After more than 30 years in which psychedelics were considered dangerous remnants of the 1960s, the drugs have begun to make a comeback, this time as potential remedies for a host of tough-to-treat maladies. Pilot studies and clinical trials of LSD, psilocybin, ketamine and MDMA have shown that the drugs, often in combination with talk therapy, can be given safely under medical supervision and might help people dealing with opiate and tobacco addiction, alcoholism, anxiety, depression and post-traumatic stress disorder, or PTSD.

After more than 30 years in which psychedelics were considered dangerous remnants of the 1960s, the drugs have begun to make a comeback, this time as potential remedies for a host of tough-to-treat maladies.

Pilot studies and clinical trials of LSD, psilocybin, ketamine and MDMA have shown that the drugs, often in combination with talk therapy, can be given safely under medical supervision and might help people dealing with opiate and tobacco addiction, alcoholism, anxiety, depression and post-traumatic stress disorder, or PTSD.

That these investigations have shown potential is not surprising to many researchers. A generation of scientists and practitioners had used psychedelics successfully with thousands of patients until the research was banned in 1970, after the drugs were embraced by an exploding counterculture that seemed to threaten the status quo.

In the panicked reaction, psychedelics were listed along with heroin in the highest rungs of prohibition. Ironically, this failed to stop recreational use, but it shut down the science. As one researcher put it, �It was as if psychedelic drugs had become undiscovered.�

But a small cadre of psychiatrists and researchers, often risking careers and reputations, pushed to bring psychedelics back to the lab and the clinic. Their persistence paid off. Beginning in the 1990s, the Food and Drug Administration approved the first human clinical studies of psychedelic drugs in a quarter of a century.

By 2004, the first FDA-

approved trial of the medicinal use of a psychedelic drug, in this case a trial of MDMA-assisted therapy for PTSD involving 24 subjects, was underway. Now, such studies are proliferating.

�For more than 30 years, I have been working to make FDA approval of psychedelic psychotherapy more than a dream,� said Rick Doblin, founder and director of the nonprofit Multidisciplinary Association for Psychedelic Studies. �Now that castle in the air has a foundation underneath it and is becoming an impending reality.�

The modern investigation of psychedelics began with the accidental discovery of the consciousness-altering properties of lysergic acid diethylamide (LSD was its German acronym) by Albert Hofmann, a chemist for a Swiss pharmaceutical firm.

Hofmann had been looking for a compound that might stimulate circulation and respiration when he combined derivatives of rye fungus and ammonia. Initial animal testing turned up nothing of note except a strange restiveness in the animals.

But for reasons Hofmann could explain only as an �odd presentiment,� he resynthesized the compound five years later, in 1943, accidentally exposing himself to it and going on history�s first LSD trip.

�In a dreamlike state, with eyes closed,� Hofmann wrote, �I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.�

He correctly understood that such a dramatic alteration of consciousness by a chemical would be of great interest to the young science of psychiatry.

By the mid-1950s, researchers had experimented with administering LSD and natural psychedelics such as mescaline (from the Mesoamerican peyote cactus) to facilitate talk therapy for a wide variety of psychic ailments. Trials involving hundreds of patients and thousands of doses of psychedelics were conducted in Europe, Canada and the United States, and most investigators reported positive and in some cases almost

miraculous results.

In 1954, psychiatrists at an English hospital set aside an entire ward for conducting LSD therapy with patients who had severe, chronic, treatment-resistant mental illness. They concluded that 61 of 94 patients improved or even completely recovered after six months.

In 1960, a physician named Sydney Cohen surveyed the findings of 44 physicians who had administered 25,000 doses of LSD or mescaline to 5,000 people under widely varying conditions. Cohen found �no instance of serious or prolonged physical side effects� or any evidence of addictive potential either in those trials or in the wider literature on psychedelic drug studies.

He did find adverse psychological reactions � including acute anxiety and psychotic breaks � but determined that they were rare and mostly related to pre-existing mental illnesses.

�Considering the enormous scope of the psychic responses it induces,� Cohen concluded, �LSD is an astonishingly safe drug.�

In 2012, researchers at Imperial College London published results of a study in which they injected volunteers with psilocybin and then observed their brains via functional magnetic resonance imaging, or fMRI. Given the psychedelic experience�s well-known assault on the senses � flashing visual patterns, intense colors, enhanced sounds, overwhelming visions and emotions � the researchers expected to see increased brain activity, which some earlier scans had found.

Instead, their screens registered decreased activity, which seemed like a mistake until it was confirmed by another fMRI scan and correlated with the participants� reports: The larger the decrease in brain activity, the more intense the psychedelic experience.

The decreased activity was not uniform throughout the brain. Task-oriented areas of the brain, such as those associated with seeing and moving, had only nominal decreases. But areas of greater complexity � those associated with self-

image, introspection and imagining past or future events � showed large decreases in activity.

This linked nicely with the reports of the subjects, who did not have significant motor impairment but talked about experiencing a loss of ego, an increased sense that objects had unusual significance and dramatic alterations in their experience of time.

The researchers noted two intriguing connections with other studies: A brain on psilocybin bore a striking resemblance to the brain of an experienced meditator during deep meditation. And the areas of the brain with decreased activity caused by psilocybin were the same regions that showed chronically increased activity in people with clinical depression.

�Regions which are reliably overactive in depression are deactivated by psilocybin,� said Robin Carhart-Harris, lead researcher in the Imperial College study.

In 2004, Michael Mithoefer, a psychiatrist in Charleston, S.C., was the first to win FDA approval for clinical studies using MDMA � known informally as ecstasy � to treat PTSD.

In the treatment manual he created, Mithoefer urges therapists not to attempt to direct the session, but to concentrate on creating an atmosphere of safety, openness and trust in the patient�s own �inner healing intelligence,� which �the medicine� � the MDMA � somehow activated.

Torsten Passie, a German researcher who is a visiting professor of psychiatry at Harvard, has developed an intriguing link between recent neurobiological research and Mithoefer�s idea that MDMA enables the mind to move naturally toward healing.

Under normal circumstances, research has shown, sights, sounds, scents and sensations from our sensory organs enter a region at the center of the brain called the thalamus. The thalamus distributes that data to the more sophisticated brain regions involved with conscious thought. The processed material � sorted for context and assessed for significance � is returned to the thalamus, which then deposits it into the hippocampus, where it is stored as memory.

In cases of a severely traumatic experience such as rape or combat, the higher brain�s ability to process is overwhelmed, according to Passie, and a more primitive method for storing memory takes over.

The sensory memory of the trauma � which is still entangled with the emotion associated with that moment � passes through the thalamus and is stored directly in the hippocampus without processing in the more sophisticated parts of the brain.

These raw memories, still tied to the fear response they provoked, are a constant threat to bolt into awareness as flashbacks, nightmares, hypervigilance or rage, which can trigger the fight-or-flight reflex centered in the amygdala. The amygdala, Passie said, acts as a guard, attempting to suppress the unprocessed traumatic memory and keep it from barging into consciousness. It�s not a healthy arrangement.

The constant tension of having the nasty secret hidden in the brain�s basement poisons the psyche, which flails around in pain, creating PTSD�s self-destructive symptoms.

Brain-scan studies support the idea that the repressive amygdala is overactive in people with PTSD, while the rationalizing power of the higher brain is suppressed. Studies also show that the opposite is true for someone given MDMA; the drug stimulates the prefrontal cortex and suppresses the amygdala.

Passie theorizes that as the amygdala lets down its guard under the drug�s quieting influence, the traumatic memories can re-emerge from the hippocampus to be sent up for the higher processing that the brain didn�t do in the immediacy of the trauma. The reprocessing is assisted by the tide of hormones MDMA causes to be released: cortisol, which is associated with emotional learning, and oxytocin and prolactin.

These hormones also are released in similarly large quantities immediately preceding and following orgasm � an event known to engender powerful feelings of intense emotion, security, closeness and well-being � exactly the mental states known to promote breakthroughs in psychotherapy. Now, at last, the conditions exist in the brain that allow traumatic memories to be properly contextualized and integrated into the personality in a healthy way.