Does acute stress play a role in the lasting therapeutic effects of psychedelic drugs?

Abstract

Psychedelic drugs, when used in the context of psychotherapy, can produce significant and long-lasting memories with enduring beneficial effects. Yet, the behavioral and neurobiological mechanisms that underlie these beneficial effects remain a mystery. Here, we suggest that both the quality and durability of memories of the drug-facilitated therapeutic experience may be mediated, in part, by the acute stress responses induced by the drugs. It is known that high doses of psychedelic drugs activate autonomic and hormonal stress responses. For evolutionarily adaptive reasons, acute stress is known to i) instill meaning to the immediate context in which it is experienced, and ii) lead to the formation of salient and lasting memories of the events surrounding the stress. Thus, the stress-inducing effect of psychedelic drugs may contribute to the reported sense of meaning, as well as the durability of the memory of the drug experience. When used in a therapeutic context these actions may i) enhance the salience of insights gained during the experience and ii) strengthen the memories formed by these experiences. Future empirical studies will help to determine whether acute stress contributes to the emotional significance and lasting effects of psychedelic-assisted psychotherapy.

There has been a surge of interest in understanding the psychological effects of psychedelic-induced experiences. These drugs produce deeply meaningful effects, which result in robust, long-lasting and usually positive memories [1]. A growing body of evidence suggests that these features may be harnessed to facilitate psychotherapy. Here, we explore the novel idea that these meaningful and lasting experiences may be attributable, in part, to the fact that psychedelic drugs induce a strong physiological stress response.

Serotonergic psychedelic drugs like lysergic acid diethylamide and psilocybin dose-dependently increase autonomic and endocrine stress systems, increasing heart rate, blood pressure and body temperature, and increase circulating levels of cortisol, adrenocorticotropic hormone and prolactin [2, 3]. However, it is not known whether, or how, these physiological stress responses are related to the subjective experience. For example, is the stress response a result of the novel and powerful subjective experience, or does the physiological stress response enhance and enrich the subjective experience? Can the subjective experience of psychedelic drugs occur without the stress response, and if so, then does the subjective experience still have lasting effects? Here we consider the possibility that the stress-inducing effects of psychedelic drugs may directly contribute to both the salience of the experience, and the subsequent vivid and persistent memories. These effects may be harnessed in the context of psychotherapy to contribute to lasting and significant therapeutic effects.

For evolutionarily adaptive reasons, acute stress can facilitate learning and enable formation of memories of the stressful context [4–6]. Complex central neurocircuitry processes stressful stimuli, and orchestrates coordinated autonomic and neuroendocrine responses, ultimately resulting in the release of norepinephrine and cortisol. A large body of evidence suggests that these neurotransmitters and hormones feed back onto the central nervous system, affecting neuroplasticity and memory formation [4]. Although acute stress can impair memory formation for tasks or stimuli unrelated to the immediate context [7], there is evidence that acute stress facilitates memory of stimuli encountered during the stressful experience [8]. Stress may improve memory by increasing attention to novel contextual stimuli [9] or by facilitating the circuits activated by the thoughts, emotions and environmental cues in the context [10]. In the case of psychedelic drugs in therapeutic settings, the co-occurrence of stress and introspection might explain the sustained and powerful learning of new insights gained during the drug experience.

There is empirical support for the idea that acute stress imparts meaning and significance to the stimuli and events that were encountered during stress. It is worth noting that acute stressors may have both positive or negative emotional content, or a mix of the two. In one study, Bierbrauer et al. [11] showed that acute public speaking stress enhanced neural representations of objects encountered during the stressful experience. Healthy adults first underwent a social stress (or control) procedure in a context with ‘examiners’ and certain physical objects. The next day their memory for the objects and faces was assessed, and they viewed images of the stress (or no stress) scene while undergoing an fMRI scan. Participants had better recollection of objects that were present during the stressful episode, and stronger neural representations in the amygdala of images of these objects during fMRI. In another study, Freund et al. [12] reported that novel auditory, olfactory and visual cues experienced during the social stress test elicited memories 7 days later that were significantly more emotional than control cues. The authors concluded that the task induced an “emotional episodic memory that is sensory-rich and personally meaningful”. Beyond these laboratory-based demonstrations that stress enhances the encoding of memories, there are many real-life examples where acute stress experienced in novel and uncertain conditions (e.g., natural disasters, war) produce vivid and long-lasting memories of the event. Indeed, stress hormones have immediate effects on attentional and mnemonic processes at the time of memory formation, and can enhance consolidation of memories [13]. Thus, the stress-inducing effect of a psychedelic drug during a therapeutic situation might impart meaning and significance to thoughts and experiences encountered during the drug-therapy session. Indeed, it is worth noting that psychedelic drugs are mainly anxiogenic [14] and not positively reinforcing in laboratory animals; this may be because laboratory animals lack the prior knowledge about the altered state, and thus cannot give meaning to the drug effect or the thoughts and emotions experienced under the influence.

To the extent that psychedelic drugs prove to be valuable in psychiatric treatment, we propose that their effectiveness may be related in part to their stress-inducing effects. A growing number of studies have reported that psychedelic drugs have lasting beneficial effects for a range of disorders, from depression to cigarette smoking [15–17]. How might the stress-inducing aspect of psychedelic drugs lead to therapeutic benefits? In the therapeutic context, psychedelic drugs are incorporated into three stages of the therapeutic process. First, patients undergo a series of preparation sessions with a therapist or guide to articulate and define the target problem [18]. Then, this preparation sets the stage for the patient to focus on the target problem during the drug experience itself. This may occur implicitly because the target problem is the reason for undergoing the drug experience, or explicitly while guides provide non-directive support and reassurance. The highly novel and immersive drug experience also activates the stress system, which, we propose, enhances the meaning and significance of new thoughts induced by the drug. That is, the physiological stress system adds salience to the experience, increasing the perceived significance any new insights gained. Further, consistent with the known effects of stress on formation of memories, patients later retain persistent and vivid recollections of these insights. During the third stage of psychedelic-assisted psychotherapy, which takes place after the dosing session(s), patients are guided to integrate their powerful memories to address the target problem in new ways. Interestingly, there is a long history in psychiatry of using acutely stressful treatments in combination with psychotherapy to relieve intractable depression and other disorders [19]. These include acute sleep deprivation, hypothermia, shock therapies, trephination, and coma therapies. Although most of these treatments have long been abandoned, it is possible that acute activation of the hypothalamic-pituitary-adrenal stress response has some role in facilitating therapeutic outcomes.

In conclusion, we note that high doses of psychedelic drugs produce acute stress responses, which may contribute to the drugs’ therapeutic effects. We suggest that the physiological stress responses may both augment the psychological meaning and significance of the drug experiences, and subsequently contribute to the lasting memory of the experience. This idea may be testable. For example, manipulations that dampen responses to stress might decrease the therapeutic impact. Alternatively, drugs that induce stress without producing the alterations in perception and states of consciousness seen with psychedelics may also be of use in psychotherapy. It will also be critical to determine whether acute stress can be integrated with current neurobiological theories of psychedelic action [20, 21]. For example, one of the leading theoretical accounts of psychedelic drug action, the ‘relaxed beliefs under psychedelics’ model [20], suggests that the drug opens a window of plasticity that allows for a re-organization of network activity: It is possible that the acute stress response contributes to this effect.

Author contributions

HdW wrote the manuscript, and MH and AKB provided valuable input and suggestions.

Competing interests

HdW is supported by PHS DA02812. HdW is a scientific advisor for Gilgamesh Pharmaceuticals and Awakn Life Sciences, and serves on the Board of Directors of PharmAla Biotech. MH is supported by the Swedish Research Council 2013–07434 and the Knut and Alice Wallenberg Foundation. He has in the past 5 years received consulting fees, research support, or other compensation from Indivior, Camurus, Molteni, BrainsWay, Aelis Farma, Lundbeck and Janssen Pharmaceuticals, and he is an Associate Editor of Neuropsychopharmacology. AKB has nothing to disclose.