Lou Genise, a compact man with a shorn head and Fu Manchu mustache, sat propped up on a mattress in a hospital room tucked away on the fifth floor of Harbor-UCLA Medical Center in Los Angeles. Wearing an eyeshade and listening to music through a headset, he was oblivious to the two psychiatrists sitting nearby, quietly monitoring his every move.

Worry and nausea had been the 37-year-old performance artist’s constant companions during his treatment for metastatic colon cancer that was diagnosed a year earlier. Yet the shroud of negativity lifted under the influence of psilocybin, the psychoactive ingredient in the hallucinogenic mushrooms used in sacred Native American rituals.

Early one morning last July, Genise had taken a little white capsule containing the psychedelic as part of a medically supervised study to test whether it could ease the mental anguish of people with terminal cancer. He had checked into the hospital the afternoon before, and Charles Grob, the UCLA psychiatrist who is conducting the study, reviewed with him the issues he wanted to confront. Genise said he had developed a Pavlovian aversion to hospitals after all he had been through and would get nauseated in anticipation of getting treatment. He was also having trouble accepting his separation from a former girlfriend, who had come to Los Angeles to care for him when he fell ill.

“I had dealt with the big, earth-shattering problems, but the day-to-day anxieties were the hard part,” Genise recalled five months later, sipping tea in his home in the L.A. neighborhood of Echo Park. “But following the session, I had two startling epiphanies. First, here I was in a hospital having a pleasurable experience, which immediately cured my anxieties. And it suddenly clicked in my head that I didn’t need to cling to my ex. It was a spectacular experience, because in a short time I was able to work through some serious issues on a very deep level.”

At a handful of sites across the country, after a four-decade hiatus, psychedelic research is undergoing a quiet renaissance, thanks to scientists like Charles Grob who are revisiting the powerful mind-altering drugs of the 1960s in hopes of making them part of our therapeutic arsenal. Hallucinogens such as psilocybin, MDMA (better known as Ecstasy), and the most controversial of them all, LSD, are being tested as treatments for maladies that modern medicine has done little to assuage, such as post-traumatic stress disorder, drug dependency, obsessive-compulsive disorder, cluster headaches, and the emotional suffering of people with a terminal illness.

While Grob’s study is not complete—he has tested 11 out of a projected 12 volunteers—patients seemed to have positive experiences. “No one had a bad trip, and most derived some benefit,” he says. “It lowered their anxiety, improved their mood and disposition, and imbued them with a greater acceptance of their situation and capacity to live in the moment and appreciate each day.”

Other early test results are equally encouraging. University of Arizona scientists recently fed psilocybin to nine volunteers whose obsessive-compulsive disorder (OCD) was so disabling that many could not hold down a job or leave the house; they would observe elaborate cleaning rituals or shower for hours until they felt comfortable. Conventional treatments such as psychotherapy and medication had failed. In each of the nine patients in the study, psilocybin drastically diminished or melted away their compulsions for up to 24 hours, and several remained symptom-free for days.

In another ongoing study, psychiatrist Michael Mithoefer of Charleston, South Carolina, is testing MDMA (3,4-methylenedioxymethamphetamine) on people suffering from severe post-traumatic stress disorder (PTSD), including rape victims and Iraq War veterans who have not gotten any relief from conventional treatments such as antidepressants and therapy.

PTSD is normally triggered by a terrifying incident—combat, childhood sexual abuse, physical abuse, a serious accident, rape, or a natural disaster—in which people feel their lives are in danger but are powerless to defend themselves. Sometimes PTSD can be triggered by growing up in a harrowing environment where a child is at the mercy of a cruel parent or parental figure. To survive such horrific circumstances, sufferers often numb themselves to their pain. The cornerstone of PTSD treatment involves reliving the trauma in a way that enables patients to process their fears in a rational way. But by definition, revisiting the experience can be frightening, and people often become locked in the grip of intense anxiety.

The drug MDMA, a chemical cousin of mescaline and methamphetamine, can kindle intense euphoria or sublime seren­ity, creating a calming therapeutic environment in which to revisit trauma. Eighteen out of a projected 21 patients in Mithoefer’s study have already been treated, and in many cases just two sessions dramatically diminished symptoms, which is remarkable because PTSD in this group of subjects has been resistant to other types of treatment.

Psilocybe zapotecorum Image courtesy of Alan Rockefeller

One of the study participants spent more than two decades in therapy in a futile attempt to heal the deep wounds inflicted by a violent and emotionally abusive stepfather. She ran away from home, was raped twice by men who picked her up hitchhiking, and ricocheted from one abusive relationship to another.

The patient, a 51-year-old woman from South Carolina, coped by deadening herself emotionally. “I knew I was messed up, but I sealed up all those feelings because they were so overwhelming,” she recalls. “They were like the monster that is locked behind a three-foot-thick steel door.”

Under the influence of MDMA, she was able to let go of the blockage that had stunted her emotionally. “The drug opened the door and removed that fear of feeling,” she says. “I never cried about those experiences before, but now I can and I welcome it. I no longer feel like I’m holding back the Red Sea.”

Success stories like these explain why psychedelics never lost their appeal for Grob and a handful of other academic scientists. Despite their promise, however, it is still difficult to get such studies off the ground. Psychedelics are classified as Schedule 1 drugs by the Drug Enforcement Administration, which outlaws their use outside a research setting. Exceptions are made for Native American church­goers, who are allowed by law to use peyote in prayer meetings, and members of a branch of a Brazilian-based church in Santa Fe, New Mexico, who have won court battles for the right to use the hallucinogenic tea ayahuasca in their religious rituals.

In the current climate, the main source of funding for studies of hallucinogens are two private philanthropies: the Heffter Research Institute in Santa Fe, which was founded in 1993 by academics and mental health professionals to finance scholarly research, and MAPS (Multidisciplinary Association for Psychedelic Studies), which has dispensed more than $10 million since it was launched in 1986 by Rick Doblin, a drug reform activist in Boston with a Harvard University Ph.D. in public policy.

But it is not just social taboos that have scared off government funders and pharmaceutical companies. Critics worry that this research will legitimize reckless recreational use, especially among impressionable young adults. “That danger needs to be considered before we open a Pandora’s box,” says Glen Hanson, a pharmacologist at the University of Utah in Salt Lake City and former acting director of the National Institute on Drug Abuse. “So much emotion is tied up with this research that it often gets in the way of critically analyzing the risks.”

Still, mainstream psychiatrists like Herbert Kleber, director of the Division on Substance Abuse at the New York State Psychiatric Institute and the Columbia University College of Physicians and Surgeons in New York City, hope these experiments will chip away at institutional resistance. “They have therapeutic potential for crippling mental maladies, especially for OCD, PTSD, and drug and alcohol addictions, which have such a high relapse rate,” says Kleber, a former deputy director for the Office of National Drug Control Policy at the White House. “These are not easy drugs to work with, and some of the side effects are unpredictable. But they are all absolutely worthy of research.”

With his salty beard, wire-frame glasses, khaki pants, tie, and sport jacket, Charles Grob, a 57-year-old professor of psychiatry, doesn’t look anything like a wild-eyed rebel of the ’60s. He squeezes in psychedelic research on weekends because his workdays are filled overseeing a large clinical program that handles 400 to 500 patients a year and supervising the child psychiatry fellows, residents, interns, psychology postdocs, and social workers in training who rotate through his department at UCLA.

Grob’s fascination with the medicinal powers of hallucinogens began in 1972, when he was babysitting dream-research experiments at Maimonides Medical Center in Brooklyn, where his father, David Grob, was chief of medicine. Having dropped out of college and with little to do but read, he dug into the library of his psychologist boss, Stanley Krippner, and was astonished to learn that after World War II scientists were achieving what seemed like miracle cures by treating once-intractable mental ills with psychedelics such as LSD. “They were at the cutting edge of psychiatric research,” Grob says.

While peyote and other plant hallucinogens had been used in shamanistic rites for centuries, the modern era of hallucinogenic research began in April 1943. At Sandoz Laboratories in Basel, Switzerland, chemist Albert Hofmann accidentally dosed himself with LSD, a rye ergot fungus he had been working with, and suddenly saw the world through kaleidoscope eyes.

That first acid trip sparked an explosion in experimentation by psychiatrists, intellectuals, artists, spiritual seekers, and even Nobel Prize–winning scientists including physicist Richard Feynman and Francis Crick, who reportedly admitted before he died in 2004 that he had visualized the double-helix structure of DNA while under the influence of LSD. In the heady postwar years, hundreds of promising studies were conducted in the United States, Canada, and Europe on the use of LSD and other psychedelics, like peyote, to treat such psychiatric maladies as schizophrenia, autism, drug addiction, alcoholism, and chronic depression. “People don’t realize today how valuable these studies were and how enthusiastic the reception was within psychiatry, which was then locked in a rigid Freudian orthodoxy,” Grob says. “Investigators were getting very rapid, positive, and transformative changes in patients.”

By the early 1960s more than 1,000 studies on LSD and other hallucinogens discussing the experiences of 40,000 patients had been published in reputable medical journals. “It was a medicine of remarkable power,” Stanislav Grof says. The Czech-born psychiatrist conducted dozens of government-sanctioned LSD experiments in the ’50s, ’60s, and early ’70s on heroin addicts, alcoholics, and terminal cancer patients in his native Prague and later at the Maryland Psychiatric Research Center, a mental health facility in Catonsville, Maryland, where he was chief of psychiatric research.

“The results were quite impressive, particularly in some of those categories that are very resistant to treatment, such as heroin addiction,” recalls Grof, who is now 76. “It could also frequently relieve pain, even pain that didn’t respond to narcotics. I found the studies with cancer patients to be the most moving, to see how their attitudes toward death changed.”

During the 1950s and early ’60s, research in Canada by psychiatrists Abram Hoffer and Humphry Osmond using mescaline and LSD on patients with severe alcohol addictions became the stuff of legend. “Alcoholics Anonymous believed many alcoholics don’t do well until they become deeply motivated by ‘hitting bottom,’” says Hoffer, who at 90 still sees patients. “We thought we could use a whip to frighten alcoholics and drive them away from a desire to drink by giving them a bad trip. After giving it to five patients, we realized that instead of hitting bottom, they were having a beneficial, pleasurable experience. It opened their minds, they developed some insights, and they began to see things they never had seen before,” which made them more receptive to psychotherapy.

This prompted Osmond to coin the term psychedelic (from the Greek, meaning “mind manifesting”) to describe the drugs’ capacity for mental enrichment. When combined with talk therapy, just one or two daylong LSD sessions blunted the desire to drink, even in alcoholics written off as hopeless. Psychedelics became part of treatment in Saskatchewan’s five treatment centers and were administered in 100- to 800-microgram doses—many times the strength of a street dose and potent enough to conjure up visions. In follow-ups two and three years later, researchers found that more than half the patients—and, in some instances, up to 90 percent—remained sober, according to Erika Dyck, a medical historian at the University of Alberta in Edmonton and author of an upcoming book on psychedelic psychiatry. Many patients said the sessions saved their lives.

But these potent potions soon became a symbol of the dark side of the ’60s counterculture. Unhinged people on bad acid trips who had taken bootleg or adulterated street drugs began showing up in emergency rooms in the throes of severe panic attacks or psychotic breakdowns. Psychedelics, and LSD in particular, were held responsible for suicides, permanent brain damage, and cult thrill killings. In response to the hysteria, Sandoz stopped supplying researchers with LSD in 1965; a year later the drug was outlawed in the United States, and by 1972 legitimate scientific research had ground to a halt.

Lack of scientific standards in many of the early studies compounded the problem. Often the reports were based on anecdotal evidence, or the studies failed to give any participants dummy pills as a basis for comparison. Nor were the tests blinded. In a blinded test, researchers don’t know whether they are giving patients the drug being tested or fake medicine. That is an important control; other­wise, personal biases and expectations can muddy test results.

At the time, though, Charles Grob thought the setbacks were only temporary. After hearing a lecture by Grof in the 1970s about his studies with the terminally ill, he decided that pursuing this line of research was what he wanted to do with his life. “His research was inspiring,” Grob recalls. “The hospice movement hadn’t occurred yet, and these patients were often pushed off into a corner of a sterile hospital. But when I told my father, he said no one would listen to me unless I had credentials.”

Grob headed back to college, earned his medical degree in 1979, and, after completing a child psychiatry fellowship, began teaching at Johns Hopkins Hospital in 1984. “Almost overnight, the field had gone into deep hibernation,” he recalls. Still, he never gave up on the drugs’ tantalizing potential. When UCLA wooed him away from the University of California at Irvine in 1993, where he was teaching and practicing after leaving Johns Hopkins, he told his future boss about his secret passion. “I hope I’m not too crazy for you,” Grob told him.

The research climate was changing once again. In 1990 Rick Strassman, a psychiatrist at the University of New Mexico in Albu­querque, got federal clearance to do the first psychedelic studies on humans in nearly two decades. Several factors helped pry open the regulatory doors, Strassman says. The countercultural excesses were a dim memory, a new regime at the FDA was more open, the little-known psychedelic he proposed to test—DMT—didn’t have the baggage of LSD, and he was persistent. “It took two years,” Strassman says. “They never said no, so I thought until they did, I would continue working on getting approval.”

Over the next five years, he injected 65 healthy adult volunteers with DMT (dimethyltryptamine), a powerful hallucinogen derived from plants that induces a trancelike state. Many of the subjects, all of whom had taken psychedelics before, reported having out-of-body and near-death experiences and felt the sessions were among the most intense episodes of their lives.

Not long after, Grob witnessed the salutary effects of psychedelics when he was invited by a colleague to do a privately funded investigation of the emotional health of people who regularly ingested these substances as part of their religion. In the summer of 1993, he traveled to Manaus, Brazil, a major port city in the Amazon rain forest, to study members of the Centro Espirita Beneficente União do Vegetal (UDV) church. Founded in Brazil in 1961, the 8,000-member religion mixes traditional Christianity with indigenous beliefs. Central to the UDV rituals is drinking ayahuasca, a tea brewed from two plants that grow in the Amazon basin. One contains DMT; the other contains an alkaloid that prevents DMT from being degraded in the stomach. Grob did a psychiatric and neuropsychological inventory comparing 15 long-term users of ayahuasca with 15 matched controls and found the church members were physiologically and psychologically healthier. They were more cheerful, confident, relaxed, even-tempered, and orderly and scored better on memory and concentration tests—and there was no evidence of deterioration of their personalities or their mental acuity.

When Grob quizzed them about their personal lives, many UDV members described themselves as angry, impulsive reprobates hell-bent on self-destruction before they entered the church. Some had unsavory histories of violence and spousal abuse and were severely alcoholic or addicted to drugs. “I was amazed because these were responsible, high-functioning pillars of the community,” Grob recalls. “They all unequivocally credited ayahuasca, when taken in the controlled setting of the church, as the catalyst for their evolution into upstanding citizens.”

Emboldened by Strassman’s success, Grob applied to the FDA for permission to test MDMA on dying cancer patients. The agency insisted that safety studies be completed first on 18 healthy volunteers to ensure that the drug didn’t trigger damaging side effects. In 1994 he administered the first dose of MDMA to a test subject. But after completing the pilot study, he abandoned the drug in favor of the less controversial psilocybin. After Grob made the switch, the FDA gave him the go-ahead, and he recruited his first terminal cancer patient in 2004.

But the real turning point was a 2006 Johns Hopkins study using psilocybin in 36 healthy adults who were spiritually inclined but had never done psychedelics. They all received both psilocybin and an amphetamine-like compound (Ritalin), which has some psychoactive effects, such as increasing heart rate and increasing concentration. Some received psilocybin first; others received Ritalin first. In follow-up interviews two months later, four out of five said that the psilocybin experience had improved their well-being and satisfaction with life, about 70 percent rated the experience as among the most spiritually significant events of their lives, and nearly 70 percent called it one of the most personally meaningful events, comparable to the birth of a first child or the death of a parent. These beneficial effects persisted more than a year, when the volunteers were interviewed again.

“Many of these people had a genuine mystical experience, which was transformative in a profound way,” says Roland Griffiths, a behavioral psychopharmacologist at the Johns Hopkins University School of Medicine and the study’s lead investigator. Especially significant was the experiment’s rigorous design, which proved that this type of research can be safely done under scientifically standardized conditions. Perhaps even more important, Herbert Kleber says, is that Griffiths is new to the field and “not a true believer.”

What are the drugs doing to create such powerful effects? At the chemical level, psilocybin, LSD, and DMT—which are classified as tryptamines—are structurally similar to serotonin, a powerful chemical messenger that expedites the transmission of nerve signals in the brain. Tryptamines work by mimicking the action of serotonin, which is responsible for controlling an array of functions, including mood, sexual desires, sleep cycles, memory, and appetite. MDMA is a phenethylamine; it taps into the neuronal reservoirs of the key brain chemicals serotonin, dopamine, and norepinephrine (adrenaline), boosting their levels in the brain. Mescaline, although it is classified as a phenethylamine, works more like LSD or DMT.

While no one knows why psychedelics exert powerful positive effects or why they transform perceptions, progress in brain imaging has allowed researchers to discover where these drugs act in the brain. Extensive animal studies and PET scans on humans reveal that tryptamines such as psilocybin stimulate an array of brain structures: the prefrontal cortex, which is the center of executive functioning; limbic regions such as the amygdala that govern our emotional life and the formation of memories; the striatum, which plays a role in cognitive functions; and the thalamus.

Scientists suspect that one of the key areas especially affected is the thalamus, a walnut-size structure at the base of the brain that is the gateway for sensory information—taste, touch, vision, and hearing. The thalamus normally acts as a filter, winnowing out extraneous sensory information before relaying data to the cerebral cortex, the seat of memory, attention, language, and consciousness. Under psychedelics, the sensory overload may overwhelm the thalamus, leading to delusions, hallucinations, thought disturbances, feelings of persecution, and loss of coherent ego experiences.

“The cortex basically takes all the information coming in and synthesizes it into reality,” says David E. Nichols, a professor of medicinal chemistry at Purdue University in West Lafayette, Indiana, who has done animal research on hallucinogens. “When you alter that circuitry, you’re essentially changing your perception of reality.”

That’s why scientists stress the importance of taking these powerful substances in a pleasant and well-supervised environment, rather than in the uncontrolled settings of recreational drug use. Psychedelics amplify whatever is going on around you and within you, Nichols says. “Taken in haste, without proper regard for their effects and in chaotic conditions, the effects can be really awful and frightening. But with the proper preparation, in a proper setting, with the right controls, the experience can be wonderful.”

Annie Levy, a participant in Grob’s study, agrees. The 54-year-old neuropsychologist underwent her psilocybin session at UCLA last May, shortly after her ovarian cancer had come roaring back in spite of two rounds of intensive chemotherapy. Overwhelmed by dread, Levy says she was “plagued by obsessive thoughts that I would suffer horribly while going through the dying process.”

A few days before her treatment, Levy says, “I had felt somewhat anxious about participating in the study, but meeting the treatment team helped calm my fears.” And once the psychedelic took hold, her despair disappeared. She was able to come to terms with her eventual death, concentrate on all the joy in her life, and stop ruminating about all the awful things that might happen in the future. The drug’s influence endured for about six months. “I wish I could go in for another session,” Levy says, “like a booster.”

Despite such glowing testimonials, some researchers worry about the potential for serious psychic damage if these compounds are used by hundreds of therapists on thousands of patients, instead of by a small cadre of dedicated scientists testing carefully screened volunteers in tightly controlled situations. “The idea of turning [these drugs] loose makes me uncomfortable,” says University of Utah pharmacologist Glen Hanson, who is also director of the Utah Addiction Center there. “Before we make them available by prescription, there needs to be compelling evidence that they’re unique and that a large population would derive substantial benefit.”

Eventually, though, this research may lead to more precisely targeted therapeutics for the disorders psychedelics seem to help, such as OCD and other compulsive ills, like bulimia and anorexia. In animal studies, repeated dosages of psilocybin diminish the number of 2A serotonin receptors, which dampens their expression. This is a process known as downregulation.

“We suspect that physiologically, this is what happened in the OCD study—that psilocybin downregulates the activity of these receptors,” says Franz X. Vollenweider, a psychiatrist and neuroscientist at the Psychiatric University Hospital in Zurich, Switzerland, who conducted many of the imaging studies and has done psychedelic research for more than a decade. “We’ve done a lot of basic research,” he adds. “Now we want to use the tools we’ve developed to see what is going on in real patients. If we could convincingly demonstrate hallucinogens alter these receptors, then we can find other compounds that have similar mechanisms but are less frightening.”

Will these studies finally open the door to acceptance? David Nichols says psychedelics researchers keep a low profile “because everyone lives in fear that some administrator will kill their project.” Roland Griffiths of Johns Hopkins, for example, who has been doing pharmacological research for more than three decades, never had a project scrutinized as thoroughly by his institution’s review board and the FDA as his 2006 psilocybin study was. Throughout the study he worried that negative publicity might halt the research.

Charles Grob is more hopeful. “Sure, it’s been Sisyphean because of the cultural stigmas, and it has taken years to go even little baby steps,” he says. “But people are making dramatic progress working with the hardest cases. We’re on the threshold of opening up an exciting new field.”