What can we learn from the history of research on psychedelic drugs in the addictions?

The history of research on the use of psychedelic drugs to treat alcohol dependence in the 1950s and 1960s suggests the need for caution in their proposed clinical use. Since 2006 there has been a revival of interest in using psychedelics to treat depression and post-traumatic stress disorders [1] and the addictions [2]. What lessons may we glean from research in the 1950s and 1960s on the use of lysergic acid diethylamide (LSD) to treat alcohol dependence [3, 4]? A ‘psychedelic’ drug ‘produces thought, mood, and perceptual changes otherwise rarely experienced except in dreams… and acute psychosis’ and does so ‘without causing physical addiction, craving, major physiological disturbances, delirium, disorientation, or amnesia’ [5]. The classic psychedelics include mescaline, psilocybin and LSD, all of which appear to act on the 5-HT-2a serotonin receptor [6]. The class has more recently been expanded to include 3,4-methyl​enedioxy​methamphetamine (MDMA) and plant-based drugs such as ibogaine and ayahuasca, with more varied effects and mechanisms of action that may be used in various combinations [7]. In the early 1950s Osmond & Hoffer used mescaline (and later LSD) to treat patients with alcohol dependence in mental hospitals in the Canadian Province of Saskatchewan [3, 4, 8, 9]. Osmond & Hoffer [4] hypothesized that large doses of mescaline could safely produce psychotic symptoms, like those in delirium tremens (DTs), and ‘scare’ alcoholics into sobriety [3, 4]. They found instead that their patients reported a mystical epiphany that led them to embrace abstinence [4]. Osmond later coined the term ‘psychedelic therapy’ to describe the use of high doses of mescaline or LSD to induce the therapeutic epiphanies [10] that he and his colleagues believed were essential for successful treatment, because they facilitated engagement with Alcoholics Anonymous (AA) to sustain longer-term abstinence [3, 4, 11]. The local chapter of AA was very supportive of this use of LSD [8], presumably because it seemed to help alcoholics to achieve the first and second of AA's 12 Steps. A colleague of Osmond & Hoffer used their approach to treat 24 patients and reported that six were greatly and six moderately improved, and 12 were unchanged 6 months after [8, 9]. Similar later reports encouraged the Provincial Alcoholism Treatment Bureau to make LSD therapy the standard treatment for alcoholism in Saskatchewan [3, 4]. Sceptics questioned these positive results [3, 8, 12, 13]. First, they argued that their studies were uncontrolled, involved small numbers of patients and did not compare psychedelic therapy with other treatments [3, 13]. Secondly, they thought that the putative 50% success rates were inflated because outcomes were assessed by therapists who were not blind to the patients’ treatment and who may have been biased by their own use of LSD [3, 4, 12]. The positive results of LSD treatment were called into question by a controlled trial at the Addiction Research Foundation (ARF) in Toronto that randomized 30 patients to receive an 800 μg dose of LSD, ephedrine and treatment as usual without a drug [9]. In this and several later trials the investigators reported that there were no better outcomes in patients who had been given LSD [9]. Osmond & Hoffer reasonably argued that the ARF study had not implemented psychedelic therapy because patients were given a large dose of LSD with no preparation or psychotherapeutic support [3]. Some later trials that more faithfully implemented Osmond & Hoffer's treatment model reported higher abstinence rates at 3 months’ follow up in patients who received LSD [9], but no differences in outcome 12–18 months after treatment. A meta-analysis of these trials found better outcomes in the LSD group up to 6 months after treatment but no differences at 12 months [14]. LSD was, unsurprisingly, not a one-shot cure for alcohol dependence. It was also not seen as a standalone treatment by Osmond & Hoffer, who used it in combination with AA to maintain long-term abstinence. Krebs & Johansen [15] suggest that LSD may have a similar role in alcohol dependence to acamprosate and naltrexone; that is, it may need to be repeated and combined with aftercare to address the multiple personal and social problems of people with addiction. A major challenge will be avoiding the irrational exuberance that psychedelics seem to produce in some therapists [16]. Some of those conducting randomized controlled trials on depression and PTSD have publicly discouraged the non-medical use of psychedelic drugs [15], but it remains to be seen whether their ‘sober advocacy’ [15] will continue if the unsupervised clinical use of these drugs is permitted before controlled trials have defined their role in treatment. In Australia, for example, Mind Medicine Australia is facilitating the use of psychedelics in psychiatric practice by using special access schemes that allow the compassionate use of unapproved medicines [17]. They are advertising training courses for therapists on how to use these drugs, and they have enlisted politically well-connected people to argue that failing to allow the use of these drugs before regulatory approval will deny patients access to effective treatments [17]. Concerns about an over-exuberant therapeutic use of psychedelics will not end with the regulatory approval of psychedelics to treat depression and post-traumatic stress disorder. We can expect these drugs to be used off-label to treat a variety of behavioural disorders, including addictions. We may also see demands for compassionate access to plant-based psychedelic drugs, such as ayahuasca and ibogaine, based on appeals to the alleged ‘entourage’ effects of the whole plant. There is also a risk that enthusiasm for the use of psychedelic drugs may reduce interest in providing more mundane but effective psychosocial and pharmacological treatments for addiction. The history of psychedelic drugs suggests the need for caution in the revival of their therapeutic use. Clinical trials of their safety and efficacy need to be conducted (e.g. [18]) in larger, more representative patient samples, and under conditions more like routine clinical practice. Once given regulatory approval, their use should be restricted to research and supervised clinical settings to enable clinicians to be trained to deliver them in ways that minimize the risks of misadventures in the hands of exuberant clinicians [16]. Such a measured approach is needed if we wish to avoid the mistakes of the past. None. Wayne Hall: Conceptualization. Michael Farrell: Conceptualization.

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