Warning: These drugs may improve your health

Originally appeared at: http://www.yaledailynews.com/news/2010/oct/08/warning-these-drugs-may-improve-your-health/ If Yale undergrads have heard anything about the Veterans Affairs Healthcare System in West Haven, it probably has to do with drugs. E-mails with subject headings like “Get Crunk, Get Paid” promise $1200 for six days of smoking Salvia out of Yale-bought vaporizers. Another experiment offers payment in exchange for volunteering to be injected with IVs filled with drugs designed to mimic the mental state of schizophrenia. But since the late 1980s, the Yale School of Medicine’s partnership with the hospital has resulted in findings pivotal toward understanding diseases like post-traumatic stress disorder (PTSD) and depression — in some cases, incorporating controlled substances like ketamine and THC into research and treatment. Just a Yale shuttle ride away, the scientists who have devoted their careers to these drugs have had to fight through professional dismissal and clinical frustration with the hope of one day seeing these compounds in the hands of therapists. “A MAGIC DRUG” Dr. Sandra Alfano, chair of Yale’s institutional review board (IRB), is acutely aware of some students’ motivation for participating when she approves research studies. She regularly worries about an “article in the Yale Daily News […] with some headline that students can get free highs,” and is intimately involved in vetting the ethics of Yale studies involving human subjects. “These are not recreational studies by any means,” she said. “The researchers are passionate about trying to find ways to help people with some of these socially stigmatizing diseases.” While Alfano acknowledges that some IRBs may be hindered by political constraints or publicity issues, she says Yale has a different outlook: “If we have robust science with adequate protection, and adequate information [is given] the subjects to allow them to make their own decisions, then we are not going to stand in the way of sound ethical research.” Yale researchers should know a thing or two about unethical studies. The infamous 1961 Milgram Experiments — conducted in the basement of Linsly-Chittenden Hall — was one of the primary catalysts for the introduction of mandatory IRBs in 1974. In 1929, when the United States Department of Veterans Affairs decided to create a hospital in New England, Yale and New Haven emphasized the need for an Elm City location. As the New Haven Journal Courier wrote in an editorial in July of that year: “What no other site in New England can offer, is New Haven’s proximity to the well-nigh infinite resources of the Yale University-New Haven hospital plant. Nothing like this combination exists in America.” These “well-nigh infinite resources” were not fully put to use for another 50 years, when Yale’s Department of Psychiatry restructured services at the VA to put more of a focus on experimental research. Dr. Dennis Charney, the current Dean of Mt. Sinai School of Medicine, was a Yale professor working at the school of medicine in 1988 when he was chosen to lead the hospital’s psychiatric service. “We needed to understand PTSD,” Charney said. “What causes it, how you treat it. It was a big need in the VA system, and still is.” To combat the problem, Charney brought together leading minds in the Yale Department of Psychiatry. For Yale psychiatrists, who could now apply for VA-specific grants, the hospital quickly became fertile ground for ambitious experimentation. “Unlike the common view of what VA hospitals are like — that they give pretty good care but aren’t very academic — our VA hospital [turned into] a major research and teaching institution, probably one of the very top in the country,” Dr. John Krystal, a member of Charney’s team, explained. In 1988, the same year that Charney’s overhaul began, Krystal came across a novel use of ketamine while looking for a “game-changing” treatment for schizophrenia. He discovered that the drug, used clinically as children’s anesthetic and horse tranquilizer but recreationally for its hallucinogenic and dissociative properties, also had a dramatic effect on patients suffering from depression. “Conventional antidepressant drugs tend to take three to eight weeks to work, when they work,” Krystal explained. His 2000 study targeted the 30 percent of patients with depression who do not respond to conventional forms of therapy — those who “failed multiple treatments and were really at their wit’s end.” Some of these patients had been depressed for decades. In a few hours, subjects “started to say things like, ‘Gosh, you know, I feel a lot better,’ or, ‘My depression is lifting,’” Krystal said. “The idea of someone getting better over 24 hours is one of the most dramatic things I’ve seen in my career.” According to Yale professor and fellow ketamine researcher Dr. Ronald Duman, Krystal’s discovery was nothing short of “a paradigm shift.” “It’s like a magic drug,” Duman said. This summer, Duman published a study explaining ketamine’s mysterious effects for the first time. Unlike other anti-depressants or electroconvulsive therapy, it stimulates an enzyme which stimulates the creation of connections between neurons — connections which are weakened in people with depression. But since these dramatic results have only lasted for at most a few weeks (at which point the depression returns), the drug has not been approved for clinical use. Krystal said doctors were scared of an “Awakenings”-style relapse, a reference to the 1990 film starring Robert De Niro in which catatonic patients experience freedom of movement for a limited time before reverting back to a vegetative state. “It could be very upsetting for some people to experience a [temporary] remission of a depression they’ve had for 10 years,” Krystal said. Yale researchers at the VA continue to study ketamine with the hope of extending its effectiveness as an antidepressant. One such study to which volunteers can currently apply aims “to determine if ketamine anesthesia can reduce the adverse cognitive effects and pain associated with electroconvulsive therapy, while increasing the antidepressant effect of the treatment.” THE AGONY AND THE ECSTASY 1988 also marks the year that Yale began to study the potential consequences of ecstasy usage. Dr. Rick Doblin, founder of the Multidisciplinary Association for Psychedelic Studies (M.A.P.S.), an organization that promotes research with the ultimate goal of precipitating a “psychedelic renaissance,” prefers to use more scientific language. Rather than “ecstasy,” he refers to the drug as “MDMA” — short for 3,4-methylenedioxymethamphetamine. He hopes that one day it will be viewed the same way as any other drug which has both recreational and medical applications. “Methamphetamine is a drug for A.D.D., cocaine a drug for anesthesia,” he explained. Doblin first came across mescaline and LSD in the early 1970s while a freshman in college. He didn’t last the first trimester, and spent the next ten years reading and tripping before pursuing higher education for a second time. Upon graduating from college, Doblin founded MAPS, which in 1988 helped fund one of Krystal’s studies to explore the aftereffects of long-term MDMA use (the VA was not involved). “The bottom line,” Krystal said, is that aside from mild memory impairment, “we really didn’t find that much.” A study he published in 1992, however, was not as generous. According to the abstract of the study, the results “raise concern about possible detrimental effects of MDMA use on neuropsychological function.” K
rystal’s findings were an unwelcome surprise to Doblin, whose organization partially funded the research. “I felt that [his reaction] was part of the general demonization of MDMA,” Doblin, who thinks he’ll continue to use psychedelics throughout his life, said of the findings. He claimed that Krystal later told him that he had slightly exaggerated the harmful effects of MDMA in order to get the paper published. Krystal thinks that Doblin misinterpreted his comments, and that his negative reaction to the paper was an outgrowth of the crippling effect the paper had on subsequent approval of MDMA studies. Despite this earlier setback, Doblin recently completed a new study — funded in part by Harvard Medical School and the federal government — that examines the long-term effects of MDMA use. It has been accepted for publication. “The results are very reassuring,” he said. “It’s yet another ratcheting down of the hysteria.” Doblin explained why previous attempts to treat PTSD have been largely ineffective. “For things that are exceedingly traumatic, oftentimes they are just imprinted on the deep brain system and not really processed,” he said. “It’s just too scary. And then it sort of lingers, it comes back in nightmares and they can never quite get past it.” Doblin believes that MDMA gives people suffering from PTSD an alternative way to address their scarred pasts. “You feel the fear, but don’t get overtaken by it. MDMA helps people to differentiate ‘you’ from ‘the past’ in ‘the present,’ as it focuses you on the present.” He cited one example of a suicidal date rape survivor who was able to use MDMA to start trusting people again. “Under the influence of MDMA, she was able to start thinking [about how she got] tricked by this guy. He liked animals, and that was a symbol to her that he could be trusted. ‘Likes animals’ is not the same as ‘can be trusted,’ — now can she differentiate.” The idea of using MDMA to treat psychological illness isn’t a new one. In the 1950s and 1960s, psychologists across the country legally administered MDMA as part of therapy regiments. The drug causes a massive level of serotonin, a neurotransmitter, to be released in the brain, leading to a state of euphoria with a sufficient dosage. This past summer, the Journal of Psychopharmacology published a MAPS-sponsored study exploring the effectiveness of PTSD therapy involving the use of MDMA. Eighty-three percent of people in the treatment group experienced a response, versus twenty five percent in the placebo group. The abstract stated, “There were no drug-related serious adverse events.” Yet the dramatic results of Doblin’s studies have not convinced the Veterans Health Administration, which spends around $5.5 billion annually for disability payments to 275,000 veterans with PTSD. Current treatment alternatives are certainly lacking. “We only have two approved medications for PTSD, and they’re both very similar,” Krystal said. (Krystal is also the Director of Clinical Neurosciences for the VA’s national PTSD center.) “And in this context, you can understand why [MAPS] would get together to at least try [MDMA therapy] out,” Krystal added. For the time being, Doblin remains disappointed with the VA’s close-minded policies toward these types of experiments. Recently, he attempted to tap into a $45 million grant program for PTSD research in Denver, but the local VA refused to accept the application. Similarly, MAPS is currently funding an MDMA-PTSD study in Charleston, SC, but the VA has not been cooperative in referring potential subjects. Despite the promising findings up to this point, Krystal maintains that this is still a risky field. “I’m not the only psychiatrist to have treated the psychiatric casualties of MDMA abuse,” he explained. Doblin retains hope for his “psychedelic renaissance.” He cited the results of a recently completed study at Harvard investigating long-term consequences of MDMA as indicative of a change in the winds. “Even at the place where people think things went off track,” he said in reference to Timothy Leary’s experiments with psychedelics, “they’re giving it another try.” He is optimistic regarding MAPS-sponsored studies around the globe. “if we can get permission in Amman, Jordan do to MDMA research in Arabic,” he said, “that’s telling you something.” The VA has not publicly expressed any interest in funding MDMA treatment studies, and the fact that grants given to research projects dealing with controlled substances like ketamine and ecstasy come almost solely from private sources continues to stymie the efforts of advocates like Doblin. He hopes that one day MDMA will be prescribed with the same social and professional acceptance as Prozac. But for now, the recognition of the impact of substances he sees as the bellwether of a new age in medicine has not breached the walls of a hospital in West Haven. An in-depth article examining the history of psychedelic research conducted at Yale and several aspects of the recent research done on ketamine for the treatment of depression. It also explores the history of MDMA research for the treatment of PTSD and incudes several quotes from MAPS founder Rick Doblin.