“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.”
