s, a huge cultural and political backlash to these drugs killed most federal funding. Now federally funded studies on psychedelics focus on these substances’ dangers, not their potential benefits. After all, the feds don’t even acknowledge that these drugs have any medical value to begin with.

Normally, drug companies could fill in a funding gap. But the pharmaceutical industry doesn’t have an incentive to do that with psychedelics: These drugs can’t be patented, since they’re existing, well-known substances. So a drug company wouldn’t be able to claim all the financial rewards if it funded a large, expensive study that found big benefits to psilocybin-assisted therapy. (These kinds of situations are one reason some policymakers want to completely reform drug research.)

This leaves it to private organizations to fund much of the psychedelics research, with the help of private donations. MAPS, the Beckley Foundation, and the Heffter Research Institute are the major groups doing this kind of work. Some of the next wave of studies that are already in progress or in development include psilocybin treatments for alcoholism and cocaine addiction, as well as more follow-up work on psilocybin’s efficacy for treating tobacco addiction and end-of-life anxiety.

But the research is expensive and labor-intensive, and requires a lot of time and training, since the psychedelic and psychotherapy sessions can span dozens of hours over months or years. So these small private groups have only been able to fund small-scale studies, hence the small sample sizes and less rigorous methodology so far.

The result is we have a lot of anecdotes, like Roy’s, and some smaller studies that show psychedelic drugs’ promise for treating some crippling medical conditions. The holes in our knowledge, however, could be easily filled. There’s more than enough promise here to merit further research and further funding for that research.

9) Bibliography

Editors: Eliza Barclay, Julia Belluz, and Ezra Klein

Visuals: Javier Zarracina

Research and writing: German Lopez

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