How to account for hallucinations in the interpretation of the antidepressant effects of psychedelics: a translational framework

Abstract

Rationale Recent trials with psychedelics in major depressive disorder and treatment-resistant depression showed remarkable improvements in depressive symptoms that can last for up to several months after even a single administration. The lack of an appropriate placebo control group—as patients are often able to discriminate the subjective effects of the drug—and an incomplete understanding of the role of the hallucinogenic and mystical experience, hampers the interpretation of these therapeutic effects. Objectives To control for these factors, we developed a translational framework based on establishing pharmacokinetic/pharmacodynamic (PK/PD) relationships in rodents and humans for hallucinogenic (i.e., discriminative stimulus effects in rodents and humans; head twitch responses in rodents; questionnaires in humans) and therapeutic effects. For the latter, we selected the pattern separation and attentional set-shifting tasks as measures for cognitive flexibility because of their high translational value. We predict that these PK/PD analyses will lead to a more objective evaluation of improvements in patients compared to relying only on the currently used self-reported questionnaires. We hypothesize that—if the role of the hallucinogenic experience is not central in the antidepressant effects of psychedelics—the ED50’s for the therapeutic effects will be significantly lower than for the hallucinogenic and mystical effects. Conclusion Our framework will help to inform future studies that aim at the elucidation of the mechanism(s) of action of psychedelics in depression, and the role of the acute subjective and/or hallucinogenic experience in their effects.

Cognitive Functions, Neurotransmitter Alterations, and Hippocampal Microstructural Changes in Mice Caused by Feeding on Western Diet

“…The HTR is mostly regarded as a measure of drug-induced hallucinogenic effects [ 28 , 64 ]. However, some argue that although hallucinogens induce HTR, they do not fully represent hallucinatory behavior [ 65 ]. Whether these HTR observed in WD-fed mice correspond to the head bobbing in HE patients, or merely a behavior caused by serotonin changes, should be further evaluated, particularly if previously identified 5-HT receptors are also involved.…”

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents – A Review

“…Here too, an ED 50 dose can be calculated. In effect, the procedure can identify (i) whether or not the test drug produces stimulus 13,62,63 As mentioned above, certain hallucinogenic indolealkylamines such as LSD (8) are structurally similar to the neurotransmitter serotonin (5-HT, 10). Hence, it was initially thought that these agents might act via a serotonergic mechanism.…”

“…183 Ketanserin (initially referred to as R 41 468) and the structurally related pirenperone were identified as the first 5-HT 2 -versus 5-HT 1 -selective antagonists in the early 1980s, 184,185 and Colpaert et al 186 found that pirenperone was a potent antagonist of LSD in rats trained to discriminate LSD from vehicle. Both ketanserin and pirenperone were soon found to very potently antagonize the stimulus effects of DOM, and DOM-stimulus generalization to, for example, mescaline (2), LSD (8), and 5-OMe DMT (9b), suggesting a common stimulus action via activation of 5-HT 2 receptors. 187 Later, the stimulus effect of DOM in monkeys, to which substitution occurred with DOI, R(−)DOM, and LSD, 188 was also blocked with 5-HT 2 antagonists including ketanserin.…”

“…e.g. − A broad structural and mechanistic variety of antidepressants are currently being explored but, as a group, serotonergic psychedelic agents represent a large class of agents with psychotherapeutic potential . In fact, recognizing their potential therapeutic utility, the U.S. Food and Drug Administration has recently published recommended guidelines for the investigation of such agents .…”

Psilocybin for Depression: From Credibility to Feasibility, What’s Missing?

“…Moreover, a stronger study design should include, apart from an inactive control, an active control condition, such as an effectively psychoactive placebo able to simulate the subjective and acute effects of psilocybin [ 58 ]. Theoretically, an active placebo that mimics psychedelic effects without providing therapeutic benefit might appear appropriate for this purpose, although one would argue that it may well be the “mystical state” itself that may drive the beneficial effects [ 31 , 32 , 82 ]. Finally, some subjects are inclined towards a rational philosophical approach that strongly denies even the mere existence of a “mystical experience”, including its role in the healing process [ 83 , 84 , 85 , 86 ].…”