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There has recently been a renewal of human research with classical hallucinogens (psychedelics). This paper first briefly discusses the unique history of human hallucinogen research, and then reviews the risks of hallucinogen administration and safeguards for minimizing these risks. Although hallucinogens are relatively safe physiologically and are...
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... However, these outcomes seem to be highly context-dependent and more likely to occur during unstructured or unlicensed activities (e.g., recreational use, "underground" therapy by unqualified or unethical practitioners). This emphasizes the importance of adequate screening, mental and emotional preparation, skilled, ethical supervision, and a safe, comfortable environment (Johnson et al. 2008). ...
... It is important to point out that the present study did not examine attitudes surrounding unsupervised use of psychedelics, use under the supervision of "underground" practitioners, or other illegal uses, which incur distinctive risks (Johnson et al. 2008;Schlag et al. 2022), including the potential for long-lasting harms . Rather, inspired by the Oregon law, the study focused exclusively on attitudes toward legal and supervised use. 1 Our results suggest that, under these circumstances, surveyed members of the US public are generally morally supportive of psilocybin use for both treatment and well-being enhancement. ...
... Mennis et al. 2021). Allowing psychedelic use in supervised settings could also possibly affect the incidence of risky, unsupervised use in other settings (Johnson et al. 2008;Schlag et al. 2022), which the current study did not explore. Such concerns should be kept in mind by policymakers. ...
The psychedelic psilocybin has shown promise both as treatment for psychiatric conditions and as a means of improving well-being in healthy individuals. In some jurisdictions (e.g., Oregon, USA), psilocybin use for both purposes is or will soon be allowed and yet, public attitudes toward this shift are understudied. We asked a nationally representative sample of 795 US Americans to evaluate the moral status of psilocybin use in an appropriately licensed setting for either treatment of a psychiatric condition or well-being enhancement. Showing strong bipartisan support, participants rated the individual’s decision as morally positive in both contexts. These results can inform effective policy-making decisions around supervised psilocybin use, given robust public attitudes as elicited in the context of an innovative regulatory model. We did not explore attitudes to psilocybin use in unsupervised or non-licensed community or social settings.
... The early research had significant methodological limitations as it is mostly qualitative/anecdotal, as controls were generally nonexistent and dependent variables were not clearly defined or objectively measured. Also, these early investigators had limited understanding of the importance of context to optimize psychedelic therapy (Robin L Carhart-Harris et al., 2018) as set (expectations), setting (therapy environment) (Hartogsohn, 2016;Johnson, Richards, & Griffiths, 2008) and matrix (home environment) (Eisner, 1997) were not fully understood and as a result, optimal circumstances were not constructed. Dosage was also not well understood. ...
This analysis of current and historical research and clinical reports observes that the relationship between psychedelics and schizophrenia is complex and there are reports of psychedelics benefiting this population. Specifically, lower doses of psychedelics (mostly LSD) appear to have a potential beneficial impact on the negative symptoms of schizophrenia.
... This neglect of context has serious ramifications for the design and interpretation of psychedelic studies. For instance, music has played key roles in ceremonial, recreational, and therapeutic uses of psychedelics [3]-indeed, participants of nearly all modern clinical trials of psychedelic-assisted psychotherapies have spent the majority of their dosing sessions listening to music [3,4]. Recent studies have demonstrated that psychedelic-music combinations have multiple potent interactions: LSD can enhance emotional and neural responses to music [5,6], music can alter the neural dynamics of psychedelic states [7], and music experiences during psychedelic therapy are predictive of subsequent antidepressant effects [3]. ...
... These apparently contradictory perspectives on the effects of psychedelic drugs cannot be reconciled without considering the influences of extrapharmacological variables; i.e., the 'set and setting' of participants receiving psychedelics [8,13], where 'set' refers to their mindsets and 'setting' refers to external environmental variables like music. Both the 'sets' and the 'settings' of modern research psychedelic studies differ greatly from the early psychotomimetic studies by, for instance, the framing of drug effects in positive lights and the use of physical environments designed to support therapeutic experiences [4]. The impacts of such contextual differences can be massive, as the stark contrast between the results of first and second waves of psychedelic research demonstrate [8], but powerful drug-context interactions are certainly not unique to serotonergic psychedelics. ...
... These broad categories represent an important starting point but vary greatly in their potential to be feasibly incorporated into research studies. The assessment of social settings and cultural factors is inherently multifaceted and complex, for example, whereas reporting preparatory protocols and compositions of musical playlists are both feasible and already becoming common practice [4,12,37]. ...
... The importance of psychotherapeutic support for individuals undergoing psychedelic-assisted treatment is a central tenet in the field of psychedelic science [23,32,33]. In clinical trials, this support takes the form of a structured approach, encompassing preparation sessions before dosing, therapeutic guidance during dosing, and integration sessions following dosing. ...
In recent years, scientific research into the therapeutic potential of psychedelic compounds has experienced a resurgence of interest. New studies have shown promising results, supporting the use of psychedelic drugs in treating various psychiatric disorders, including treatment-resistant depression, post-traumatic stress disorder, and even alcohol addiction. The FDA has recognized 3,4-methylenedioxymethamphetamine (MDMA) as a breakthrough therapy to treat symptoms of post-traumatic stress disorder. At the same time, interviews with recreational MDMA users have documented experiences of emotional intimacy while using MDMA, often without the desire for penetrative sex. However, some people have reported that MDMA increases their sexual arousal and specifically use it to enhance their sexual performance. This study aims to analyze current and planned research on the psychophysiological effects of entactogens on human sexuality. With their prosocial potential, the pharmacokinetic and neuroendocrine effects of entactogens may recreate the subjective experience of emotional intimacy, the initiation of intimate relationships, or even feelings of ‘falling in love’ with previously neutral individuals while under the influence of entactogens. This includes MDMA-induced sexual arousal-like effects observed through subjective behavioral perceptions of desire and arousal and specific physiological markers such as oxytocin and prolactin. Modern MDMA-assisted psychotherapy (MDMA-AP) protocols are transparent and follow strict ethical guidelines. However, despite these proposed ethical principles, little consideration has been given to the potential neurobehavioral effects of entactogens on the sexuality of participants in MDMA-AP protocols. The psychophysiological and sexual effects of entactogens should be discussed more openly in current MDMA-AP protocols, including the potential experience of the phenomenon of sexualized pharmacotransference.
... As it currently stands, psychedelic-assisted therapy costs several thousand dollars per session (Marseille et al., 2022;Chrysanthos, 2023), making this effective therapy inaccessible for a large portion of the patient population, especially those from lower socioeconomic areas. Furthermore, regulatory and legal barriers still exist, which makes treatment implementation problematic (Johnson et al., 2008). There are also concerns that the hallucinogenic action of serotonergic psychedelics could produce hallucinogen-persisting perception disorder (Ford et al., 2022) and irreversible psychotic episodes in susceptible populations, which has already led to routinely excluding patients with a family history of bipolar disorder or schizophrenia from participating in psychedelic clinical trials (Johnson et al., 2008). ...
... Furthermore, regulatory and legal barriers still exist, which makes treatment implementation problematic (Johnson et al., 2008). There are also concerns that the hallucinogenic action of serotonergic psychedelics could produce hallucinogen-persisting perception disorder (Ford et al., 2022) and irreversible psychotic episodes in susceptible populations, which has already led to routinely excluding patients with a family history of bipolar disorder or schizophrenia from participating in psychedelic clinical trials (Johnson et al., 2008). This underscores the importance of determining psychedelics' mechanism of action. ...
Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.
... It seems that among all psychedelics showing AD activity, psilocybin (mainly its active metabolite, psilocin) is characterized by the lowest physiological toxicity and abuse liability having the safest profile. Its use, however, is not free of adverse effects like overwhelming distress during drug action ("bad trip") or persisting perceptual disturbances [66,67]. New wave of placebo-controlled, randomized trials showed promising therapeutic outcomes and no serious adverse effects. ...
The desire to find a gold-standard therapy for depression is still ongoing. Developing one universal and effective pharmacotherapy remains troublesome due to the high complexity and variety of symptoms. Over the last decades, the understanding of the mechanism of pathophysiology of depression and its key consequences for brain functioning have undergone significant changes, referring to the monoaminergic theory of the disease. After the breakthrough discovery of ketamine, research began to focus on the modulation of glutamatergic transmission as a new pharmacological target. Glutamate is a crucial player in mechanisms of a novel class of antidepressants, including hallucinogens such as ketamine. The role of glutamatergic transmission is also suggested in the antidepressant (AD) action of scopolamine and psilocybin. Despite fast, robust, and sustained AD action hallucinogens belonging to a group of rapid-acting antidepressants (RAA) exert significant undesired effects, which hamper their use in the clinic. Thus, the synergistic action of more than one substance in lower doses instead of monotherapy may alleviate the likelihood of adverse effects while improving therapeutic outcomes. In this review, we explore AD-like behavioral, synaptic, and molecular action of RAAs such as ketamine, scopolamine, and psilocybin, in combination with mGlu2/3 receptor antagonists.
... However, the persisting and distressing manifestation of these experiences may lead to hallucinogen-persisting perception disorder [51]. Related risks are prolonged psychoses triggered by these compounds, especially in individuals with a personal or family history of psychotic disorders or other psychiatric disorders [52]. ...
... Dosing sessions take place in the presence of one or two experienced guides, who fulfil the roles of both researcher and therapist during the trial. Dosing occurs in a relaxing, aesthetically pleasant and comfortable non-clinical environment, with participants reclining with an eye mask and headphones through which a specially designed music playlist is played throughout the session [13]. Importantly, dosing sessions are embedded within a wider program of drug-free psychological support, which aims to establish rapport with and prepare patients in advance of the drug sessions, and to support the sober reflection on and integration of material evoked by those sessions. ...
... As such, the therapeutic relationship between a psychedelic researcher-therapist and trial participant is liable to be one of unusual depth and intensity. Since the success of the trial will involve the safe and effective administration of the therapeutic intervention, and the therapeutic intervention may be dependent on the researcher-therapist/patient relationship [13,67], researcher-therapists will consciously seek out and cultivate deep and intense relationships with patients in a partially instrumental fashion, thereby increasing the weight of obligation of researcher-therapists towards their patients. ...
... Importantly, although these spaces are often held by therapists, they are not therapy sessions, but are more akin to peer support groups. 13 Consider the structurally similar phenomenon of teachers in underfunded schools feeling compelled to purchase school supplies from their own salaries. Although teachers are the proximate actors embedded in a relational context which may generate obligations towards schoolchildren, teachers do this work on behalf of a range of stakeholders, and it is appropriate that the costs of the task of teaching are divided fairly. ...
The ethical value—and to some scholars, necessity—of providing trial patients with post-trial access (PTA) to an investigational drug has been subject to significant attention in the field of research ethics. Although no consensus has emerged, it seems clear that, in some trial contexts, various factors make PTA particularly appropriate. We outline the atypical aspects of psychedelic clinical trials that support the case for introducing the provision of PTA within research in this field, including the broader legal status of psychedelics, the nature of the researcher-therapist/participant relationship, and the extended time-frame of the full therapeutic process. As is increasingly understood, the efficacy of psychedelic-assisted psychotherapy is driven as much by extrapharmacological elements and the cultural therapeutic container as by the drug itself. As such, we also advocate for a refocusing of attention from post-trial access to a broader concept encompassing other elements of post-trial care. We provide an overview of some of the potential post-trial care provisions that may be appropriate in psychedelic clinical trials. Although the World Medical Association’s Declaration of Helsinki calls on researchers, sponsors, and governments to make provisions for post-trial access, such provision may feel impracticable or out-of-reach within psychedelic trials that are already constrained by a high resource demand and significant bureaucratic burden. We show how conceiving of post-trial provision as an integral site of the research process, and an appropriate destination for research funding, will serve to develop the infrastructure necessary for the post-legalisation psychedelic medicine ecosystem.
... Additionally, the resurgence of psychedelic-assisted treatments has drawn attention and threatened traditional therapy approaches. It has been shown that drugs like psilocybin and 3,4methylenedioxymethamphetamine (MDMA) can treat diseases, including depression, anxiety, and posttraumatic stress disorder (PTSD) [14]. These methods show that the mind-body link and the study of altered states of consciousness are once again prioritized in treating mental illness. ...
This article offers an extensive review of the changing field of mental health therapies, charting a transformational path from traditional methods to modern breakthroughs and speculating on potential future developments. The story develops by investigating historical viewpoints while reflecting on the present and highlighting the lessons learned and their impact on contemporary practices. We have advanced from the stigmatized constraints of asylums to a paradigm that puts human rights, dignity, and individualized, culturally sensitive treatment first. Modern methods are much more varied and evidence-based, from cutting-edge technical advancements to evidence-based psychotherapies. The ethical considerations arising from the delicate balance of pharmacological therapies underline the responsibility of administering drugs that significantly affect mental health. Cultural factors become a pillar, highlighting how crucial cultural sensitivity is to promoting tolerance. By acknowledging how many facets of the human experience are interrelated, holistic methods help close the gap between the mind and body. Integrative medicine and alternative therapies represent a shift away from reductionist approaches and toward a holistic viewpoint. The delivery of mental health treatment is being reimagined by technological advancements, with virtual and digital environments opening up new access and support channels. These developments cut beyond regional boundaries, reinventing conventional therapy dynamics and paving the way for individualized therapies. Cultural concerns highlight the significance of cultural competency in navigating the complex mental health treatment system and adapting interventions to fit the particular requirements of various cultural contexts. With telepsychiatry, virtual reality, and artificial intelligence among the new technologies that promise to further revolutionize mental health therapies, the essay looks to the future. This review concludes by imagining a day when mental health is prioritized, therapies are available, and the diversity of human experience is valued. The path to a society that values, nurtures, and celebrates mental health continues.
... (p21),(p24),(-p27),(p28),(p33),(p36),(p37) This might be, in part, because of a highexclusion rate of modern trials, which do not enroll individuals with a personal or family history of a variety of psychiatric disease, including schizophrenia and bipolar disorder. 43 Indeed, a recent retrospective, online survey analysis suggested that patients living with bipolar disorder and taking lithium as a mood stabilizer were more likely to experience seizures with concomitant psychedelic use compared with those who utilized lamotrigine for treatment. 44 Another online survey noted that approximately one-third of people living with bipolar disorder reported increasing, mostly manic, symptoms following psilocybin intake. ...
