Coined by Humphry Osmond in 1956, the term “psychedelic” originates from the Greek words meaning “mind manifesting” [1]. This term is used to describe the subjective effects of these substances, highlighting their ability to induce profound experiences and alter perception.

Psychedelics constitute a class of drugs obtained from specific plants, animals, and fungi, and they can be categorized into three primary classes based on their chemical structure: tryptamines, ergolines, and phenethylamines ^[2][3][2,3]. Tryptamines, such as psilocybin, N, N-dimethyltryptamine (DMT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) are characterized by an indole (aromatic group separated from a basic amine by a two-carbon linker) and share structural similarities with the neurotransmitter serotonin. Ergolines, such as lysergic acid diethylamide (LSD), are characterized by the presence of a tetracyclic ergoline ring, and were originally derived from the ergot fungus [4]. Phenethylamines, such as 2C-B, mescaline, amphetamine analogues—e.g., 2,5-Dimethoxy-4-iodoamphetamine (DOI) and 2,5-Dimethoxy-4-methylamphetamine (DOM), and derivatives such as 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine (25I-NBOMe)—are characterized by a benzene ring with an amino group attached through a two-carbon chain [3]. In addition to classical psychedelics, there are atypical compounds like 3,4-Methylenedioxymethamphetamine (MDMA), muscimol, scopolamine, salvinorin A, ibogaine, nitrous oxide, phencyclidine (PCP), and ketamine that produce similar psychological effects but work through different mechanisms. These compounds are sometimes considered psychedelics under a broader definition [4].

Psychedelics have been used by humans for centuries. Historical records indicate that these substances have been consumed in ancient cultural rituals with the purpose of healing, attaining altered states of consciousness, and gaining spiritual insights, tracing back to prehistory ^[5][6][5,6]. The synthesis of mescaline in the early 1900s and the groundbreaking discovery of the classical hallucinogen LSD by Albert Hofmann in 1938 marked the beginning of Western psychedelic science ^[7][8][9][7,8,9]. During the 1950s and 1960s, these substances gained popularity in therapeutic and psychiatric settings due to their ability to facilitate psychotherapy [7]. However, in 1970, the U.S. Drug Enforcement Agency classified psychedelics as Schedule I drugs, which had a profound impact on research in the field [10]. Prior to their classification, over 1000 clinical studies were published, documenting promising therapeutic effects of psychedelics in more than 40,000 subjects. ^[7][11][12][7,11,12]. These studies indicated therapeutic benefits in various conditions such as anxiety and obsessive-compulsive disorders (OCD), depression, alcohol addiction, and sexual dysfunction, as well as pain and anxiety relief in patients with terminal cancer ^{[10][13][14][15][16][17][18][19]}[10,13,14,15,16,17,18,19]. This regulatory decision effectively curtailed psychedelic research for approximately 30 years [20].

The advent of advanced neuroimaging techniques in the 1990s, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), played a pivotal role in enhancing theour comprehension of molecular and physiological mechanisms within the central nervous system [21]. These breakthroughs also sparked a renewed interest in exploring the effects of psychedelic substances [22]. In the last three decades, there has been a resurgence in the exploration of psychedelics, reigniting research interest in their therapeutic potential. This renewed focus has led to anticipated FDA approvals for the use of psychedelics in treating various conditions, marking a period of exponential scientific growth in this field ^[23][24][25][23,24,25].

In recent years a growing number of clinical trials and studies have been conducted or are currently underway, investigating the therapeutic potential of psychedelics such as LSD and psilocybin for various mental health conditions including depression, anxiety, cancer-related anxiety disorders, addiction, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, terminal illness, stroke, traumatic brain injury (TBI), neurodegenerative disorders, and chronic pain ^{[22][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]}[22,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]. In response to this growing interest, the U.S. Food and Drug Administration recently released a new draft guidance aimed at emphasizing essential considerations for researchers exploring the use of psychedelic drugs as potential treatments for medical conditions [42].

Randomized Phase II trials have so far demonstrated significant reductions in symptoms and long-lasting benefits following psilocybin-assisted psychotherapy for major depressive disorder, anxiety, and treatment-resistant depression ^{[43][44][45][46]}[43,44,45,46]. Remarkably, even one or two doses of psilocybin have led to rapid and sustained improvements in mood and perspective, with symptomatic relief lasting for at least 3–12 months ^{[28][45][46][47]}[28,45,46,47]. Furthermore, enduring positive effects and improved well-being following psilocybin administration have also been observed in healthy individuals. Recent Phase 3 trials investigating MDMA for PTSD have shown promising results, and hint at a potential paradigm shift in psychiatry towards utilizing substances with acute psychoactive effects to generate long-term benefits for psychiatric patients [48].

2. Psychedelics Exert Their Effects on the Brain at Multiple Levels, Engaging in Intricate and Multifaceted Mechanisms

The impact of psychedelics on the brain can be examined from multiple perspectives, including molecular/cellular, circuit/network, and overall brain levels, all of which are inherently interconnected (Figure 1). At the molecular/cellular level, psychedelics stimulate the serotonin 2A receptor (5-HT2R) along with other serotonin sub-receptors, tropomyosin receptor kinase B (TrkB), and dopamine receptors ^[49][50][50,51]. Classic psychedelics have been shown to elevate levels of glutamate and oxytocin ^{[22][51][52][53][54]}[22,52,53,54,55], promote the production of brain-derived neurotrophic factor (BDNF) ^[50][55][56][51,56,57], stimulate neurogenesis ^[22][51][22,52], and exhibit anti-inflammatory properties ^[57][58]. On a cellular level, psychedelics also induce an increase in the expression of various genes that encode for the synthesis of a range of proteins that facilitate neuroplasticity and learning, even following a single dose ^[58][59][60][59,60,61]. At the circuit and network levels (Figure 1), both ketamine and serotonergic psychedelics have been observed to enhance synaptic growth and increase the complexity of dendrites, consequently leading to a greater number of synapses ^[61][66]. This, in turn, results in an increased connectivity among neurons ^{[62][63][64][65][66][67][68]}[67,68,69,70,71,72,73]. The structural and neuroplastic changes induced by psychedelics originate from a series of processes discussed earlier at the molecular and cellular levels. This resviearchw will shed light on some of these mechanisms. This cascade of network changes has led to psychedelics being characterized as “psychoplastogens”, substances with the capability to facilitate rapid neural plasticity both in terms of structure and function ^[62][69][67,74]. At the level of the brain (Figure 1), several distinct and frequently complementary neuroscientific explanations have been put forth to elucidate the effects of psychedelics and the mechanisms underlying the psychedelic experience ^[70][71][75,76]. The three most prominent theories encompass the cortico-striato-thalamo-cortical (CSTC) model ^[72][63], the relaxed beliefs under psychedelics (REBUS) model ^[73][64], and the claustro-cortical circuit (CCC) model ^[74][65]. The CSTC model proposes that psychedelics, through the stimulation of 5-HT2ARs, disrupt information processing in the brain by altering the thalamo-cortical gating of external and internal information to the cortex ^[72][63]. This disruption leads to an increased flow of information or feedforward processing, resulting in various effects, including impaired sensorimotor gating, alterations in cognitive functioning, and changes in sensory and somatomotor cortical regions. This model is substantiated by both behavioral observations of impaired sensorimotor gating in humans following the administration of psilocybin ^[75][76][77,78], LSD ^[77][79] and ayahuasca ^[78][80], and neuroimaging findings demonstrating increased thalamic functional connectivity and synchronisation of cortical sensory regions in response to LSD ^[79][80][81,82]. The REBUS model suggests that psychedelics reduce the precision of high-level priors (or expectations and beliefs about the world) while simultaneously increasing the flow of bottom-up sensory information ^[73][64]. This model integrates the entropic brain hypothesis ^[81][83] and the free-energy principle, explaining how psychedelics influence brain function by altering the relative importance of prior beliefs and sensory information. This shift in signal weighting makes recurrent message transfer within the brain more responsive to modulation by incoming sensory signals, ultimately leading to increased complexity and entropy in neuronal dynamics. Preliminary empirical evidence supports this model, demonstrating that psychedelics like LSD, psilocybin, DMT, ketamine, and ayahuasca enhance signal diversity and measures of entropy in brain activity ^{[82][83][84][85][86]}[84,85,86,87,88]. While the REBUS model has influenced the field of psychedelic research as a potential overarching framework, it has faced criticism both conceptually (such as regarding entropy definition, low- and high-level brain region demarcation) and methodologically (small sample sizes of the studies and analytical choices), necessitating further rigorous research for confirmation ^[70][71][75,76]. The CCC model proposes that psychedelics interfere with coordination between cortical regions and the claustrum by directly activating 5-HT2ARs, which are abundant in the claustrum ^{[74][87][88][89]}[65,89,90,91]. This coordination plays a crucial role in cognitive control, which is diminished by the effects of psychedelics ^[74][89][65,91]. This model has substantial support from neuroimaging studies that have demonstrated that psilocybin significantly disrupts networks associated with cognitive control and the proper functioning of the claustrum ^[63][68]. While the CCC model holds promise in explaining the widespread effects of psychedelics on various brain networks, it currently lacks specificity in detailing how these changes in the claustrum affect specific canonical circuits ^[70][75]. Advanced imaging techniques, such as higher field fMRI, will be needed to better understand the flow of information between the claustrum and other brain regions. Additionally, although reduced cognitive control may contribute to some psychedelic effects, it appears insufficient to explain all of the varied acute subjective experiences associated with these substances ^[70][75]. The models and levels of analysis presented in Figure 1 include extra-pharmacological factors, such as social, contextual, and cultural elements, commonly referred to as “set” (comprising individual beliefs, expectations, and mindset) and “setting” (involving the environment and socio-historical context). Of particular note, music has consistently played a pivotal role in guiding and enhancing the therapeutic experience in the history of psychedelic research, and recent findings emphasize its ability to support processes like meaning-making, emotional responses, and mental imagery following psychedelic administration, ultimately contributing to positive clinical outcomes in psychedelic therapy ^[90][92].

3. 5-HT2A Receptor Signaling

Psychedelics have a similar chemical structure to serotonin (5-HT) ^[91][93]. Recent studies using advanced techniques like X-ray diffraction and cryo-electron microscopy have revealed the crystal structures of serotonin receptors when they are bound to psychedelic substances like LSD, psilocin, and others ^[92][93][62,94]. These studies provide new insights into how psychedelics work at the molecular level and their potential use in developing psychedelic-based treatments. Phenethylamines exhibit a greater level of specificity for 5-HT2A, 5-HT2B, and 5-HT2C receptors in comparison to tryptamines and ergolines ^[3][94][3,95]. In the past, it was widely believed that the therapeutic effects of psychedelics were mainly attributed to their activation of the 5-HT2AR ^{[95][96][97][98]}[96,97,98,99], but recent research has revealed the involvement of other receptors in producing these effects ^[50][51]. This belief is substantiated by evidence showing that the particular neural circuits in the central nervous system impacted by serotonergic psychedelics align with the distribution of serotonin receptors (Figure 2) ^[99][100]. The occupancy of 5-HT2ARs also exhibits a correlation with the subjective effects induced by psychedelics and these effects are suppressed by serotonin-2A antagonists ^{[65][99][100][101][102][103][104]}[70,100,101,102,103,104,105]. The 5-HT2ARs are prominently found in pyramidal neurons situated in layer 5 of the neocortex, the thalamus, and the reticular nucleus, with a significant concentration observed in the prefrontal cortex (PFC) ^{[103][105][106][107][108][109][110][111][112]}[104,106,107,108,109,110,111,112,113]. These brain areas are associated with functions like visual perception and attention, which likely contribute to the broad and diverse effects of psychedelics on cognitive, perceptual, and emotional processes. However, it is worth noting that other studies have indicated that the greatest concentration of these receptors is found in the striate and extrastriate visual cortex ^[78][103][80,104]. This observation could explain the frequent occurrence of visual hallucinations, a distinctive hallmark of classic psychedelics. Moreover, a recent study used a whole-brain model of serotonergic neuromodulation to investigate the entropic effects of 5-HT2AR activation, confirming the earlier findings of increased entropy and emphasizing that the most significant changes in entropy occurred in the visuo-occipital regions. Interestingly, this study also revealed that the overall reorganization of brain activity was more strongly associated with the brain’s anatomical connectivity than to the density of 5-HT2AR, offering valuable insights into the mechanisms behind the psychedelic experience and the broader regulation of brain functions by pharmacological means ^[113][114]. The expression of HT2AR is highest in excitatory neurons within the cortex, but it is also found in inhibitory interneurons. Specifically, in the prefrontal cortex, 5-HT2ARs are predominantly located on the postsynaptic side ^[114][115]. The 5-HT2AR, classified as a Class A G-protein-coupled receptor, is activated by its natural ligand, 5-HT, acting as an agonist. However, in contrast to 5-HT, psychedelic agonists targeting this receptor induce profound changes in perception and cognition. These effects can be explained by the ternary complex model of receptor activity for agonists ^[115][116][116,117]. This model suggests that drug molecules can shift the equilibrium between different receptor conformations, leading to “bias” in activating either G-protein-dependent or β-arrestin-dependent signaling pathways (Figure 3) ^{[117][118][119]}[118,119,120]. In a recent study, cryo-EM structures of LSD-bound HTR2B provided snapshots of LSD’s action. These revealed transitions from transducer-free, partially active states to transducer-coupled, fully active states, highlighting the potential for biased agonists with functional selectivity, which could be safer and more effective drugs for specific G-protein-coupled receptors (GPCRs) ^[120][121]. In the context of Gq-dependent signaling, both the psychedelic and non-psychedelic activators of 5-HT2AR stimulate Gq-like G proteins ^[121][123]. The process begins with the activation of PLCγ (Figure 3). This activation subsequently initiates the release of intracellular calcium through inositol trisphosphate (IP3) and triggers the activation of protein kinase C (PKC) via diacylglycerol (DAG). This, in turn, sets off various interconnected downstream pathways, including but not limited to the ERK, CREB, and mTOR pathways (Figure 3). Ultimately, these cascading events result in neuronal firing through multiple mechanisms, such as membrane depolarization, reduced afterhyperpolarization, and decreased spike frequency adaptation ^{[122][123][124][125]}[124,125,126,127] (Figure 3). The entry of calcium, along with the activation of calmodulin-dependent protein kinase II (CaMKII), which interacts with NMDA-type glutamate receptors and phosphorylates AMPA-type glutamate receptor subunits, leads to the specific strengthening and structural fortification of synapses, contributing to the process of long-term potentiation (LTP) that enhances synaptic connections during learning (Figure 3) ^[126][127][128,129]. Beyond G-protein-coupled pathways, 5-HT2AR agonism can also engage in β-arrestin signaling via PI3K and AKT (Figure 3) ^{[95][128][129]}[96,130,131]. Both of these signaling pathways can contribute to neural plasticity ^[130][131][132,133], and may underlie the persistent improvements observed in psychiatric disorders. However, recent research conducted in mice suggests that the therapeutic effects of psychedelics may be most closely linked to the activation of the BNDF-TrkB signaling pathway, rather than the 5-HT2AR ^[50][51]. Specifically, several studies have shown that the “head twitch response” in rodents, which is used as a proxy for the hallucinogenic effects of psychedelics in humans ^[94][95], relies on 5-HT2AR activation ^{[50][132][133]}[51,134,135], but that blocking the 5-HT2AR in mice did not prevent induced structural plasticity changes ^[50][51]. However, selectively restoring 5-HT2ARs in cortical pyramidal neurons was sufficient to rescue hallucinogen-induced head twitching in transgenic mice lacking 5-HT2Ars ^[134][135][136,137].