The psychedelic experience and treatment-resistant depression

Interest in the use of serotonergic agonists such as psilocybin in treatment-resistant depression (TRD) has grown more quickly than the evidence on which to base a final opinion, as emphasized by McIntyre et al1 in their review. Psilocybin, once metabolized to psilocin, activates 5-HT2A receptors, enhancing GABA function in local circuits in the cortex and increasing connectivity between functional modules in the brain. The emergent consequences can be measured in healthy volunteers and patients by the Altered States of Consciousness Rating Scale (5D-ASC) in five domains: oceanic boundlessness, anxious ego dissolution, visual restructuralization, auditory alterations, and reduction of vigilance2, 3. While the content of these experiences is very personal, their form is relatively stereotyped and very similar between various study populations. While aspects of personality or emotionality may influence the strength of effects, it is impossible to regard them as simply imaginary or the results of suggestibility. The largest randomized control trial (RCT) of psilocybin in TRD (COMP001) showed a striking dose-effect relationship4. A25 mg dose of the investigational drug, COMP360 (a synthetic psilocybin formulation), produced an effect on depressive symptoms significantly greater than a 1 mg dose at the 3-week primary endpoint. The effect of a 10 mg dose was intermediate and tended to fade towards the 1 mg arm over time. A superiority for the 25 mg compared with the other two doses was seen up to 12 weeks. The strength of oceanic boundlessness, in particular, correlated with the outcome measured by conventional scales for mood. The main objections to a simple interpretation that psilocybin acts to improve depressive symptoms in TRD, or in general in major depressive disorder (MDD), are summarized by McIntyre et al1. First, the psychedelic experience is often said to be unblinding. In conventional RCTs, this implies that the active drug is identified because of some adverse effect or other cue when it should ideally be indistinguishable from placebo. In the case of psilocybin and related drugs, the actual problem is the absence of a psychedelic experience, which will reveal to patients that they have received placebo, a low dose of psilocybin, or another drug. Does such unblinding necessarily occur, and does it matter? I would argue that it may not5. The reason is that the psychedelic experience within the dose ranges currently in use is quite variable. The overlap between active doses due to this variability means that a dose-response relationship cannot credibly be attributed to “unblinding”, since patients and staff cannot be certain of what dose has been administered. This will be particularly the case if patients do not have previous psychedelic experience, as in over 90% of participants in the COMP001 trial. In addition, the problem with unblinding of an inactive dose is, in theory, the potential for a nocebo effect. Nocebo in this context refers to the possibility that unblinding leads to patients scoring lower when reporting a subjective outcome such as mood than they would if they had simply failed to respond to an active dose. This effect can be checked in all adequately sized trials by comparing the non-response profile in the placebo group with that in the active group. This is not usually done in conventional trials, but in the case of escitalopram a pooled analysis shows very clearly that responders and non-responders have very similar profiles irrespective of whether they receive drug or placebo6. In addition, unblinding might be expected to lead to more adverse events, including suicidality. This was not observed for the 1 mg arm in COMP0014. Second, any psychotherapy provided alongside a drug could be potentially confounding: indeed, it is common to hear the expression “psychedelic-assisted psychotherapy” overused uncritically as synonymous with psilocybin treatment. That expression is appropriate for 3,4-methylenedioxymethamphetamine (MDMA), which increases the potential for empathy and interaction with a therapist7. It is instead an oxymoron when applied to psilocybin, since the full psychedelic experience is largely incompatible with psychotherapy as usually understood. The psychological support that has been provided in clinical trials of psilocybin means preparation, a supportive presence on the day of drug administration, and integration soon afterwards. Preparation entails instruction, explanation and the establishment of trust. Support during a psychedelic experience is usually minimal: patients don eye shades, listen to music and are encouraged to direct their attention inwards. Integration is non-directive enquiry about the experience and how patients see it affecting their future beliefs and behavior. In most of the depression trials, it was scheduled to be two visits of up to 1 hour each. In all the MDD and TRD studies published so far, high depression scores were registered at baseline, after preparation had occurred. Moreover, in COMP001, the obvious mood change registered on the day after drug treatment was fully developed before integration had taken place. Hence, there is little reason to attribute clinical improvement to anything other than drug effect on the day of administration. From the perspective of mechanism of action, this is an important conclusion because, if psychotherapy provided the main mechanism of change, understanding the drug contribution would be more difficult, and its approval as a medicine could be compromised. The assumption that psilocybin treatment is necessarily “combined with psychotherapy” has another risk. Unregulated psychotherapy practice can lead to ethical violations. The risk of such practice in “psychedelic-assisted psychotherapy” is very real and has been highlighted recently8. This is another reason for de-emphasizing the role of psychotherapy unless, as with MDMA, it is clearly a key part of the treatment. To refer accurately to psychological support does not diminish its importance in facilitating an optimal psychedelic experience. This support is also ethically essential as a safeguard for patients on the day of drug administration. The qualifications and training of the people providing such support must be to high standards, and a clear protocol should be used. However, the professional background of the therapist is probably less important, because what is involved is not psychotherapy. It is difficult to see how a more minimal package could be safely used as a comparator to “deconstruct” the approach and generate “an evidence base” as suggested by McIntyre et al. The potential for psilocybin to enhance the effect of conventional psychotherapies remains of great interest. Work in animals suggests that activation of 5-HT2A receptors produces changes in synaptic function that could underpin greater behavioral plasticity9. The challenge for the future, along with safe delivery of the experience, appears likely to be the choice of appropriate additional treatment which may have the potential to enhance outcomes in the long term, be it pharmacological, neurostimulatory or psychotherapeutic. For the present, however, the challenge is to complete a convincing phase 3 programme leading to eventual approval of psilocybin as a medicine. We are not there yet.