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There's a big problem with the way we study psychedelic drugs

  1. Phungushead
    After "mind-expanding" drugs like LSD and magic mushrooms were banned in the 1970s, research on their therapeutic uses basically stopped for two decades.

    Now, thanks to a few high-profile efforts, some researchers are starting to study them again. But there's a problem.

    As anthropologist and science historian Nicolas Langlitz of the New School for Social Research in New York writes in an opinion piece for Aeon Magazine, the placebo-controlled trial, the Food and Drug Administration's gold standard for evaluating drugs, doesn't take into account the cultural differences in how the drugs are administered.

    And the environment in which you take these drugs can have a big impact on your experience.

    Psychedelics as medicine

    Despite numerous studies in the 1960s suggesting potential benefits of drugs like LSD in psychiatric treatment, the Controlled Substances Act of 1970 declared that drugs like LSD, ecstasy (MDMA), psilocybin, and marijuana had no accepted medical use, and effectively banned research on them until the 1990s.

    Scientists have since studied the therapeutic use of psychedelics for the treatment of everything from cluster headaches to depression and addiction. Nevertheless, these studies have been small and researchers say it's tough to come to any definitive conclusions based solely on them.

    But two organizations are revamping some of this research, Langlitz writes.

    The nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS) in California is conducting clinical trials of MDMA, or ecstasy, as a treatment for post-traumatic stress disorder (PTSD), while a New Mexico-based nonprofit Heffter Research Institute is investigating the use of psilocybin in the treatment of anxiety and depression in cancer patients, as well as its use in treating alcoholism and smoking addiction.

    The primary tool for these studies is the placebo-controlled trial, a study in which participants receive either the drug or an inactive substance (placebo). All other conditions are kept the same, the idea being that only the drug's effects are being measured.

    The problem with placebo-controlled trials

    The problem is, the experience of taking a psychedelic drug can vary widely depending on the context in which you take it, Langlitz writes.

    The Harvard psychologist Timothy Leary, who experimented heavily with LSD, called this concept "set and setting." Leary argued that the "character" of a psychedelic experience is determined primarily by the user's character, expectations, and intentions (the "set"), as well as by the social and physical surroundings where the user took the drug (the "setting").

    But most placebo-controlled studies don't take this into account. And simply measuring the effect of these drugs compared with a placebo is missing some crucial components of the user's experience.

    In one study, researchers interviewed nearly 100 current or former ecstasy users about their experiences with the drug, and found that bad experiences were almost always related to the set and setting. Specifically, participants reported that the negative effects they experienced were affected by their mood or expectations, beliefs about the brand of ecstasy they used, and experiences of seeing how it affected their friends.

    Another small study from 1975 looked at people who smoked marijuana in a "favorable" or "neutral" environment, and found that their mental set had an big impact on how people reported how the drug was affecting them. The results suggested users' experiences were influenced by their mental state.

    And researchers looking into the "Acid House" trend of taking psychoactive drugs at musical concerts in 1980s Britain found that the nature of the music, especially the drumming, "seems instrumental in providing altered states of consciousness."

    So, rather than testing psychedelics using the placebo-controlled trial, some researchers have suggested doing "culture-controlled" trials, in which they'd compare the experience of study participants in specific settings. For example, you could compare the experience of teenagers taking ecstasy at a rave with that of the same teens taking the drug in a sterile lab setting.

    As more of these drugs make their way into therapeutic research, this approach could be increasingly important.

    18 December 2015

    Tanya Lewis
    Business Insider


  1. Calliope
    This is a very interesting (and important!) topic, both specifically as a concern about how the value of clinical trials is possibly limited in crucial ways for psychedelic drugs but also (and this is central to one big part of drugs forum itself) more generally as a difficulty accompanying any scientific inquiry into the therapeutic usefulness of psychoactive drugs in self-aware creatures. The almost paradoxical thing is that the placebo effect itself is both an instance of the complication that as self-aware creatures our beliefs about the substances we ingest can play a causal role in their effects and what randomized double-blind trials are precisely designed to control for!

    I tracked down the original opinion piece by Nicolas Langlitz who is the author of Neuropsychedelia: The Revival of Hallucinogen Research Since the Decade of the Brain (2012) and an anthropologist and historian of science at the New School for Social Research in New York. I thought it was worth reproducing it here for anyone who has an interest. See it below. Given he is a historian of science I would have liked to see Langlitz look a bit more closely at some of the 1950s and 1960s psychedelic research where you can find discussion of almost precisely the issues he is raises about double-blind trials and the inevitable role of set, setting and culture in the experience of psychedelic drugs. Perhaps such details were cut by the Aeon editor (and are in his book). Or maybe what happened on the hellscape of the frozen Canadian prairie doesn't feature so prominently in the mindset of New York City historians of science lol! With this is mind, after Langlitz's piece I've added a few remarks on this earlier psychedelic research.

    [IMGL="white"]https://drugs-forum.com/forum/attachment.php?attachmentid=47584&stc=1&d=1451148060[/IMGL]Psychedelics can’t be tested using conventional clinical trials

    Psychedelic research is back from underground laboratories to university hospitals. When LSD, mescaline and psilocybin were prohibited in 1970, all academic research on humans was abandoned for two decades. Now the return of psychedelic drugs to highly regarded research facilities, which began in the 1990s, is on the verge of reaching its goal. Two large clinical trials of psilocybin and MDMA (Ecstasy) are in the making. Should they show medical applications of these drugs to be effective, psychedelics would become part of our medicine cabinet. But there is a problem ahead. These odd substances might escape the current paradigm of pharmacology.

    The resurgence of psychedelic research became possible thanks to a strategic decision of the two main organisations responsible for making these drugs presentable again. Both the Multidisciplinary Association for Psychedelic Studies (MAPS) in California and the Heffter Research Institute in New Mexico broke with the philosophy of the counterculture best summed up by Timothy Leary’s advice to ‘Turn on, tune in, and drop out.’ Instead, the proponents of the revival have made every effort to integrate psychedelic drugs into mainstream society. When the US President George H W Bush declared the 1990s to be the Decade of the Brain and neuroimaging popularised the belief that the human mind was little more than grey matter, what better mainstreaming vehicle could there have been than neuropsychopharmacology?

    Neuropsychopharmacology learns about drugs through a simple experimental paradigm: the placebo-controlled trial. While all other conditions stay the same, test subjects either receive a pharmacologically active drug or an inactive placebo. The underlying assumption is that all psychosocial and cultural factors are also at work when the placebo is given. Hence, when comparing the effects of the actual drug to those of the placebo, the drug’s own activity will come to the fore.

    But here is the rub. In the late 19th century, experimental psychologists gave the mescaline-containing peyote cactus to Euro-American test subjects in the laboratory while anthropologists observed its ingestion by Native Americans in religious rituals. These two groups reported very different experiences. Western test subjects were often haunted by horrible visions and gloomy depression whereas the participants of Native American peyote ceremonies expressed religious enthusiasm about contact with a higher order of reality.

    Half a century later, Leary coined the still-current terms set and setting to describe the impact that personality, mood and expectations, as well as social, cultural and physical environment, had on the psychedelic experience. These non-pharmacological factors determine whether you end up in heaven or in hell, as the writer Aldous Huxley put it.

    To this day, there is a broad consensus among psychopharmacologists studying psychedelic drugs that the psychoactive effects of these compounds are strongly affected by set and setting. If neuroscientists are right that different mental experiences go along with different neural processes, this is not just a matter of various subjective interpretations of one and the same brain state. Set and setting shape the very drug action, which psychopharmacologists investigate. Placebo-controlled trials do not account for set and setting. They make it appear as if the drug alone determined what test subjects and patients experienced.

    In the late 1950s, when placebo-controlled trials were only just about to become the gold standard of pharmacological research, the anthropologist Anthony Wallace – at the time director of clinical research at the Eastern Pennsylvania Psychiatric Institute, where hallucinogen experiments were conducted – suggested to supplement placebo-controlled trials with culture-controlled trials. He called for systematic experiments on how the context of drug administration determined the effects of psychedelics and other psychoactive substances. But Wallace’s proposal never caught on. Too many powerful institutions had and continue to have an interest in attributing the effects of drugs to drugs alone. The War on Drugs has been based on a demonisation of certain substances as inherently bad. Meanwhile, pharmaceutical companies advertise their products as working under all circumstances. Neither governments nor industry were willing to spend money on showing how the effects of psychotropic drugs also depended on users’ and patients’ mindsets, doctors’ suggestions, and the social and economic environment.

    The researchers associated with MAPS and the Heffter Research Institute are well aware of the importance of set and setting. Treating patients suffering from post-traumatic stress disorder and the intense anxiety experienced by many end-stage cancer patients, they have revived therapeutic approaches from the 1960s integrating drug treatment and psychotherapy. Studies involving a small number of patients suggest that such applications of MDMA and psilocybin are safe and effective. Now MAPS and Heffter have announced that they will seek approval from the Food and Drug Administration (FDA) for so-called Phase III trials to determine their drugs’ therapeutic efficacy in hundreds of patients at several clinical sites.

    But what will happen as the drugs are administered by a broader set of therapists in a variety of different settings, including new social milieus? The tight-knit community of researchers who conducted the phase I and II studies in the past two decades largely share a particular culture influenced by the unchurched forms of spirituality, which have become popular since the 1960s. This culture also affects patients’ treatment experiences. Being guided through your trip by a psychedelic veteran might not be the same as receiving the drug from your born-again oncologist in the Bible Belt.

    The problem is that the trials required by the FDA fail to control for the impact of different subcultures and their psychotherapeutic practices on treatment outcomes. Being so close to making psychedelics part of mainstream medicine, this might not be the right moment for MAPS and Heffter to initiate a paradigm shift beyond placebo-controlled trials. If training programmes and treatment handbooks can acculturate psychedelically naive doctors and therapists enough to repeat recent therapeutic achievements, it is possible that placebo-controlled trials will get MDMA and psilocybin through the FDA approval process. But should these drugs really become part of medicine cabinets from San Francisco to America’s heartland, it will be high time to develop drug tests that control for the cultural diversity of this country’s doctors and patients. Such an expansion of psychopharmacologists’ and drug regulators’ minds would crown the psychedelic revival with a genuine scientific revolution.

    Nicholas Langlitz
    14 December, 2015
    Image: John Shephard/Flickr

    Calliope's addendum:

    If the expansion of mind Langlitz suggests for psychopharmacologists and drug regulators were to happen it would be a return to the type of research that several researchers in western Canada, among others, aimed for in the early days of LSD research. One of these, psychiatrist Humphrey Osmond, provided the mescaline Aldous Huxley famously described taking in his Doors of Perception. He tripsat Huxley that day, after briefly fretting not only that flying to Los Angeles from Canada with the mescaline might have been criminal but, moreover, that he might end up beingg responsible for this famous writer freaking out and having a psychotic break.

    Huxley didn't go insane, Osmond coined the term 'psychedelic,' and, along with several other psychiatrists in Saskatchewan, over the next decade continued a series of experiments (and self-experiments!) with mescaline and LSD.

    Osmond had immigrated from England to Canada to take a position as deputy director of psychiatry at the Saskatchewan Mental Hospital in 1951. Saskatchewan was early in an unbroken twenty year period of socialist governments formed by the CCF party who established the first system of universal health care insurance in North America (the model then adopted at the federal level in Canada in the late 1960s) and who gave notable support for the LSD and mescaline research conducted by Osmond and Abram Hoffer. Many provincial politicians believed this research held promise for a revolution in psychiatric approaches to mental illness.

    For example, in 1953, Hoffer and Osmond tested a theory that LSD could treat alcoholism by giving a single 200 mcg dose of LSD to two patients who were in the Saskatchewan Mental Hospital for chronic alcoholism. These treatments were considered enough of a success to justify further study; one patient immediately stopping drinking and the other stopped within six months.

    Following this, a clinical trial involving 24 patients admitted for chronic alcoholism was carried out by Saskatchewan psychiatrist Colin Smith. It consisted of a series of therapy sessions over several weeks. During one of the later ones patients received either a 200-400 mcg dose of LSD or a 0.5 g dose of mescaline; patients then spent several more days in hospital and were encouraged to join or continue participating in AA after discharge. This study was published in 1958 after a three year follow-up and reported 12 of the 24 patients were either improved or much improved, which meant either a significant reduction in drinking and positive lifestyle changes or complete abstention from drinking.

    Smith's study provoked some rather strongly negative reactions from other researchers. Several from the Addiction Research Foundation in Toronto argued any claim to a 50% response rate was bogus because the trial had not been controlled and couldn't therefore show that LSD or mescaline were effective. Then they did exactly what Langlitz expresses worry about: they tried to replicate in a spectacularly uninsightful way.

    "In an effort to test LSD’s capacity to inhibit problem drinking, the ARF conducted its own LSD trial. Researchers Reginald Smart and Thomas Storm contended that the reaction to the drug needed to be isolated to determine its efficacy. In other words, influences from other stimuli needed to be controlled for. As a result, subjects were given the drug and subsequently blindfolded and (or) restrained, and observers were instructed not to interact with the subjects. In this way, investigators were better equipped, in their opinion, to monitor the effects of the drug without controlling for the influence of additional stimuli. Subjects used in the ARF study did show some improvements, but overall, the controlled trial environment demonstrated that LSD did not produce results analogous to those claimed by the Saskatchewan group." (Dyck, E. Psychedelic Psychiatry: From Clinic to Campus. 2008.) ​

    What I find surprising is that any subjects in such a study showed any improvement at all! After having been restrained, blindfolded and observed while on a hefty dose of LSD I can only imagine how badly I would want more than one drink! Putting that aside, Hoffer and Osmond specifically objected to the ARF claims that the Saskatchewan LSD study results weren't replicable and they did so on the grounds that using controls in the way ARF did meant merely studying subjects' reactions rather than their experiences. Describing the early studies in their 1967 book The Hallucinogens, Osmond and Hoffer say, "From the beginning, LSD was not considered a chemical that could produce a major change in the alcoholic on its own. It was always looked upon rather as an essential factor in an overall treatment program in which were included other important therapeutic variables..." And more generally they claim that "the LSD produces the powerful emotional reaction and the therapist and setting provide the persuasive elements. In our opinion any research with LSD therapy where either factor is neglected or abused will fail. So-called controlled experiments which do not take these factors into account have no bearing on psychedelic psychotherapy."
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