Classic psychedelics as therapeutics for psychiatric disorders
This chapter (49, Handbook of Behavioural Neuroscience) reviews the use of classical psychedelics and the resurgence of research of them as therapeutics for psychiatric disorders.
Authors
- Peter S. Hendricks
Published
Abstract
Recently, there has been a resurgence of interest in the study of classic serotonergic hallucinogens, now widely referred to as classic psychedelics. These studies include fundamental molecular and cellular neuroscience and pharmacology, neuroimaging, and psychological experiments. In the early days of classic psychedelic research during the 1950s through the 1970s, classic psychedelics were examined for their therapeutic potential to treat disorders ranging from addiction to schizophrenia. After scheduling laws essentially halted classic psychedelic research worldwide for decades, beginning in the mid-2000s, a few select research groups were given regulatory approval to reinitiate clinical investigations with psilocybin. These studies demonstrated safety and allowed for the development of standardized methodology for conducting clinical trials with psilocybin and other classic psychedelics. There are now data from several clinical trials approved by the proper regulatory agencies in the United States, Europe, and elsewhere, suggesting safety and potentially profound efficacy to treat a variety of psychiatric disorders including anxiety, depression, and addiction.
Research Summary of 'Classic psychedelics as therapeutics for psychiatric disorders'
Introduction
Classic psychedelics have a long history of scientific and clinical interest, beginning with the isolation of mescaline in the late 19th century and the discovery of LSD's psychoactive effects in 1943. Earlier decades saw substantial research on LSD and related compounds, but much of this early work lacked the methodological rigour now expected in clinical science. More recent human studies have renewed interest in the therapeutic potential of classic psychedelics for conditions including anxiety, depression, end-of-life distress, and addiction, with particular clinical attention paid to psilocybin and ayahuasca. This chapter aims to assemble and evaluate the clinical evidence for classic psychedelics as therapeutics for psychiatric disorders and to consider putative mechanisms that might underlie observed benefits. Nichols and colleagues survey clinical trials, pilot studies, and preclinical findings, and they outline biological and psychological models — including a proposed role for the emotion of awe — that could link psychedelic experiences to durable clinical change. The authors frame current findings as promising but emphasise the need for rigorous, larger-scale research to resolve remaining uncertainties.
Methods
The extracted text does not provide a discrete Methods section describing a formal search strategy or selection criteria. From the content, the work appears to be a narrative review that synthesises historical studies, open-label trials, randomised controlled trials, observational reports, and preclinical animal data relevant to classic psychedelics and psychiatric disorders. Where specific trials are discussed, the authors summarise study designs and key procedural features reported in the original publications (for example, double-blind, placebo-controlled crossover trials in cancer-related anxiety; open-label pilot studies for treatment-resistant depression; small randomised trials of ayahuasca). However, a reproducible literature search methodology, inclusion/exclusion criteria, or risk-of-bias assessment for included studies is not presented in the extracted text. If such methods appear elsewhere in the full chapter, they are not included in the provided extraction.
Results
Clinical safety and feasibility: Early modern-era feasibility studies established that psilocybin and LSD can be administered safely in carefully controlled clinical settings when participants are screened and monitoring/support are provided. Across the described trials, no serious adverse events attributable to psychedelic administration during sessions were reported. Anxiety and depression in life‑threatening illness: Small double-blind, placebo-controlled crossover trials in patients with advanced cancer and reactive anxiety showed trends favouring psilocybin and LSD; one LSD study reported significant anxiety improvement with a higher dose. Two larger, recently completed double-blind crossover trials at Johns Hopkins and New York University examined psilocybin in cancer patients. At Johns Hopkins (N=51), participants received a high dose (~25 mg/70 kg) and a very low dose (~2 mg/70 kg) in counterbalanced order; standard preparatory and integrative psychological support was provided. At NYU (N=29) a similar crossover design used 21 mg/70 kg psilocybin with niacin as the control. Both studies reported rapid and sustained reductions in depression and anxiety measures, with the Johns Hopkins trial reporting about an 80% reduction from baseline on several clinician- and self-rated scales that persisted through 6 months of follow-up. Treatment-resistant depression and other mood disorders: An open-label pilot at Imperial College (high and low doses of psilocybin given 7 days apart) reported antidepressant effects at 1 week and 3 months, with a follow-up finding significant reduction at 6 months. Observational and small open-label studies of ayahuasca also reported rapid antidepressant effects lasting days to weeks, and a single randomised trial in treatment-resistant depression (N=29) showed significant reductions in depressive symptoms through 7 days after dosing. Addiction: Psilocybin-assisted interventions in small, mostly single-arm trials yielded promising signals. A smoking cessation pilot (N=15) combining up to three psilocybin sessions with cognitive-behavioural therapy reported biologically confirmed abstinence rates of 80% at 6 months and 60% at 2.5 years post-target quit date. An open-label alcohol dependence pilot (N=10) with up to two psilocybin sessions plus motivational enhancement therapy showed pronounced reductions in alcohol consumption sustained to 9 months. An observational study of ayahuasca-assisted therapy among First Nations individuals (N=12) reported reductions in alcohol, tobacco, and cocaine use. These studies lacked control arms, so findings are preliminary. Mechanistic and preclinical findings: The authors review serotonergic biology relevant to mood and addiction. Classic psychedelics act primarily as agonists at 5‑HT2A receptors and also engage 5‑HT1A receptors (psilocybin/psilocin). Proposed biological mechanisms include rapid neural plasticity (dendritic spine growth), desynchronisation and transient destabilisation of the Default Mode Network (DMN) with subsequent ‘‘reset’’ of network connectivity, induction of hyperconnectivity across brain regions, and anti-inflammatory effects that may help maintain therapeutic gains. Preclinical models provide evidence that psychedelics can reduce drug-seeking behaviours and alcohol consumption in rodents, though receptor-level effects are complex: 5‑HT2A activation can increase dopaminergic release, whereas 5‑HT2C activation tends to decrease it. Psilocin does not uniformly reduce mesolimbic dopamine, indicating that therapeutic mechanisms are not limited to simple reductions in dopaminergic signalling. Psychological mechanisms: The authors highlight a proposed role for the discrete emotion of awe. Psychedelic-induced awe — marked by a diminished sense of self, feelings of unity, and a reorientation away from self-focused rumination — is hypothesised to promote social integration, reduce maladaptive self-directed thought, and motivate behavioural change relevant to addiction and end-of-life distress. The degree to which peak or mystical-type experiences mediate clinical benefit is reported to correlate with outcomes across trials, though whether such experiences are necessary for efficacy remains debated.
Discussion
Nichols and colleagues interpret the accumulated evidence as indicating substantial therapeutic promise for classic psychedelics across several psychiatric indications, particularly anxiety and depression associated with life‑threatening illness, treatment-resistant depression, and certain forms of addiction. They underline that modern clinical trials conducted under careful screening and with psychological support have demonstrated rapid, sometimes large, and in several cases durable improvements in mood and anxiety symptoms, and that pilot addiction studies have produced unusually high cessation or reduction rates compared with standard treatments. The authors situate contemporary findings against a historical backdrop in which much early research lacked methodological rigour. They therefore emphasise the importance of recent randomised, double-blind trials and FDA‑approved Phase II trials in moving the field forward. At the same time, they acknowledge limitations across the literature: many studies are small, open-label, or lack control groups; longer-term follow-up and larger samples are often absent; and causal mechanisms remain incompletely understood. The debate over whether peak or mystical experiences are necessary mediators of therapeutic benefit is highlighted as an unresolved question. Mechanistically, the discussion integrates biological and psychological perspectives. Biologically plausible mechanisms include 5‑HT2A‑mediated changes in network connectivity, rapid synaptogenesis, and anti-inflammatory effects; psychologically, experiences of awe and reduced self-focus are proposed as important drivers of change. The authors recommend further investigation to disentangle these interacting components and to determine which elements of treatment (pharmacology, psychological preparation, set and setting, and integrative therapy) are essential for enduring clinical benefit. Finally, the chapter underscores practical considerations for safe clinical implementation: rigorous patient screening to exclude those at elevated risk, delivery within a therapeutic framework by trained professionals, and careful monitoring. The authors call for larger, methodologically robust trials and mechanistic studies to confirm efficacy, characterise safety, and inform optimal clinical protocols.
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University in 2006. In this study, 30 normal, healthy, and hallucinogen-naive volunteers were administered either psilocybin or methylphenidate, and underwent a session that consisted of the volunteer lying in a bed wearing eye shades and listening to preselected music through headphones for 8 h. Questionnaires assessing the effects of the drugs were administered immediately after, and 2 months later. Assessments from the longer time point of 14 months were published in 2008. The vast majority of the volunteers had sustained positive changes in attitudes and behavior associated with the psilocybin treatment. At the 14-month follow-up, nearly 70% of volunteers rated the experience as one of the five most meaningful of their life with sustained positive well-being and attitudes toward life. Three years later, in 2011, the first study examining the utility of a classic psychedelic to treat a psychological disorder was performed by Dr. Charles Grob at UCLA. After receiving regulatory approval, Grob and colleagues performed a double-blind, placebo-controlled crossover study in 12 patients with advanced cancer and reactive anxiety. Each was assigned an active placebo of niacin, or psilocybin, and underwent a treatment protocol that consisted of the patient lying in a bed wearing eye shades and listening to preselected music through headphones for 6 h. Evaluations using accepted instruments for the measure of depression and anxiety (e.g., Beck Depression Inventory, State-Trait Anxiety Inventory) were performed at 2 weeks and 6 months post session. Although no significant changes in depression and anxiety were identified between the psilocybin and niacin control groups, several trends were observed, and mean depression scores were significantly improved at 6 months compared to scores assessed at study screening, suggesting a positive therapeutic effect of psilocybin. Perhaps most significantly, this study established the safety and feasibility of testing psilocybin in a psychiatric patient population. A report on the use of LSD in patients with lifethreatening diseases was published by. In this study, either a large dose of LSD (200 mg) or a small dose of LSD (20 mg) were administered 2 to 3 weeks apart and combined with psychotherapy sessions for 12 patients in an open-label crossover design. Assessments at 2 months and 12 months found a statistically significant improvement in anxiety associated with the higher dose of LSD. As was reported byfor psilocybin, safety and feasibility of the use of LSD in a patient population was established. Other studies have also reported on the safety of the use of LSD in a clinical setting. Soon after these feasibility and safety studies were reported for both psilocybin and LSD, the results of additional studies were published on the use of classic psychedelics to treat anxiety and depression. The vast majority of these were on the use of psilocybin. Although psilocybin is produced by several species of mushrooms, and these mushrooms are what are taken recreationally, the psilocybin used for each of these human studies was carefully synthesized in a laboratory under controlled conditions. This is critically important as it allows for standardization of dosing and protocols for use in the clinic. A small open-label pilot study was conducted by Carhart-Harris et al. at Imperial College, UK, in 2016 demonstrating for the first time potential efficacy for treatment-resistant depression in a patient population where the depression was not linked to a life-threatening disease. A high (25 mg) and low (10 mg) dose of psilocybin were administered 7 days apart with psychological support. Results indicated that psilocybin treatment was associated with antidepressant effects at 1 week and 3 months post treatment. A follow-up study found a significant reduction in depressive symptoms at 6 months. Consistent with this preliminary trial of psilocybin, several recent studies indicate that ayahuasca may be a safe and effective treatment for depression. An observational study of individuals participating in ayahuasca ceremonies (N ¼ 57) found that depression significantly decreased as long as 4 weeks after the ceremonies. In an open-label pilot trial of ayahuasca among hospitalized inpatients with recurrent Major Depressive Disorder (N ¼ 6), a single administration of ayahuasca (2.2 mL/kg, with 0.8 mg/mL dimethyltryptamine content) was associated with rapid reductions in depressive symptoms that endured 21 days post administration. These results were then replicated by the same research group in a larger sample (N ¼ 17;. In the only randomized clinical trial of a classic psychedelic for treatment-resistant depression to date,randomly assigned participants (N ¼ 29) to receive either ayahuasca (0.36 mg/kg dimethyltryptamine) or placebo. Those randomized to receive ayahuasca demonstrated significant and substantial reductions in depressive symptoms through 7-day followup. No serious adverse events attributable to ayahuasca administration were reported in any of these studies. Rigorous, larger-scale, double-blind, placebocontrolled, FDA-approved phase II clinical trials were also recently conducted at Johns Hopkins University and New York University (NYU) to investigate the anxiolytic and antidepressant effects of psilocybin in patients with life-threatening cancer. In the Johns Hopkins University study, 51 participants were randomized to a group that received a high dose (w25 mg/70 kg) first and a very low dose (w2 mg/70 kg) second, or a group that received a very low dose first followed by a high dose second. The main protocols followed were consistent with the earlier studies in healthy volunteers and involved two or more preparatory sessions prior to the first drug administration session, taking the drug and laying on a bed or couch with eye shades and listening to headphones with preselected audio for 6 h in a comfortably decorated room, followed by several postsession integrative meetings. Five weeks later patients received the second drug administration according to their group, followed by several postsession meetings. Patients were assessed by several instruments prior to the treatment, and at 1, 2, and 6 months after the drug dosing sessions. In the NYU study, a similar doubleblind crossover design was followed with 29 participants taking 21 mg/70 kg psilocybin. A difference in this trial was that niacin was used as the placebo control group rather than a very low dose of psilocybin. Also, postsession assessments of depression were measured after 1 day, 6 weeks, and 6 months. Remarkably, as demonstrated in both studies, the high-dose treatments of psilocybin resulted in rapid and sustained antidepressant and anxiolytic effects. For example, in the Johns Hopkins University study, the Hamilton Depression Rating Scale, Beck Depression Inventory, and Hamilton Anxiety Rating Scale assessments decreased each by about 80% below baseline measurements that persisted through the 6 months of monitoring. Importantly, in all of the clinical trials conducted to date, there have been no adverse reactions such as a health crisis during the treatment session or psychotic reaction. This underscores the need to conduct therapy sessions incorporating classic psychedelics within the framework of behavioral therapy and trained professionals in a clinical setting. Another important contributing factor has been the successful screening of patients to exclude those at risk for potential reactions. In each of these studies, there was a high degree of correlation between the subjective experience culminating in a "peak" or "mystical" transcendent experience and the antidepressant and anxiolytic effects, with mediator analyses indicating that such experience accounts for the efficacy of psilocybin treatment. There has been some debate in the field as to whether a transcendent experience is necessary for the antidepressant effects, or is merely a biomarker indicating that sufficient drug has been administered to produce a therapeutic effect. The nature of the subjective transcendent experience and its consequences and putative contribution to therapeutic effects are discussed later in the context of awe. Interestingly, psilocybin has been shown to produce profound and persistent antidepressant and anxiolytic effects in a rat model of treatment resistant depression (C. Nichols, unpublished data), suggesting that there may be a purely biological component as well.
B. ADDICTION
With regard to addiction, a single-arm, open-label pilot trial of smoking cessation treatment (N ¼ 15) involving as many as three administrations of psilocybin (w0.29 mg/kg on the target quit date, w0.43 mg/kg 2 weeks later, and w0.43 mg/kg 8 weeks after the target quit date, with the option of w0.29 mg/kg on the second and third psilocybin administrations depending on participant response) using established protocols and in conjunction with cognitive-behavioral therapy yielded biologically confirmed abstinence rates of 80% and 60% 6 months and 2.5 years after the quit date, respectively. Although this pilot trial did not include a comparison group, abstinence rates notably outpaced those typically observed for even the most intensive of smoking cessation treatments. Furthermore, a single-arm, open-label pilot trial of treatment for alcohol dependence (N ¼ 10) involving up to two administrations of psilocybin (0.3 mg/kg on the first administration and 0.4 mg/kg on the second administration, with the option of 0.3 mg/kg on the second administration depending on participant response) using established protocols and in combination with motivational enhancement therapy produced pronounced reductions in alcohol consumption sustained through 9-month follow-up. Finally, an observational study of ayahuasca-assisted therapy for addiction among First Nations individuals in Canada (N ¼ 12) found that participating in up to two ayahuasca ceremonies was associated with reductions in alcohol, tobacco, and cocaine use. No serious adverse events attributable to classic psychedelic administration were reported in these investigations. Though designs employing larger samples and control conditions are needed to form more definitive conclusions, these findings suggest that further research is warranted.
III. MECHANISMS UNDERLYING THE THERAPEUTIC EFFECTS OF CLASSIC PSYCHEDELICS A. BIOLOGICAL/PHYSIOLOGICAL
Although major depression is a complex multifactorial disorder involving changes in central nervous system, endocrine, and immune system functions (Chirit a,, dysfunction in the serotonergic system has been tightly linked to its presentation. Evidence includes decreased blood platelet levels of 5-HT, and low plasma levels of its biosynthetic precursor, L-tryptophan, in depressed individuals. Further, dietary depletion of L-tryptophan can lead to depressive-like behaviors in both humans and in animal models. Increasing 5-HT levels using medications like selective serotonin reuptake inhibitors (SSRIs) can decrease the symptoms of depression, and SSRIs as a class are currently the most effective medications used to treat major depression in the clinic. Exactly how increasing brain 5-HT levels treats depression remains largely unknown but there are several theories. The receptor most studied in relation to major depression has been the 5-HT 1A receptor, which is coupled to G ai and inhibition of adenylate cyclase. Acutely, increasing 5-HT levels in the dorsal raphe nuclei of the brain stem leads to activation of 5-HT 1A somatodendritic autoreceptors, a decrease in firing rates, and a decrease in cortical 5-HT release from afferents in structures like the prefrontal cortex, hippocampus, and amygdala. Chronic exposure of the 5-HT 1A autoreceptors in the dorsal raphe nucleus to high levels of 5-HT produced by SSRI blockade of the 5-HT transporter eventually leads to downregulation and desensitization of these receptors (Le. Because these neurons now have fewer functional autoreceptors to respond to the negative feedback signal of 5-HT, their firing rate increases, and release of 5-HT from afferents is ultimately increased above pre-SSRI levels and remains increased for the duration of treatment. The neuroadaptation that occurs over time, involving changes in 5-HT receptor expression and function, likely underlies the antidepressant effects of SSRIs. Another 5-HT receptor linked to major depression is the 5-HT 2A receptor. It is widely expressed in the brain postsynaptically on nearly every cell type including excitatory pyramidal glutamatergic neurons, inhibitory GABA interneurons, astrocytes, and glia. The 5-HT 2A receptor is coupled to G aq and its activation is considered excitatory. In general, the presence of 5-HT at this receptor facilitates depolarization of neurons by either lowering the resting membrane potential, or by directly inducing depolarization, and facilitating release of the neurotransmitter associated with the cell that it is expressed on. The role of this receptor in mood and depression has not been well defined, but there are several studies linking polymorphisms of the HTR2A gene with depression and antidepressant medication response. In humans, SSRI treatment has been linked to a decrease in receptor density, and in animal models blockade of the receptor has been shown to potentiate the antidepressant effects of SSRIs. Therefore, reduction in 5-HT 2A receptor function, likely due to desensitization and downregulation of enhanced 5-HT levels, has been suggested as a mechanism underlying SSRI efficacy to treat depression. How then might classic psychedelics produce antidepressant effects in humans? In animal models and in humans, classic psychedelics can acutely produce activation of the hypothalamicepituitaryeadrenal (HPA) axis and anxiety. It is not until the behavioral effects have subsided that subjects report improved affect. Remarkably, the improved mood and antidepressive effects can be long-lasting and those from a single treatment can last at least several months. The primary classic psychedelic used in clinical trials, psilocybin, is an agonist at both 5-HT 2A and 5-HT 1A receptors, with its primary psychoactive effects mediated by activation of 5-HT 2A receptors. It is highly unlikely that its antidepressant effects are mediated by molecular mechanisms similar to those of SSRIs, which require long term neuroadaptation to occur. There are likely two primary components: a psychological component and a biological component that together interact to produce its profound effects. The psychological component will be discussed in a later section. At the biological level there are likely several mechanisms at play. Classic psychedelics directly activate a small percentage of excitatory neurons, the Trigger Population, which then leads to activation of small populations of inhibitory interneurons, astrocytes, and glia cells, with an overall activation of neural circuitry. Significantly, the nature of how these cells and circuits are activated is different between different regions of the brain. These molecular and cellular changes manifest at the systems level to likely desynchronize neuronal activity and destabilize the Default Mode Network (DMN), and produce a hyperconnectivity between brain regions. Differential changes in connectivity likely result from differential cellular and molecular responses to classic psychedelics between brain regions. One theory proposes that network connectivity is abnormal in the depressed state, and that after the desynchronization and hyperconnectivity produced by classic psychedelics, the DMN resets to a normal nondepressed state of synchronicity and connectivity. A modification of this theory to address the long lasting effects after a single treatment involves the anti-inflammatory effects of classic psychedelics. In this scenario, the classic psychedelic treatment will not only reset the DMN, but also reduce and eliminate comorbid neuroinflammation, preventing the brain from relapsing to an abnormal state again due to persistent neuroinflammation. Another factor that may contribute to antidepressant effects is the ability of 5-HT 2Areceptor agonists to rapidly induce dendritic spine growth and density, similar to what has been observed for ketamine, which can also elicit significant and rapid antidepressant effects. The effects of ketamine, however, are not long-lasting and typically subside after a few weeks. This may be due to the lack of anti-inflammatory properties associated with ketamine.
B. DRUG ABUSE
Mesolimbic and basal ganglia pathways form the foundation of the brain's reward circuitry, and their roles in addiction have been clearly demonstrated by a variety of methods that include lesioning in whole animals, behavioral pharmacology, and sophisticated imaging techniques. Although dopamine (DA) is a crucial neurotransmitter involved in the response to stimulant drugs, 5-HT has been found to also be important in mammalian response both as a dopaminergic modulator and by direct action. There have been many studies exploring the role of individual 5-HT receptors in addiction, with a focus on the 5-HT 2 and 5-HT 1A receptor families. 5-HT 2A/C receptors are expressed in key areas of the brain that mediate reward and addiction including the ventral tegmental area (VTA) and nucleus accumbens (NAc), and modulate DA levels. Interestingly, 5-HT 2A and 5-HT 2C receptors functionally oppose one another, with activation of 5-HT 2A receptors increasing DA release and 5-HT 2C receptors decreasing DA release. The ability of 5-HT 2A receptor stimulation to increase DA levels likely results from their expression on VTA dopaminergic neurons, where their stimulation can directly lead to DA release, and their expression on cortical glutamatergic neurons, where their stimulation facilitates excitatory glutamatergic input to the VTA leading to an indirect enhancement of DA release. Although inhibitory GABAergic interneurons in the VTA and PFC express both, 5-HT 2A and 5-HT 2C receptors, expression of 5-HT 2C receptors on these cells is significantly higher. Therefore, selective activation of these receptors produces GABA-mediated inhibition of dopaminergic release from VTA neurons, and of glutamatergic inputs from the prefrontal cortex (PFC). With respect to alcohol use, against which psilocybin has demonstrated clinical efficacy as described above, the amygdala is believed to substantially contribute to the development and maintenance of dependence. One of the major changes induced by alcohol addiction is a facilitation of GABAergic neurotransmission in the central amygdala (CeA) that results in disinhibition of output signals to other structures like the hypothalamus and locus coeruleus. 5-HT 2A receptors are expressed on glutamatergic pyramidal neurons and GABAergic interneurons of the basolateral amygdala (BLA), as well as on glutamatergic neurons of the vmPFC, which send projections to the amygdala and modulate its function and influence emotions. Therefore, 5-HT 2A receptor function in the amygdala and ventro-medial PFC may have a critical role in the etiology of alcohol dependence. Similar to the potential therapeutic effects of classic psychedelics to treat depression, there are likely psychological and physiological components to the efficacy of classic psychedelics to treat addiction. Unlike with depression, where there is currently no evidence definitively establishing a physiological component, there is data from animal models demonstrating that classic psychedelics have efficacy to block drug seeking behaviors ranging from cocaine self-administration to alcohol preference. The simplest explanation is that classic psychedelics, which nonselectively activate both 5-HT 2A and 5-HT 2C receptors, have therapeutic effects by activating 5-HT 2C receptors and that this activity overcomes the effects of 5-HT 2A receptor activation to produce an overall net decrease of DA release in the mesolimbic system. A reduction in the dopaminergic response would be predicted to reduce craving and drug-seeking behavior. This is the predicted mechanism of 5-HT 2C selective agonists like lorcaserin for decreasing drug craving. This is not the case, however, with the classic psychedelic 2,5-Dimethoxy-4-iodoamphetamine(DOI), which when given systemically leads to a dramatic increase in VTA DA levels, despite activation of both receptor isoforms. Perhaps the ability of psilocybin to activate 5-HT 1A receptors in addition to 5-HT 2 receptors is significant for therapeutic efficacy? Data show that psilocin, the active metabolite of psilocybin, does not alter DA levels in the VTA, but increases levels in the NAc. Together, these data indicate that the likely therapeutic mechanism of action does not involve classic psychedelic-mediated reductions in mesolimbic DA levels. Nevertheless, preclinical studies have shown that classic psychedelics like psilocybin and DOI can reduce alcohol consumption in rat models, without altering taste perception. Potentially relevant to this is that 5-HT 2A receptor activation has been demonstrated to dramatically enhance the process of fear memory extinction. With regard to nicotine dependence, DA in the mesolimbic system is also known to play a key role, as is the amygdala. Studies with rodents have indicated that, as with other stimulants, treatment with selective 5-HT 2C agonists reduces the effects of nicotine. Interestingly, activation of 5-HT 2A receptors also blocks the effects of nicotine. In another study, activation of 5-HT 1A receptors had no effect on nicotine responses, suggesting that the therapeutic effect of psilocybin to treat nicotine dependence likely does not involve its activation of these receptors. In summary, the mechanisms underlying the ability of classic psychedelics to treat alcohol and nicotine dependence likely primarily involve 5-HT 2A receptor activation, with minimal contribution from other receptors like 5-HT 2C and 5-HT 1A . The role of 5-HT 2A receptor activation in these processes is likely complex, and remains to be elucidated at the cellular and molecular level. The anti-inflammatory effects of classic psychedelicsmay also contribute to their efficacy to treat drug addiction at the cellular level. Neuroinflammation has been found to be associated with aspects of drug addiction including cocaine seeking, opioid dependence, and alcohol use disorder. Conversely, nicotine has been shown to impair immune responses within the CNS, and whereas nicotine itself has inhibitory effects on immune cell activation, other components of tobacco smoke likely produce the bulk of immune cell dysfunction in smokers.
C. AWE
At the psychological level,recently proposed that the discrete emotion awe might be responsible for effects of classic psychedelics. As expounded by Hendricks, awe is experienced whenever humans encounter stimuli so vast and novel that they must alter their understanding of reality. Nature, religious/spiritual practices, and music are common elicitors of awe. At the core of awe's acute effects is the small self, which involves attention being directed away from the self, feelings of unity with others and/ or the environment, and diminishment of individualistic tendencies. From the perspective of the social functional approach to emotions in which emotions aid in the coordination of social interaction, awe is believed to be the quintessential binding emotion that drives social integration and cooperation, which are crucial to evolutionary success. According to Hendricks, classic psychedelics may ultimately produce profound awe. Thus, for those suffering from addiction marked by considerable disruption in social functioning, an experience that highlights the discrepancy between the hedonic pursuit of drug rewards and the eudaimonic pursuit of a cause greater than self (e.g., family) may provide the motivation for sustained sobriety. For those suffering from end-of-life distress, depression, or other conditions characterized by maladaptive, self-directed rumination, attention directed away from the self and toward the transcendent may account for improvements in anxiety and mood. Of course, these effects may be reflected in the biological/physiological mechanisms mentioned above. These are hypotheses to be tested by future research.
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