In this edition of Dose of Science, we are going to take a look at a meta-analysis of using LSD therapy to treat alcoholism [1]. ‘Meta-analysis’ means that the study pools together data derived from multiple trials and re-analyses the combined evidence. The advantage is that the combined evidence reduces the statistical uncertainties, and permits more robust conclusions than any of the individual studies in isolation.
According to the World Health Organisation, 5.1 % of the global burden of disease and injury is attributable to alcohol [2]. Despite the considerable harm alcohol causes, there is no effective therapy available for alcohol dependence. How can LSD help people with alcohol problems? The hypothesis is that during the psychedelic experience the patient, may come to understand the underlying causes of the addictive behaviour. The new self-understanding and the spiritual component of the experience can provide a strong motivation to kick old habits. Note that the hypothesis is not specific to alcohol dependence: LSD does not modify molecular pathways thus leading to decreased drinking, but it rather acts on the psychological level. Therefore, in theory, LSD therapy is applicable to many forms of addiction. Today, LSD is illegal, but this was an area of active research during the sixties.
To study the effectiveness of LSD therapy for alcohol dependence, the authors had to first find the records of the relevant clinical trials. Most of the trials were either non-randomised or open label (patients knew whether they are in the control group or not). The standards for clinical trials have been raised since the sixties, and these practices are nowadays considered serious methodological flaws. Thus, the authors excluded these papers from their meta-analysis, and only included studies with randomised controlled trials, where the control group received some form of active treatment. Six eligible trials have been identified. Among these trials, several studies lacked a detailed description of how the patients were recruited, so selection bias could not be completely eliminated. Two of the trials, moreover, have a risk of bias as treatment allocation was only concealed until the end of the LSD session (that is – before the follow-up sessions, patients knew whether they were in the treatment or control group). These are legitimate concerns, and they weaken the conclusion of the meta-analysis.
536 patients participated in the trials, with 325 (61%) randomly assigned to LSD treatment, and the remainder assigned to the control groups. In all of the trials, a single oral dose of LSD was administered. The median dose was 500µg – that is, an extremely high dose in terms of recreational use (a typical blotter paper contains 120µg, although there are wide variations). The control conditions included active placebo, for example d-amphetamine, and very low doses of LSD (up to 50µg). Each of the trials had multiple follow-up sessions, where it was assessed whether the patient's alcohol problem had improved or not. The follow-up sessions were pooled together to form three time-categories: short (2-3 months), medium (6 months) and long term (12 months) follow-ups .
To summarise the effectiveness of the LSD treatment and the control groups, the odds ratio was calculated (at each follow-up session). Without getting too technical, the odds ratio is the quotient of the odds that a patient has improved in the treatment group and the probability that a patient has improved in the control group. If the odds ratio is > 1 then the treatment is favoured over the control and the higher its value is, the more effective is the treatment compared to control.
Across all trials, the odds ratio was 1.85/1.66/1.19 at the short/medium/long term follow-ups. The difference between the LSD and control groups was statistically significant at the short- and medium-term, but not at the long-term follow-up. Looking at the odds ratios for different follow-up times, two observations should be made. The odds ratio suggests that LSD treatment is effective (1), but with its benefit diminishing with time (2). To account for the success, one study was quoted as saying that, “it was rather common for patients to claim significant insight into their problems, to feel that they had been given a new lease on life, and to make a strong resolution to discontinue their drinking”. This statement seems to reinforce the hypothesis behind LSD therapy. As for the diminishing benefits, one of the papers commented that “most alcoholics report a waning of the initial inspiration, euphoria, and good intentions gleaned from the LSD experience when they are again confronted with the former stress and difficulties of their lives”. To transfer the benefits to the long term, researchers have suggested extending the LSD treatment to multiple sessions, where each session is separated by a few months. In theory, the repeated LSD experiences could reinforce the will to quit. One could also, however, argue that the repeated LSD sessions would not be as motivating as the first one, as the patient gradually becomes more familiar with the experience.
An important question to ask is how the results of LSD therapy compared to the results of other treatments? To address this question, the authors compared the effectiveness of LSD with Naltrexone, Acamprosate and Disulfiram treatments, all of which are common prescription medicines to help with alcohol addiction. The full statistical analysis would require much more technical detail, but in summary, it can be said that LSD compared favourably against all of these alternative drug treatments.
Before concluding, one more note. Most trials made little effort to prepare the patients for the psychedelic experience. Typically, there was a brief orientation session, but there was rarely an in-depth discussion of LSD’s effects. The authors point out that 8 patients (out of the 325; ~2%) experienced temporary adverse reaction to LSD (e.g. anxiety). Given the very high dosages and the lack of preparation, this is a somewhat surprisingly low number.
So what was learned from the paper and what further research does it suggest? LSD would appear to be an effective treatment for alcohol dependence in the short and medium term, but the positive effects are diminished after 12 months. Despite the weakening effect, and the legitimate criticisms over possible bias of the trials, this meta-analysis provides evidence that argues for further research. Future studies could address whether repeated doses might extend the initial euphoria to long-term change, and whether the combination of LSD therapy with more conventional approaches could lead to lasting benefits. Furthermore, the trials used different doses of LSD; more empirical data is needed, in order to refine the dosage that maximises the benefits and minimises the adverse reactions. It remains to be seen whether scientists will be allowed to investigate these questions.
References:
[1]: Krebs, Teri S., and Pål-Ørjan Johansen. "Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials." Journal of Psychopharmacology 26, no. 7 (2012): 994-1002.
[2]: http://www.who.int/mediacentre/factsheets/fs349/en/ (Accessed on: 16 Sept 2015)
