Sustained effects of single doses of classical psychedelics in humans

A unique and compelling feature of classical psychedelics is that intake of just a single psychedelic dose is associated with long-lasting (i.e., weeks-years) effects in humans. These include effects on behaviors, attitudes, values, and personality, i.e., elements of a human’s individuality that normally are regarded as relatively stable throughout adulthood. Moreover, these effects are apparent not only in healthy individuals but also in patients diagnosed with various neuropsychiatric disorders, most notably depression and anxiety, who may experience amelioration of their depressive and anxious symptoms. The evidence for the effects is reviewed below; here, acute effects are defined as those present while the drug is still present in plasma and long-term effects are those observed after 1 week, or later.

In a ten-year follow-up study including 247 individuals, intake of LSD, whether with or without a psychotherapeutic setting, resulted in positive personality changes but only in the 23% who subsequently used LSD again [1]. A smaller but controlled study of 16 healthy individuals who were followed-up after 12-months found no changes in personality [2]. In another better controlled longitudinal study of 52 psychedelic-naïve healthy participants who underwent up to four session involving varying doses of psilocybin, the personality trait Openness (as measured with NEO-PI) was increased 1–2 months and 14 months after the intervention [3]. In a subset of this cohort, individuals also reported on externally validated positive changes in attitudes, mood, and behavior 14 months later, with the ascending dose sequence showing greater positive effects [4] and this has since been replicated in several studies [5], including a large web-based study involving different psychedelics [6]. The observation of long-lasting effects on Openness after a single dose of psilocybin in healthy individuals has subsequently been replicated in, e.g., [7]. Compared with placebo, psilocybin also enhances mindfulness and improves psychosocial functioning at 3-4-month follow-up [8].

Data on personality and well-being from classical psychedelics other than psilocybin are more limited. In a placebo-controlled study in 20 healthy volunteers, Openness was significantly increased 2 weeks post LSD [9] whereas a similar trial in 16 healthy individuals did not find significant changes in Openness one and 12 months after LSD [2]. On the other hand, the latter study did reveal higher positive attitudes about life and/or self, positive mood changes, social effects, and behavioral changes, and well-being/life satisfaction both at 1 and 12 months [2]. Ayahuasca (consisting of N,N-Dimethyltryptamine (DMT) and a monoamine oxidase inhibitor) also seems to produce less consistent effects on personality; Openness 3 weeks post-drug intake increased in only one of two trials [10], but relative to baseline, it enhanced emotional and cognitive processes, lasting up to 4 weeks after the experience [11, 12]. It should be mentioned that some of these studies were observational and far from all placebo controlled. The field of psychedelic research is particularly prone to suffer from inability to appropriate blinding and by study participants often being biased towards use of psychedelics. The psychological effects of psychedelics in healthy controls and patient groups were recently assessed in a systematic review and meta-analysis [13] which also identified the need for careful, large-scale, placebo-controlled randomized trials.

Given that moderate-high doses of psilocybin are required to induce lasting changes in personality and mood, does the content of the experience then matter? Such observations would be important to understand whether the psychedelic experience is a prerequisite for long-term effects. In a seminal paper, it was noted that participants who had so-called mystical experiences during their psilocybin session, Openness remained significantly higher than baseline more than one year after the session and the change was correlated to the intensity of the mystical experience [3]. There is also additional evidence that the strength of mystical experience may correlate with therapeutic effects in smokers [14] and with diminished anxiety and depression in terminal cancer patients [15,16,17]. Common dimensions in mystical experiences include the experience of profound unity with all that exists, a felt sense of sacredness, a sense of the experience of truth and reality at a fundamental level, deeply felt positive mood, transcendence of time and space, and difficulty explaining the experience in words, this has been assessed with different versions of the Mystical Experience Questionnaire (MEQ), developed and validated based on psilocybin sessions [18]. Interestingly, we have observed in our studies that those individuals who have a psilocybin-elicited mystical experience (roughly half of them) also tend to have a mystical experience when sessions are repeated later (unpublished observation). These as well as other observations have fostered a functional neural model of mystical experience [19].

A separate question is if these psychedelics-associated effects on personality and mood in healthy individuals are mechanistically related to the therapeutic effects reported in patients with depression or anxiety. There is some data in support of that view: In 20 patients with moderate or severe, unipolar, treatment-resistant depression (TRD), psilocybin (10 and 25 mg, one week apart) lead to an increase in Openness and an increase in Extraversion at 3-month follow-up [20]; this observation should be seen in the light of observed increase in Neuroticism and decrease in Extraversion found in patients with seasonal affective disorder when comparing their depressed state to their symptom-free states [21]. The psilocybin-associated increase in Openness might thus constitute an effect more specific to psychedelic therapy. Cognitive flexibility, broadly defined as the ability to adaptively switch between different cognitive operations in response to changing demands, is a core characteristic of Openness [22] and is often impaired in major depressive disorder (MDD). It has indeed been found that patients with MDD who are treated with psilocybin have increased cognitive flexibility for at least 4 weeks after [23].

Psychedelic therapy for psychiatric disorders is also unique in that the effects are instantaneous after the first session and to the extent that there are follow-up data beyond 6–12 months, it does not (always) require additional sessions to maintain the effect beyond that observation period. In a recent review of 10 independent psychedelic-assisted therapy trials (7 with psilocybin, 2 with ayahuasca, and one with LSD), including patients with anxiety, depression, obsessive-compulsive or substance abuse disorders, the therapeutic effects appeared to be long-lasting (3 weeks - 6 months) after only 1 to 3 treatment session(s) [24]. New studies are continuously added, e.g., a recent study where ayahuasca was given to patients with depression shows beneficial effects, lasting for more than a year [25].

How do these personality and mood effects of psychedelics in humans then back-translate to animals? That could be the topic of whole other review, but it suffices here to say that the drug-induced head twitch response (HTR), commonly taken as a proxy for acute psychedelic effects in animal, does require comparably larger psychedelic doses in animals and generally, most animal studies do involve larger drug doses. Since psychedelic effects of psilocybin in humans correlate with 5-HT2AR occupancy and plasma psilocin levels [26] we have previously suggested that in order to compare animal behavior to human psychedelic effects [27], one should use doses that also generate a 5-HT2AR occupancy of 40–70% in animals.

The neurobiological mechanism behind the stunning psychological long-term action of classical psychedelics has recently become a key question, that mostly has been investigated in animal studies, as reviewed in, e.g., [28]. The findings point to psychedelics inducing molecular and cellular adaptations related to neuroplasticity and these are suggested to occur in parallel to and potentially underly the clinical effects of psychedelics. A relevant question is if epigenetic-driven changes in synaptic plasticity are the mechanistic substrate of psychedelic’s long-lasting actions in humans; data on this topic is also starting to emerge [29].

The remaining part of this review will address how the effects of psychedelics on the neuroplasticity measured observed in animal studies can be tested in humans. Although the methodologies that can be applied to study molecular, structural or functional neuroplasticity in humans are more limited, the evidence for neuroplastic effects taking place and potentially explaining some of the beneficial effects in humans are summarized below.

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