American radical and psychedelic drug pioneer Timothy Leary once said, “I am 100 percent in favor of the intelligent use of drugs and 1,000 percent against the thoughtless use of them, whether caffeine or LSD.” A similar sentiment might have been in the mind of Yale junior George Aki Nikolaidis when he volunteered to take small doses of the hallucinogen ketamine last July as part of a controlled experiment run by the Yale School of Medicine.
“I started it mainly because I was curious in the research. Research in drugs I had a serious interest in,” says Nikolaidis. “It appealed to me that I could experience a hard drug in a really safe, controlled setting.”
The study, which took place at the neurology department of the West Haven VA Medical Center in West Haven, Connecticut and was conducted by Yale professors, is part of an ongoing project to use ketamine to revolutionize the treatment of schizophrenia.
“In the late 1980s and to this day,” says John Krystal, lead investigator on the experiment, Robert L. McNeil, Jr. Professor of Clinical Pharmacology, and deputy chairman for research for the Department of Psychiatry, “our group of investigators at Yale studying schizophrenia were among the first groups in Connecticut and, in some cases, the world, to prescribe new medication treatments that were introduced for schizophrenia.”
Over a period of two weeks, Nikolaidis made four trips to the West Haven VA facility to participate in the double-blind study. With electrodes on his head, an IV in his left arm to draw blood, and another in his right arm to administer a combination of saline solution, ketamine, and nicotine, Yale researchers recorded his brain waves using an electroencephalogram (EEG) test and monitored his vital signs. Twice he was given a placebo; twice he was given an injection of ketamine, once by itself and once in combination with nicotine.
“Words couldn’t describe what happened,” Nikolaidis says. “I thought that when it was over I would be able to describe it to people, but I found myself completely unable to describe my experience. It was much more on a tactile level than cerebral—I just mean cerebral in the sense of being rational.”
His difficulty explaining the experience is not unusual: ketamine, originally invented by pharmacist Calvin Stevens in 1962 as an anesthetic, has strong dissociative properties, affecting both the hippocampus (a region of the brain associated with memory) and the prefrontal cortex (associated with abstract thought). While it has a number of medical uses, ketamine has been known to induce near-death experiences, cognitive distortion, hallucinations, and the so-called “K-Hole,” a state of drug-induced paralysis. “It was definitely interesting,” says Nikolaidis.
By tripping on ketamine, Nikolaidis may have participated in some of the most important psychopharmacological research in decades. These tests, conducted by the Yale School of Medicine on otherwise healthy subjects, may be the key to revolutionary new treatments for illnesses ranging from clinical depression to schizophrenia. One student’s K-Hole may be several million’s door to a life of relative normalcy.
Yale’s ketamine research dates back to the late 1980s and has been innovative in a number of ways. When used to treat mental disorders such as schizophrenia, ketamine targets the N-methyl-D-aspartate (NMDA) glutamate receptor, a chemical receptor in the brain associated with the coordination of different neural networks. Krystal explains that all of the treatments that are approved currently by the Federal Food and Drug Administration for the treatment of schizophrenia work through blockading one type of receptor target in the brain for the chemical messenger dopamine. He says he and his colleagues and were “convinced that advances in the treatment of schizophrenia were not going to come from drugs primarily targeting the dopamine-2 receptor.”
Building off a body of earlier work on schizophrenia, including the use of phencylidine, another drug which affects NMDA receptors, and preliminary work by Yale researchers on novel drug treatments in the late 1980s, Krystal and his colleagues have used ketamine to simulate some symptoms of schizophrenia in healthy patients like Nikolaidis. Post-mortem analyses of brain tissue have indicated that glutamine receptors—the same receptors ketamine affects, causing its users to get, as Nikolaidis puts it, “really fucked up”—are naturally abnormal in schizophrenic patients. A paper Krystal and several colleagues published in 2003 posed the question: If ketamine can be used to induce the symptoms of non-paranoid schizophrenia in healthy patients, might it be possible to develop an ‘anti-ketamine’ to reverse those same effects in mentally ill patients? “The full range of benefits and limitations of glutamatergic treatments remains to be demonstrated,” Krystal and his colleagues concluded, “but the promise of these agents constitutes one of several hopeful new avenues for addressing the distress and disability that still often plagues those individuals suffering from schizophrenia.” Researchers hope that experiments like the one performed on Nikolaidis will shed light on these avenues.
Other scientists are also using ketamine to treat mental disorders. George Sanacora, associate professor of psychiatry and director of the Yale Depression Research Program, has been conducting his own research on the effects of ketamine on treatment-resistant depression—depression which, much like the schizophrenia Krystal is studying, does not respond to drugs that target dopamine and serotonin receptors. “I think Yale, along with the National Institute of Mental Health, is really one of the only places doing this kind of research,” Sanacora says.
Sanacora, who also ran his study out of the West Haven VA hospital and conducted it on ten clinically depressed subjects over the course of a year, reported dramatic findings. After a single administration of ketamine, seventy percent of patients reported that their symptoms improved, with one-third of patients reporting that their symptoms disappeared completely for days or even weeks. “Obviously,” says Sanacora, “it’s been an exciting turn for the field.” Though one patient had to be removed from the study because of an adverse reaction to the placebo, Sanacora claims that the study has not included any other negative reactions. Pfizer has already presented data on a drug that uses a mechanism similar to the one Yale researchers have been studying. Sanacora is optimistic that such a drug might be available on the market within the next four years. “It would be a completely novel treatment for depression,” he says.
The potential use of ketamine in prescription anti-depressants and anti-psychotics, as well as its experimental use on healthy volunteer research subjects, conflicts with the public’s perception of the drug as a dangerous, recreational psychedelic. While ketamine has been used since its inception as an anesthetic in environments ranging from veterinary offices and pediatric wards to the battlefields of Vietnam, it is more often associated with its countercultural proponents than its medical ones. Psychedelic gurus like astrologer Marcia Moore, who advocated the recreational use of ketamine in her 1978 book, Journeys into the Bright World, and D.M. Turner, author of The Essential Psychedelic Guide, remain powerful images of the pitfalls of ketamine and its place in American drug culture. Moore disappeared from her house in 1979, presumably under the influence of ketamine. Her skeleton was discovered two years later in a tree, where she had frozen to death. On New Year’s Eve of 1996, Turner drowned in his bathtub tripping on ketamine.
Ketamine is currently listed as a Schedule III narcotic by the United States Drug Enforcement Agency, along with anabolic steroids and GHB, “the date rape drug.” Known on the street as “Special K,” ketamine has become popular on the rave scene in recent years. “It is an entirely different, and a potentially dangerous situation, when somebody abuses ketamine,” says Krystal. “When abused, ketamine is often ingested in combination with other substances that impair perception or judgment, like cannabis. The compounding of intoxicant effects could have unpredictable results.”
Such stigma has deterred some would-be research subjects. Nikolaidis first learned of the trial from his friend, Spencer Gray, another Yale junior who had been scheduled to participate in the study, but dropped out before it began. “I had some issues,” says Gray, who has participated in a number of other Yale studies, including MRIs and glucose tolerance tests. Gray’s motivations, unlike his friend’s, were primarily financial. “My parents told me to get a job last year,” Gray says, “so I came up with the idea of doing experiments.” The ketamine trial, which was advertised in the Yale post office, would have been a major windfall: completing the two week trial brought with it an $875 paycheck.
Gray signed up for the experiment, went through a preliminary four-hour psychological evaluation, and consulted friends and acquaintances about it. Many urged him to reconsider. His mother finally convinced him to change his mind.
“She flipped out,” Gray recalls. “I called her and told her I was thinking about doing it. She started crying on the phone and asked me not to do it. It was Mother’s Day and her birthday, and she asked me not to do it as a gift to her.”
While he ultimately decided not to participate, Gray believes the experiment is safe. “They’re pretty careful about past history of psychosis and depression and stuff. They were pretty open about the whole procedure. I didn’t feel deceived or anything.”
“Participants are screened very carefully with regard to their psychological and physical health,” Krystal confirms. “We believe that this may be a reason that ketamine has been so safe in our studies and in the studies conducted by our colleagues around the world.” While ketamine alters judgement and perception, it can, says Krystal, “be studied safely in people who have been prepared for its effects, who are supervised by people who have experience in dealing with symptoms that it produces, and when it is administered in a setting that is safe and comfortable.”
Sanacora similarly emphasizes the relative safety of ketamine. “It’s been around for quite a while,” he says. “It can raise blood pressure, but otherwise it is pretty well-tolerated.”
Jerald Block is a Washington-based psychiatrist who has criticized some of Yale’s past human experiment policies—particularly a recent clinical trial on Zyprexa, a medication designed to treat schizophrenia that was administered to adolescents over a period of several years. He views human testing as a balancing act. “I don’t think researchers go into their studies trying to deceive people,” he says. “Rather, we can get excited by a concept, lose perspective, and may take it too far. That is the role of Institutional Review Boards—to rein people in a bit. It is a tough balance. If the IRB is too intrusive, they hold back important research and people are harmed. If they are too loose… people can also get hurt.”
Nonetheless, Block, who has not specifically investigated Yale’s ketamine experiments, sees potential in the drug. “I do not know the protocol so I cannot address it, specifically,” he says. “However, I will say that ketamine is interesting… the literature seems to indicate some rather amazing data coming out on the use of ketamine in treating depression. So, it is an important substance to study and has the potential for a breakthrough discovery.”
For others, the touted safety of such a study is not enough to convince them to participate. Michelle Castaneda, a friend of Gray’s who became concerned after she learned of his plans to participate in the experiment, called her father, a professor at New York University School of Medicine and Director of Inpatient Psychiatry at Bellevue Psychiatric Hospital in New York, to ask him his opinion on the subject.
“He did some reading on it, and said ketamine testing seemed pretty safe and pretty legitimate, but when I asked him if he would ever let me do it, he told me ‘never, ever, ever, ever, ever.’”
Nikolaidis, a psychology major who runs a lab in which he conducts non-drug-related psychology experiments on volunteers of his own, defends the testing. “I could not have imagined a more well-run study,” he says. “I think in terms of having my best interest at heart, I could not have imagined better researchers.” Nikolaidis admits that he could be exceptional in his willingness to lend his mind to science. “It might just be me,” he says, “but I’m just curious about drugs.”
