Vigorous research into psychedelic drugs, which began more than a half-century ago, effectively came to a halt in 1970 when Richard Nixon signed the Controlled Substances Act, outlawing the most common hallucinogens. But improvements in brain imaging, combined with a better understanding of neurochemistry, are helping psychedelics regaintheir status as promising therapeutic agents for curbing addiction, anxiety, depression, OCD, and other ills.
“These were considered drugs of abuse, and were not attractive for researchers,” said David Nichols, a professor of pharmacology at Purdue University who synthesized psilocybin, MDMA, and other psychedelics for researchers when the drugs were difficult to obtain and co-founded the Heffter Institute, which supports psychedelic research. “Now I would say that in 10 years there might be a host of treatments that employ psilocybin or related substances for anxiety, depression, and addiction.”
Hallucinogens stimulate serotonin 5-HT2A receptors, plentiful in the cortex at the surface of the brain and elsewhere, say Swiss researchers Franz X. Vollenweider and Michael Kometer. In a paper published in Nature Reviews Neuroscience in September 2010, they suggest that this stimulation promotes a complex interaction between serotonin and glutamate, which boosts activity in neurons in the prefrontal cortex (PFC), the part of the brain vital to analysis, planning, and other uniquely human functions. This produces downstream effects that increase serotonin and dopamine, a neurotransmitter active in the brain’s pleasure circuits, and also appear to promote synapse formation in the PFC and other brain regions.
Psychedelics also appear to act on the complicated circuitry targeted by antidepressants. Atypical antipsychotics, used to reduce the hallucinations and thought disorders of schizophrenia, also block 5-HT2A receptors. Based on their findings, the authors suggest that "psychedelics might be useful in the treatment of major depression, anxiety disorders, and OCD.”
But unlike antidepressants and antipsychotics, psychedelics don’t seem to produce passive alterations in brain chemistry. Rather, they seem to produce relief by altering thoughts and emotions, which in turn lead to profound and long-lasting shifts in perspective. Roland Griffiths, in a 2008 paper in the Journal of Psychopharmacology, found that 58 percent of people who took psilocybin under his guidance reported “mystical-type” experiences that they considered to be “among the five most personally meaningful” of their lives. And those changes persisted during many months of follow-up.
More recently UCLA psychiatrist Charles Grob found that psilocybin triggered thoughts that helped curb “the psychological, spiritual and existential crises” of 12 people who had terminal cancer. In a paper in the January 2011 issue of the Archives of General Psychiatry, he and his colleagues point out that similar research conducted from the late 1950s to the early 1970s found that critically ill cancer patients who took psilocybin experienced “psychospiritual epiphanies” and often achieved “sustained improvement in mood and anxiety as well as diminished need for narcotic pain medication.”
“One woman in our study said, ‘I’ve been so preoccupied with my illness and the limited amount of time I have left that I neglected to appreciate the beauty of each and every day,’” Grob said. “We’re talking about a drug that seems to shift an individual’s level of awareness and perspective. Patients who take it seem to become more grounded and better able to withstand stressors.”
How does psilocybin alter cognition and emotion?
Psilocybin is rapidly metabolized to psilocin, which acts on serotonin receptors 1A, 2A, and 2C, say Grob and his colleagues. In their paper they point out that psilocybin “produces a global increase in the cerebral metabolic rate of glucose, most markedly in the frontomedial and frontolateral cortex, anterior cingulate, and temporomedial cortex.” Those brain areas contribute to self-awareness and the processing of emotions.
Other psychedelics also appear to produce powerful therapeutic effects. Ketamine, an anesthetic and a recreational drug known as Special K, has been shown to rapidly reduce the risk of suicide in profoundly depressed people. This raises hopes that ketamine might be able to stave off suicidal impulses while conventional antidepressants, which need two to three weeks to improve mood, take effect, said Ron Duman of the Yale University School of Medicine.
“Ketamine has shown some incredible effects in treatment-resistant depressed patients,” he said. “Multiple clinical studies show that a low dose of ketamine produces a rapid anti-depressive effect within a couple of hours, with effects sustained up to seven days. Ketamine can rapidly treat suicidality.”
Ketamine appears to work by blocking glutamate NMDA receptors, ultimately promoting the release of glutamate. In a recent paper in Science, Duman and colleagues showed that a protein kinase pathway known as mammalian target of rapamycin, or mTOR, is rapidly activated by ketamine, which may reduce depression and anxiety by promoting the swift creation of new synapses in the medial prefrontal cortex, a brain region implicated in depression.
“I think the ketamine story is extremely exciting and has a lot of potential,” Duman said.
MDMA, better known as ecstasy, a recreational drug that can produce powerful feelings of intimacy and a decline in anxiety, appears to help people who have post-traumatic stress disorder, said Michael C. Mithoefer, a psychotherapist in South Carolina.
Mithoefer gave MDMA to 20 people with PTSD, and found that the drug gave them a window of 4–6 hours during which they could relive painful memories without becoming overwhelmed by them.
“The processing of trauma has to occur within a window of tolerance in terms of arousal,” he said. “People with PTSD often have either over-arousal when revisit trauma, or under-arousal, or under-engagement. They can report trauma but don’t connect emotionally with it. In either case, therapy doesn’t seem to be effective.”
In a paper published July 2010 in the Journal of Psychopharmacology, Mithoefer and his colleagues reported that 10 patients improved so much that their symptoms no long qualified as PTSD.
“They can process the trauma in a way they haven’t been able to before,” he said. “No one hallucinated, but they described seeing their trauma contained in spheres floating by so they could look at it without being overwhelmed, or they described going down a ladder into difficult feelings, then coming up a few steps when they needed to, and then going back down.”
Mithoefer thinks that MDMA helps by quelling increased activity in the fear circuitry of people with PTSD. “There are studies of MDMA in normal volunteers that show decreased activity in the left amygdala and increased activity in prefrontal cortex,” he said. “That would kind of fit with what we’re seeing.”
Still, FDA approval of MDMA is a long way off, Mithoefer said. When—and if—it were approved, people would not receive a prescription for the drug.
“Our thought is that it would be licensed to clinics,” Mithoefer said. “With all of these drugs, the setting makes a big difference. If you have proper support, and you’re prepared to be as present as you can with what comes up, something that might have been frightening or harmful in another situation could become therapeutic.”