Chemistry

Psychedelics can be divided into three classes based on their chemical structure: tryptamines, ergolines, and phenethylamines (Figure 1). Tryptamines are characterized by an indole, which is a 6-member benzene ring fused to a 5-member pyrrole ring with an ethylamine chain at the C3 position. Addition of methyl groups to the ethylamine chain and different functional groups at other positions, e.g. C4 and C5, yields psilocybin, psilocin (the active metabolite of psilocybin), DMT, and 5-MeO-DMT (see Figure 1 for full names). These compounds are closely related to the endogenous neurotransmitter serotonin (also 5-hydroxytryptamine, or 5-HT), which is a tryptamine with a hydroxyl group at the C5 position. Ergolines, initially isolated from the ergot fungus and then further processed via chemical reactions, include LSD. The phenethylamine class, based on a scaffold of a benzene ring with an amino group attached through two-carbon, includes 2C-B, mescaline, amphetamine analogues such as DOI and DOM, and derivatives such as 25I-NBOMe.

In addition to the classical psychedelics, there are atypical compounds that produce related psychological effects, but do not share the same mechanism of action. These include some phenethylamines such as MDMA, deliriants such as muscimol and scopolamine, and dissociatives such as salvinorin A, ibogaine, nitrous oxide, phencyclidine (PCP), and ketamine. These atypical compounds are sometimes referred to as psychedelics, under a broader definition.

Psychedelics can be found naturally in fungi, plants, and animals. Psilocybin, for instance, is present in a few hundred species of mushrooms, some of which were used for healing and spiritual purposes by the Mayan and Aztec cultures of Mesoamerica. Naturally occurring psychedelics such as mescaline (found in peyote and San Pedro cactus) and DMT (as part of ayahuasca) may have also held cultural significance for early Indigenous peoples of the Americas, although the historical prevalence of these practices is less clear and a matter of debate. Other compounds are synthetic and were discovered as part of pharmaceutical development programs; these include MDMA by Anton Köllisch in 1912 and LSD by Albert Hofmann in 1943 (after initial synthesis in 1938). Today, psychedelics can be produced in multiple ways. For example, psilocybin can be obtained through extraction from mushrooms, enzymatic reactions in a bioreactor with bacteria or yeast, or chemical synthesis.

Properties

Psychedelics undergo various chemical reactions upon entering the body. Some are prodrugs, meaning that the parent compound is inert but is converted to metabolites that can enter the brain to be psychoactive. For example, psilocybin is typically taken through the mouth and dephosphorylated to psilocin in the intestinal lining and liver before entering blood circulation. By contrast, DMT is not bioavailable when orally ingested because it is rapidly eliminated by monoamine oxidase A (MAO-A) in the body. Concurrent use of DMT and an MAO inhibitor greatly increases exposure to the drug, leading to enhanced and prolonged drug effect. Depending on the route of administration, psychedelics are generally considered fast-acting drugs. Psilocin has a half-life of 2.5 hours in blood plasma following oral administration of psilocybin in humans with onset of psychoactive effects beginning at 20–40 minutes, with peak concentration and effects between 60–90 minutes, followed by an approximate 60-minute plateau before decreasing concentration. Within 6–8 hours, the subjective drug effects have mostly disappeared. However, psilocybin administered intravenously has a shorter half-life of 30 minutes and a much shorter duration of psychoactive effects of 15–30 minutes. Eventually, much of the psilocin is converted further to more soluble metabolites such as glucuronides and excreted in urine.

Psychedelics exert varied effects on perception, cognition, and mood. First-person accounts of the drug-evoked experiences indicate both overlapping and dissimilar features across the many compounds. Controlled studies have been performed for several compounds, including psilocybin, LSD, and MDMA. For example, psilocybin is reported to increase feelings of unity and transcendence of time and space, and to produce perceptual alterations akin to visual hallucinations, illusions, and synesthesia. However, it can also induce anxiety and distressing effects including a dread of ego dissolution, i.e. the loss of one’s sense of self. The acute episode is typically remembered long after the drug has left the system; in one study, most participants ranked it two months later as a significant, personally meaningful experience. There are typically minimal intellectual or memory impairments, and only slight autonomic side effects. Dose and route of administration are important variables contributing to the variance in behavioral effects.

A cornerstone of psychedelic administration is the concept of ‘set and setting’, which emphasizes the importance of participants’ psychological state (set) and the external environment in which the administration takes place (setting). There is evidence that administration in a safe physical environment with interpersonal support can mitigate negative experiences. With repeated use within days, people develop diminished response to psychedelics. Indeed, drug tolerance is rapidly induced and there is cross-tolerance across different psychedelics, which may be one reason that dependence and abuse are less common than with many other illicit drugs. Psychedelics are generally considered to be physiologically well tolerated, with relatively low toxicity. Adverse events are rare at psychoactive doses when administered in a controlled, supervised clinical setting.

Animal models

Psychedelics are noted for their ability to alter consciousness. Since the subjective experience cannot be observed externally, other proxy measures are needed to study the impact of psychedelics in animals. One popular assay is the head-twitch response. After the administration of a psychedelic, animals such as mice, rats, and rabbits exhibit rapid and stereotypical head movements that can be recorded with high-speed videography or magnetic sensors. When dozens of psychedelics were compared, their hallucinogenic potencies in humans correlate with their capacity to evoke head twitches in mice. Moreover, antagonist drugs that block psychedelic-induced hallucinations also abolish head-twitch responses. For these reasons, notwithstanding a few compounds that are known false positives, head-twitch response is considered a reliable surrogate readout for the hallucinatory experience. Another frequently used assay is drug discrimination. Animals undergo operant training for many weeks to distinguish a psychedelic (e.g. LSD) from saline and report by pressing one of two levers. During testing, a novel compound is presented and its ability to substitute for the psychedelic is evaluated by the lever presses. Drug discrimination can yield precise dose-dependence curves; these are typically assessed with rats, with fewer studies in mice and monkeys.

In addition to these psychedelic-selective assays, an array of general behavioral tests can be used to assess other aspects of drug effects. For example, depressive-like behavior can be studied using tests such as learned helplessness and sucrose preference. Psilocybin, for one, has been shown to ameliorate stress-induced deficits in mice. However, these assays were popularized based on their effectiveness in identifying first and second generation antidepressants. An important question is whether the tests are also suitable for characterizing the unique effects of psychedelics. Another example is the study of pro-social effects of MDMA, which can be modeled by measuring social approach in mice (and octopuses!). Fear extinction, the decrease in fear after repeated exposure associated with a conditioned stimulus, models aspects of exposure therapy for post-traumatic stress disorder and may be useful for evaluating the effects of psychedelics in trauma-related disorders. Overall, findings in animals suggest potentially beneficial actions, but extrapolating such findings to humans is difficult because each species has its own idiosyncratic behavioral repertoire. Moreover, there are species-specific differences in the blood–brain barrier permeability and pharmacokinetics of drugs and their metabolites.

Effects on the brain

The effects of psychedelics on the brain can be considered at multiple levels: molecular, cellular, circuit, and network (Figure 2). At the molecular level, psychedelics activate serotonin receptors at nanomolar concentrations, particularly the 2A subtype of serotonin receptors (5-HT_2A). Binding of tryptamine and ergoline psychedelics to 5-HT_2A receptors in the brain is required for the compounds’ consciousness-altering effects. The best evidence for this comes from studies involving the administration of selective 5-HT_2A antagonist ketanserin and the partial antagonist risperidone, which block the subjective effects of psychedelics. Other receptor subtypes likely also contribute: most psychedelics bind to 5-HT_2C receptors as well, and many tryptamines and ergolines have high affinity for 5-HT_1A receptors. Empathogens such as MDMA are exceptions because they act primarily by inhibiting serotonin reuptake. Non-serotonin receptors and multi-receptor heterocomplexes may also be involved in the effects of psychedelics, but have only been examined in a few studies. An exciting recent development is the structural determination of a psychedelic-bound 5-HT_2A receptor at near-atomic resolution. This detailed reconstruction of the receptor paves the way for computer simulations to test how thousands of candidate compounds may bind to serotonin receptors, enabling a new era of drug discovery.

The binding of psychedelics to serotonin receptors activates different signal transduction pathways within neurons. The canonical pathway involves the G-protein G_αq, which upon receptor activation dissociates from the receptor and from its G_βγ partners and activates other downstream effector proteins. There is a parallel, G-protein-independent pathway mediated by β-arrestins. Some psychedelics appear to be biased ligands such that they preferentially engage 5-HT_2A receptors in conformations that favor β-arrestin signaling over the G-protein pathway. In contrast to 5-HT_2A receptors, the 5-HT_1A receptors are G_i/o-protein coupled and activate other signaling proteins.

Engagement of these receptors and signal transduction pathways drives neural plasticity. Psychedelics can alter gene expression, including increasing the transcription of immediate early genes such as c-fos and other activity-dependent transcription factors associated with neural plasticity. Moreover, psychedelics modify the morphology of dendrites, the compartment of a neuron that receives most of the inputs from other cells. In cultured neurons, various psychedelics, including LSD, DMT, and DOI, have been shown to induce proliferation of dendritic branches. In live mice, when dendrites are imaged and tracked over time, the administration of a single dose of psilocybin increases the number of dendritic spines, the sites of excitatory inputs, for at least a month. Collectively, these enduring transcriptional and structural effects of psychedelics are important, because they persist beyond the short half-life of psychedelics in the body, reflecting long-lasting modifications to the brain.

Psychedelics are expected to act on certain cell types and in particular brain regions, a selectivity shaped by the complex expression patterns of serotonin receptors. 5-HT_2Areceptors are found predominantly in the neocortex, thalamus, locus coeruleus, ventral tegmental area, and claustrum. In the neocortex, most 5-HT_2A receptors reside on the dendrites of excitatory glutamatergic pyramidal neurons, although some are expressed in other cell types, such as inhibitory GABAergic interneurons. Consistent with this expression pattern, functional studies have shown that the administration of 5-HT agonists to apical dendrites produces an increase in the excitatory postsynaptic potentials. Less is known about the subcellular localization of other serotonin receptor subtypes. The impact of psychedelics on spiking activity dynamics has been reported for a handful of brain regions, such as the frontal cortex and dorsal raphe, but is largely unexplored in other brain areas.

At the level of whole brain, effects of psychedelics on different regions can be visualized using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Studies in humans revealed that psilocybin reduces activities in the medial frontal cortex and posterior cingulate cortex, which compose the default mode network. The default mode network is a set of brain regions that are more active during wakeful rest and less so when engaging the external world. Connectivity analyses of fMRI data suggest that activity covaries more tightly across many regions under the influence of psychedelics. These observations have led to intriguing hypotheses, including the idea that default mode network suppression may explain the experience of ego dissolution. However, many cognitive tasks, disease states, and drugs can also influence the default mode network, so whether this phenomenon is unique to psychedelics remains to be clarified.

Therapeutic potential

Mental health professionals in the 1950s and 1960s studied the potential beneficial effects of psychedelic drugs, especially LSD. While these studies were not up to modern methodological standards, they revealed promising effects in mood disorders and addiction. Unfortunately, unregulated recreational use produced a cultural and legal backlash, culminating in the Controlled Substances Act of 1970, which all but extinguished research into the potential therapeutic benefits of these agents. Research began to pick up in the late 1990s at a handful of institutions in the United States and Europe. It has accelerated enormously over the past ten years, and there is a growing belief among many that psychedelic pharmacology may represent a new era in psychiatric therapeutics.

Most clinical studies described over the past decade have focused on psilocybin. Much attention has been devoted to developing the appropriate set and setting to accompany the dosing experience; this focus sets the therapeutic use of psychedelics apart from many other pharmacological interventions, at least in current research practice. Trust and rapport are developed between the participant and facilitators through conversations prior to drug administration, in which the goal and intentions of treatment are thoroughly discussed. During the dosing session, one or two trained facilitators are present in the room and serve as an anchor for the participant. There are variations: depression studies tend to provide interpersonal support primarily during dosing with potentially a few follow-up integration sessions, but trials for substance use disorders have embedded psychedelic administration in a multi-week course of psychotherapy.

The first controlled studies of psilocybin treatment in the modern era, beginning in 2011, investigated its use to ameliorate the anxiety and depressive symptoms experienced by patients with advanced cancer. In 2016, investigators from Johns Hopkins University described a randomized, blinded, crossover study of low versus high dose psilocybin in 51 patients with advanced cancer. The high dose of psilocybin (22 or 30 mg/70 kg) produced a marked and lasting (>6 months) improvement in anxiety and depression symptoms, quality of life, life meaning, and optimism in 80% of patients. Investigators from New York University simultaneously published a study in 29 cancer sufferers treated with psilocybin (0.3 mg/kg) in comparison to an active placebo, niacin; psilocybin treatment led to lasting improvements. These landmark studies garnered enormous attention and made it clear to the broader community that the modern era of rigorous research into psychedelic therapeutics had arrived.

There have been similarly exciting early studies in the treatment of major depressive disorder (MDD) with psilocybin. Placebo-controlled studies have begun to appear in 2021. Griffiths and colleagues administered two doses of psilocybin (20 mg/70 kg and 30 mg/70 kg, one week apart, in conjunction with psychological support) to 27 patients with MDD, either immediately or after a waiting-list delay. Depression was markedly improved in the psilocybin group, compared to little change in the wait-list group. In another study, Carhart-Harris and colleagues randomized 59 patients with MDD to receive psilocybin (25 mg, with psychological support) and daily placebo to low-dose psilocybin (1 mg, with psychological support) and daily escitalopram, a commonly prescribed antidepressant. Both groups improved; the trend was towards greater improvement in the psilocybin group, though this did not reach statistical significance. These studies are small but impressive and suggest a substantial therapeutic benefit in MDD, comparable to or greater than that of standard medications. Larger studies are needed to corroborate these findings; several are in process.

Treatment studies of psilocybin in numerous other conditions are at an earlier phase. A proof-of-concept study in 10 subjects with alcohol use disorder showed that addition of psilocybin to standard psychotherapeutic treatment improved abstinence for up to 36 weeks. Results from a follow-up, controlled study are expected soon. Studies are also underway in obsessive-compulsive disorder, body dysmorphic disorder, anorexia nervosa, headache, substance use disorder, and a variety of other conditions.

In parallel work, investigators led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have investigated the use of MDMA with structured psychotherapy in the treatment of post-traumatic stress disorder (PTSD), with extremely promising results. The 90 participants were randomized to receive either MDMA or placebo, in conjunction with 12 psychotherapy sessions. Those receiving MDMA had a markedly and significantly greater reduction of PTSD symptoms and disability, without significant adverse events. This finding, capping more than two decades of focused work, represents one of the most promising new advances in the treatment of PTSD in many years.

This promising early data, across diagnoses, has caught the attention of regulators. Psilocybin and MDMA remain Schedule 1 drugs and thus legally available only in carefully regulated research settings, under federal law. In a few cases, such as Oregon, state and local laws have moved towards a more relaxed stance towards psilocybin use, creating a complicated regulatory landscape. The US Food and Drug Administration granted both psilocybin and MDMA ‘breakthrough therapy’ status for the treatment of depression and PTSD, respectively, acknowledging the promising early data and speeding the regulatory path towards approval, if controlled data continue to be positive. However, the legal status of these drugs has not been changed, and the data are not yet sufficient for them to be approved for any indication.

Open questions

For a more in-depth treatment of the state of the field, we refer the readers to several excellent review articles (e.g. Nichols, Pharmacol. Rev., 2016; Vollenweider and Preller, Nat. Rev. Neurosci. 2020). There are several key questions for which we lack clear answers. We know that the 5-HT_2A receptors are essential for the subjective effects of psychedelics. Is it the same or a different receptor subtype that is responsible for the potential therapeutic actions? Relatedly, can we engineer novel psychedelic-like compounds that minimize the subjective effects but retain the beneficial actions? What behavioral assays and neural measurements will be most effective for screening these new compounds? Psychedelics have been shown to promote neural plasticity. Is there something special about those new synaptic connections — for example, do they strengthen certain neural pathways in the brain? Finally, what are the neural and behavioral consequences of microdosing (the use of psychedelics at sub-hallucinogenic dose)?

Summary

We are at an interesting juncture in the research of psychedelics. On the one hand, there is enormous optimism and enthusiasm, motivated by positive results in small, careful studies in mood and anxiety disorders, and early experience in a range of other conditions. On the other hand, it must be acknowledged that work to date remains preliminary and needs validation by robust multi-site studies. Looking ahead, a deeper understanding of the chemistry and neurobiology of psychedelics will facilitate their use and accelerate the discovery of novel compounds — advances that will hopefully fulfill the immense potential of psychedelic pharmacology for treating neuropsychiatric disorders.

Chemistry

Psychedelics are classified into three main groups based on their chemical structure: tryptamines, ergolines, and phenethylamines. Tryptamines feature a specific chemical structure made of fused rings and an ethylamine chain. Examples include psilocybin, psilocin (which is the active form of psilocybin), DMT, and 5-MeO-DMT. These compounds share structural similarities with serotonin, a natural chemical messenger in the body. Ergolines, such as LSD, were originally found in a type of fungus and then altered through chemical processes. The phenethylamine group is built around a benzene ring with an attached amino group, and includes compounds like 2C-B, mescaline, and amphetamine-like substances such as DOI, DOM, and 25I-NBOMe.

Beyond these classical psychedelics, there are atypical compounds that produce similar psychological effects but work through different mechanisms. These include some phenethylamines like MDMA, deliriants such as muscimol and scopolamine, and dissociatives like salvinorin A, ibogaine, nitrous oxide, phencyclidine (PCP), and ketamine. These atypical compounds are sometimes broadly referred to as psychedelics.

Psychedelics occur naturally in fungi, plants, and animals. For instance, psilocybin is found in hundreds of mushroom species, some of which were historically used for healing and spiritual purposes by ancient Mesoamerican cultures. Other naturally occurring psychedelics, such as mescaline (from peyote and San Pedro cactus) and DMT (part of ayahuasca), may also have held cultural significance for early Indigenous peoples of the Americas, though historical details are debated. Some compounds are synthetic, discovered during pharmaceutical development; these include MDMA (synthesized in 1912) and LSD (synthesized in 1938 and its effects discovered in 1943). Today, psychedelics can be produced through various methods, including extraction from natural sources, enzymatic reactions in bioreactors, or chemical synthesis.

Properties

Once ingested, psychedelics undergo various chemical changes within the body. Some are prodrugs, meaning they are inactive in their original form but are converted into active substances that can affect the brain. For example, psilocybin, typically taken orally, is changed into psilocin in the gut and liver before entering the bloodstream. In contrast, DMT is not effective when taken by mouth because the body's monoamine oxidase A (MAO-A) enzyme quickly breaks it down. However, taking DMT with an MAO inhibitor significantly increases its presence in the body, leading to stronger and longer-lasting effects. Depending on how they are administered, psychedelics generally act quickly. Psilocin has a half-life of 2.5 hours in blood plasma after oral psilocybin use in humans, with effects starting in 20–40 minutes, peaking around 60–90 minutes, and then gradually diminishing over 6–8 hours. When administered intravenously, psilocybin has a shorter half-life of 30 minutes, resulting in psychoactive effects lasting only 15–30 minutes. Eventually, most psilocin is further converted into more water-soluble forms, such as glucuronides, and then excreted in urine.

Psychedelics create diverse effects on perception, thinking, and mood. Personal accounts suggest both common and unique experiences across different compounds. Controlled studies have been conducted on several compounds, including psilocybin, LSD, and MDMA. For example, psilocybin is reported to enhance feelings of unity and a sense of transcending time and space. It can also produce changes in perception, such as visual hallucinations, illusions, and synesthesia (where senses mix). However, it may also cause anxiety and distressing effects, including a fear of ego dissolution, which is the loss of one's sense of self. The intense experience is typically remembered long after the drug has left the system; in one study, most participants still considered it a significant, personally meaningful experience two months later. Generally, there are minimal problems with intellect or memory, and only minor effects on automatic body functions. The dose and method of administration significantly influence the behavioral effects.

A fundamental concept in psychedelic administration is "set and setting," which emphasizes the importance of a person's psychological state (set) and the external environment (setting) during the experience. Evidence suggests that administration in a safe, supportive environment can reduce negative experiences. With repeated use over short periods, individuals quickly develop a reduced response to psychedelics. This rapid development of drug tolerance, including cross-tolerance among different psychedelics, may contribute to why dependence and abuse are less common compared to many other illicit drugs. Psychedelics are generally considered to be well-tolerated by the body and have relatively low toxicity. Serious negative events are rare at mind-altering doses when administered in a controlled, supervised clinical setting.

Animal models

Psychedelics are known for their ability to alter consciousness. Since the subjective experience cannot be directly observed in animals, other indirect measures are used to study their impact. A common test is the head-twitch response. After receiving a psychedelic, animals like mice, rats, and rabbits show rapid, repetitive head movements that can be recorded. When dozens of psychedelics were compared, their ability to cause head twitches in mice correlated with their hallucinogenic strength in humans. Additionally, drugs that block psychedelic-induced hallucinations also prevent head-twitch responses. For these reasons, despite a few known false positives, the head-twitch response is considered a reliable indicator of the hallucinatory experience. Another frequently used test is drug discrimination. Animals undergo weeks of training to distinguish a psychedelic (e.g., LSD) from a salt solution by pressing one of two levers. During testing, if a new compound causes the animal to press the psychedelic lever, it indicates a similar drug effect. Drug discrimination tests can provide precise information about how effects change with different doses; these studies are typically done with rats, less often with mice and monkeys.

In addition to these specific tests for psychedelics, a range of general behavioral tests can assess other effects. For example, depressive-like behavior can be studied using tests such as learned helplessness and sucrose preference. Psilocybin, for instance, has been shown to improve stress-related problems in mice. However, it is important to consider whether these tests, popularized for identifying first and second-generation antidepressants, are suitable for characterizing the unique effects of psychedelics. Another example is studying the pro-social effects of MDMA, which can be modeled by measuring social approach in mice (and octopuses). Fear extinction, the reduction of fear after repeated exposure to a feared stimulus, models aspects of exposure therapy for post-traumatic stress disorder and may be useful for evaluating the effects of psychedelics in trauma-related conditions. Overall, findings in animals suggest potential benefits, but applying these findings to humans is challenging due to each species' unique behaviors, and differences in how drugs and their active forms cross into the brain and are processed by the body.

Effects on the brain

The effects of psychedelics on the brain can be examined at multiple levels: molecular, cellular, neural circuit, and overall brain network. At the molecular level, psychedelics activate serotonin receptors, particularly the 2A subtype (5-HT2A), even at very low concentrations. For tryptamine and ergoline psychedelics to alter consciousness, they must bind to 5-HT2A receptors in the brain. Strong evidence for this comes from studies where selective 5-HT2A blockers, like ketanserin and risperidone, prevent the subjective effects of psychedelics. Other receptor subtypes likely contribute as well: most psychedelics also bind to 5-HT2C receptors, and many tryptamines and ergolines have a strong affinity for 5-HT1A receptors. Empathogens, such as MDMA, are exceptions because their primary action is to prevent serotonin from being reabsorbed by neurons. Non-serotonin receptors and complex groupings of multiple receptors might also be involved in psychedelic effects, but these have been less studied. A recent breakthrough is the identification of the atomic structure of a 5-HT2A receptor with a psychedelic attached. This detailed understanding of the receptor enables computer simulations to predict how thousands of potential compounds might bind to serotonin receptors, opening new avenues for drug discovery.

The binding of psychedelics to serotonin receptors activates different signaling pathways within neurons. The standard pathway involves a G-protein called Gαq. When the receptor is activated, Gαq separates and activates other proteins further down the signaling chain. There is also a parallel pathway that does not involve G-proteins, but is mediated by β-arrestins. Some psychedelics appear to be "biased ligands," meaning they preferentially activate 5-HT2A receptors in a way that favors the β-arrestin signaling pathway over the G-protein pathway. In contrast to 5-HT2A receptors, 5-HT1A receptors are linked to Gi/o-proteins and activate other signaling proteins.

Engagement of these receptors and signaling pathways drives neural plasticity, which is the brain's ability to change and adapt. Psychedelics can alter gene expression, including increasing the production of immediate early genes like c-fos and other genes linked to neural plasticity that are activated by brain activity. Moreover, psychedelics modify the shape of dendrites, which are parts of neurons that receive most signals from other cells. In cultured neurons, various psychedelics, including LSD, DMT, and DOI, have been shown to cause dendrites to grow more branches. In living mice, imaging dendrites over time revealed that a single dose of psilocybin increases the number of dendritic spines, the points where excitatory signals enter, for at least a month. Collectively, these lasting changes in gene activity and brain structure are significant because they persist long after the psychedelics have left the body, reflecting enduring modifications to the brain.

Psychedelics are expected to act on specific cell types and brain regions, a selectivity influenced by the complex distribution patterns of serotonin receptors. 5-HT2A receptors are found mainly in the neocortex, thalamus, locus coeruleus, ventral tegmental area, and claustrum. In the neocortex, most 5-HT2A receptors are located on the dendrites of excitatory pyramidal neurons that use glutamate, though some are also found in other cell types, such as inhibitory interneurons that use GABA. Consistent with this distribution, functional studies have shown that activating 5-HT receptors on apical dendrites increases excitatory signals entering the neuron. Less is known about the exact location within cells of other serotonin receptor types. The impact of psychedelics on patterns of electrical activity has been reported for a few brain regions, such as the frontal cortex and dorsal raphe, but remains largely unexplored in other areas.

At the level of the whole brain, the effects of psychedelics on different regions can be visualized using brain imaging techniques like positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Studies in humans have shown that psilocybin reduces activity in the medial frontal cortex and posterior cingulate cortex, which are components of the default mode network. This network consists of brain regions that are more active during wakeful rest and less active when a person is interacting with the external world. Connectivity analyses of fMRI data suggest that brain activity across many regions becomes more coordinated under the influence of psychedelics. These observations have led to intriguing hypotheses, including the idea that reduced activity in the default mode network might explain the feeling of losing one's sense of self. However, many cognitive tasks, disease states, and drugs can also influence the default mode network, so whether this phenomenon is unique to psychedelics is still unclear.

Therapeutic potential

Early research in the mid-20th century explored the therapeutic potential of psychedelic drugs, especially LSD, for mood disorders and addiction. While these studies did not meet modern methodological standards, they showed promising effects. Unfortunately, widespread unregulated recreational use led to a cultural and legal backlash, culminating in the Controlled Substances Act of 1970, which largely halted research into these compounds' therapeutic benefits. Research began to resume in the late 1990s at a few institutions in the United States and Europe, accelerating significantly over the past decade. There is a growing belief that psychedelic pharmacology may represent a new era in psychiatric treatments. A key aspect of modern therapeutic use involves the concept of "set and setting," emphasizing the importance of the patient's psychological state and the supportive environment during administration. This includes developing trust and rapport with facilitators through discussions before drug administration, thoroughly reviewing treatment goals and intentions. During the dosing session, one or two trained facilitators are present to provide support. While approaches vary (e.g., depression studies often focus on support primarily during dosing with some follow-up, while substance use disorder trials integrate psychedelics into multi-week psychotherapy), the core emphasis on personalized support remains.

Recent clinical studies have largely focused on psilocybin. The first controlled studies in the modern era, beginning in 2011, investigated its use to reduce anxiety and depressive symptoms in patients with advanced cancer. In 2016, researchers at Johns Hopkins University published a randomized, blinded, crossover study in 51 patients with advanced cancer. They found that a high dose of psilocybin (22 or 30 mg/70 kg) produced a marked and lasting improvement (over six months) in anxiety, depression symptoms, quality of life, life meaning, and optimism in 80% of patients. Simultaneously, New York University researchers published a study in 29 cancer patients treated with psilocybin (0.3 mg/kg) compared to an active placebo (niacin), with psilocybin leading to lasting improvements. These landmark studies garnered significant attention, making it clear to the broader scientific community that a new era of rigorous research into psychedelic therapeutics had arrived.

Similarly exciting early studies have emerged regarding the treatment of major depressive disorder (MDD) with psilocybin. Placebo-controlled studies began appearing in 2021. In one study, 27 patients with MDD received two doses of psilocybin (20 mg/70 kg and 30 mg/70 kg, one week apart, with psychological support), either immediately or after a waiting-list delay. Depression significantly improved in the psilocybin group, with little change in the wait-list group. In another study, 59 patients with MDD were randomized to receive either psilocybin (25 mg, with psychological support) and daily placebo, or low-dose psilocybin (1 mg, with psychological support) and daily escitalopram, a common antidepressant. Both groups showed improvement; while the trend suggested greater improvement in the psilocybin group, it did not reach statistical significance. These studies, though small, are impressive and suggest a substantial therapeutic benefit in MDD, potentially comparable to or greater than that of standard medications. Larger studies are currently underway to confirm these findings.

Treatment studies of psilocybin for numerous other conditions are in earlier stages. A proof-of-concept study involving 10 individuals with alcohol use disorder showed that adding psilocybin to standard psychotherapeutic treatment improved abstinence for up to 36 weeks. Results from a follow-up, controlled study are anticipated soon. Research is also underway for obsessive-compulsive disorder, body dysmorphic disorder, anorexia nervosa, headache, other substance use disorders, and a variety of additional conditions.

In parallel work, researchers led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have investigated the use of MDMA with structured psychotherapy for post-traumatic stress disorder (PTSD), yielding extremely promising results. In a study, 90 participants were randomized to receive either MDMA or placebo, alongside 12 psychotherapy sessions. Those who received MDMA experienced a markedly and significantly greater reduction in PTSD symptoms and disability, without significant adverse events. This finding, representing over two decades of dedicated work, is considered one of the most promising new advancements in PTSD treatment in many years.

This promising early data, across various diagnoses, has captured the attention of regulatory bodies. Under federal law, psilocybin and MDMA remain Schedule 1 drugs, meaning they are legally available only in carefully regulated research settings. In some cases, like Oregon, state and local laws have moved towards a more relaxed stance on psilocybin use, creating a complex regulatory landscape. The U.S. Food and Drug Administration has granted both psilocybin and MDMA "breakthrough therapy" status for the treatment of depression and PTSD, respectively. This status acknowledges promising early data and aims to speed up the regulatory path toward approval, provided controlled data continue to be positive. However, the legal status of these drugs has not yet changed, and the data are not yet sufficient for them to be approved for any general medical use.

Open questions

Several key questions regarding psychedelics currently lack clear answers. It is known that 5-HT2A receptors are essential for the subjective effects of psychedelics. A crucial question is whether the same or a different receptor subtype is responsible for their potential therapeutic actions. Relatedly, can novel psychedelic-like compounds be designed that minimize subjective effects while retaining beneficial actions? What behavioral and neural measurements will be most effective for evaluating these new compounds? Psychedelics have been shown to promote neural plasticity; is there something unique about these new synaptic connections, such as whether they strengthen specific brain pathways? Finally, what are the neural and behavioral consequences of microdosing (the use of psychedelics at very low, non-hallucinogenic doses)?

Summary

Research into psychedelics stands at a critical point. On one hand, there is significant optimism and enthusiasm driven by positive outcomes in small, carefully conducted studies for mood and anxiety disorders, and early findings in a range of other conditions. On the other hand, it must be recognized that current research is still preliminary and requires confirmation through large-scale, multi-site studies. Looking ahead, a more thorough understanding of psychedelic chemistry and neurobiology will aid their use and speed up the discovery of new compounds. These advancements are expected to realize the vast potential of psychedelic medicine for treating brain and mental health disorders.

Psychedelics

Chemistry

Psychedelics are classified into three main groups based on their chemical structure: tryptamines, ergolines, and phenethylamines. Tryptamines feature an indole structure, which combines a six-member benzene ring with a five-member pyrrole ring, and an ethylamine chain. Examples of tryptamines include psilocybin, psilocin (the active form of psilocybin), DMT, and 5-MeO-DMT. These compounds share a close chemical resemblance to serotonin, a natural brain chemical. Ergolines, which were first found in a fungus, include substances like LSD. Phenethylamines are built around a benzene ring with an amino group connected by two carbon atoms. This group contains compounds such as 2C-B, mescaline, and other related substances like DOI, DOM, and 25I-NBOMe.

Beyond these traditional psychedelics, some atypical compounds produce similar psychological effects through different mechanisms. This broader category includes some phenethylamines like MDMA, deliriants such as muscimol and scopolamine, and dissociatives like salvinorin A, ibogaine, nitrous oxide, phencyclidine (PCP), and ketamine. These atypical compounds are sometimes also referred to as psychedelics, depending on the definition used.

Psychedelics occur naturally in fungi, plants, and animals. For example, psilocybin is found in hundreds of mushroom species, some of which were historically used for healing and spiritual purposes by ancient Mesoamerican cultures. Naturally occurring psychedelics like mescaline (from peyote and San Pedro cacti) and DMT (in ayahuasca) may have also held cultural importance for early Indigenous peoples of the Americas, though historical evidence for these practices is less clear. Other psychedelic compounds are synthetic, developed during pharmaceutical research. MDMA was discovered in 1912, and LSD was first synthesized in 1938 and its psychoactive effects noted in 1943. Today, psychedelics can be produced in various ways, including extraction from natural sources, enzymatic processes using bacteria or yeast, or chemical synthesis.

Properties

Psychedelics undergo various chemical changes within the body. Some are "prodrugs," meaning the original compound is inactive until the body converts it into an active form that can reach the brain. For instance, psilocybin, typically taken orally, is changed into psilocin in the gut and liver before entering the bloodstream. In contrast, DMT is not effective when taken by mouth because an enzyme called monoamine oxidase A (MAO-A) quickly breaks it down. However, taking DMT with an MAO inhibitor significantly increases its presence in the body, leading to stronger and longer-lasting effects. Depending on how they are administered, psychedelics generally act quickly. Psilocin, after oral psilocybin intake, has a half-life of 2.5 hours in the blood plasma, with effects beginning in 20–40 minutes, peaking around 60–90 minutes, and largely fading after 6–8 hours. Intravenous psilocybin, however, has a shorter half-life of 30 minutes and effects lasting only 15–30 minutes. Most psilocin is eventually converted into more soluble forms and excreted in urine.

Psychedelics influence perception, thinking, and mood in various ways. Personal accounts of drug-induced experiences describe both shared and unique effects across different compounds. Controlled studies have been conducted on several psychedelics, including psilocybin, LSD, and MDMA. For example, psilocybin is reported to enhance feelings of unity and a sense of timelessness, and to cause changes in perception such as visual alterations, illusions, and synesthesia. However, it can also lead to anxiety and distressing experiences, including a fear of "ego dissolution"—the loss of one's sense of self. The intense experience is usually remembered long after the drug's effects have worn off; one study found that participants still considered it a significant, personally meaningful experience two months later. Typically, intellectual and memory functions remain largely intact, with only minor physical side effects. The dose and method of administration are important factors influencing the behavioral effects.

A key principle in psychedelic use is "set and setting," which emphasizes the importance of a person's psychological state (set) and the environment where the drug is administered (setting). Research suggests that administration in a safe, supportive setting can help reduce negative experiences. With repeated use over several days, individuals develop a diminished response to psychedelics. This rapid development of drug tolerance, and cross-tolerance between different psychedelics, may contribute to why dependence and misuse are less common compared to many other illicit drugs. Psychedelics are generally considered to be physically well-tolerated and have relatively low toxicity. Adverse events are rare at psychoactive doses when administered in a controlled, supervised clinical environment.

Animal models

Psychedelics are known for their ability to alter consciousness. Since the subjective experience cannot be directly observed in animals, researchers rely on other measurable behaviors to study their effects. One common test is the "head-twitch response." After receiving a psychedelic, animals like mice, rats, and rabbits show rapid, repetitive head movements that can be recorded. When comparing dozens of psychedelics, their ability to induce head twitches in mice correlates with their hallucinogenic potency in humans. Furthermore, drugs that block psychedelic-induced hallucinations in humans also prevent head-twitch responses in animals. For these reasons, despite a few known exceptions, the head-twitch response is considered a reliable indicator of hallucinatory effects. Another frequently used test is "drug discrimination." Animals are trained for weeks to distinguish a psychedelic (e.g., LSD) from a saline solution by pressing one of two levers. During testing, a new compound is introduced, and its ability to produce the same lever press response as the known psychedelic indicates its similarity. Drug discrimination tests, often conducted with rats, can provide precise dose-response curves.

In addition to these specific psychedelic tests, a range of general behavioral tests can assess other aspects of drug effects. For example, behaviors associated with depression can be studied using tests like learned helplessness and sucrose preference. Psilocybin, for instance, has been shown to alleviate stress-induced deficits in mice. However, it is an important question whether these tests, popularized for identifying traditional antidepressants, are also suitable for characterizing the unique effects of psychedelics. Another area of study is the pro-social effects of MDMA, which can be modeled by observing social approach behaviors in mice (and even octopuses). Fear extinction, which involves reducing fear after repeated exposure to a feared stimulus, models aspects of exposure therapy for post-traumatic stress disorder (PTSD) and may be useful for evaluating psychedelic effects in trauma-related conditions. Overall, animal findings suggest potential benefits, but translating these findings to humans is challenging due to species-specific behaviors and differences in how drugs and their active forms move through the body and brain.

Effects on the brain

The effects of psychedelics on the brain can be examined at various levels: molecular, cellular, circuit, and network. At the molecular level, psychedelics activate serotonin receptors, particularly the 2A subtype (5-HT2A), even at very low concentrations. The binding of tryptamine and ergoline psychedelics to 5-HT2A receptors in the brain is necessary for their consciousness-altering effects. This is supported by studies where selective blockers of 5-HT2A receptors, such as ketanserin and risperidone, prevent the subjective effects of psychedelics. Other receptor subtypes likely also play a role; most psychedelics bind to 5-HT2C receptors, and many also have a strong affinity for 5-HT1A receptors. Empathogens like MDMA are different, as their primary action is to inhibit serotonin reuptake. Non-serotonin receptors and complex multi-receptor interactions might also be involved, but these have been explored in only a few studies. A recent breakthrough is the detailed structural mapping of a psychedelic-bound 5-HT2A receptor, paving the way for computer simulations to predict how thousands of potential compounds might bind to serotonin receptors, leading to new drug discovery approaches.

When psychedelics bind to serotonin receptors, they activate different signaling pathways within neurons. The primary pathway involves a G-protein called Gαq, which, upon receptor activation, separates from the receptor and its partners to activate other proteins inside the cell. There is also a separate pathway that does not involve G-proteins, mediated by proteins called β-arrestins. Some psychedelics appear to be "biased ligands," meaning they preferentially activate 5-HT2A receptors in ways that favor the β-arrestin pathway over the G-protein pathway. In contrast to 5-HT2A receptors, 5-HT1A receptors are linked to Gi/o-proteins and activate different signaling proteins.

The activation of these receptors and signaling pathways drives neural plasticity, meaning the brain's ability to change and adapt. Psychedelics can alter gene expression, including increasing the activity of "immediate early genes" like c-fos and other genes involved in neural plasticity. Additionally, psychedelics modify the structure of dendrites, the parts of a neuron that receive signals from other cells. In laboratory-grown neurons, various psychedelics, including LSD, DMT, and DOI, have been shown to cause new dendritic branches to grow. In live mice, single doses of psilocybin have been observed to increase the number of dendritic spines—the sites where excitatory signals are received—for at least a month. These lasting changes in gene expression and brain structure are significant because they persist long after the psychedelics have left the body, indicating long-term modifications to the brain.

Psychedelics are expected to act on specific cell types and brain regions, a selectivity determined by the complex distribution patterns of serotonin receptors. 5-HT2A receptors are found mainly in the neocortex, thalamus, locus coeruleus, ventral tegmental area, and claustrum. In the neocortex, most 5-HT2A receptors are located on the dendrites of excitatory neurons called pyramidal neurons, though some are found on other cell types, like inhibitory GABAergic interneurons. Consistent with this distribution, studies have shown that activating 5-HT receptors on apical dendrites increases excitatory signals. Less is known about the exact locations of other serotonin receptor subtypes within cells. The impact of psychedelics on the electrical activity of neurons has been reported for a few brain regions, such as the frontal cortex and dorsal raphe, but remains largely unstudied in other areas.

At the whole-brain level, the effects of psychedelics on different regions can be visualized using imaging techniques like positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Studies in humans have shown that psilocybin reduces activity in the medial frontal cortex and posterior cingulate cortex, which are part of the default mode network. The default mode network is a group of brain regions more active during resting states and less active when engaging with the outside world. Connectivity analyses of fMRI data suggest that under the influence of psychedelics, activity in many brain regions becomes more strongly linked. These observations have led to interesting theories, such as the idea that suppression of the default mode network might explain the experience of ego dissolution. However, many cognitive tasks, medical conditions, and other drugs can also influence the default mode network, so whether this phenomenon is unique to psychedelics requires further clarification.

Therapeutic potential

In the 1950s and 1960s, mental health professionals explored the potential benefits of psychedelic drugs, especially LSD. While these early studies did not meet modern scientific standards, they showed promising effects for mood disorders and addiction. Unfortunately, widespread unregulated recreational use led to a cultural and legal backlash, culminating in the Controlled Substances Act of 1970. This legislation effectively halted research into the therapeutic potential of these substances. Research slowly began to resume in the late 1990s at a few institutions in the United States and Europe. It has accelerated dramatically over the past decade, and many now believe that psychedelic pharmacology could usher in a new era in psychiatric treatment.

Most clinical studies conducted over the past decade have focused on psilocybin. Much attention has been given to developing the appropriate "set and setting" to accompany the dosing experience. This emphasis distinguishes the therapeutic use of psychedelics from many other drug treatments, at least in current research practices. Participants build trust and rapport with facilitators through conversations before drug administration, thoroughly discussing treatment goals and intentions. During the dosing session, one or two trained facilitators are present, serving as a supportive presence for the participant. While depression studies tend to provide interpersonal support primarily during dosing with some follow-up integration sessions, trials for substance use disorders have incorporated psychedelic administration within a multi-week course of psychotherapy.

The first controlled studies of psilocybin treatment in the modern era, beginning in 2011, investigated its use to alleviate anxiety and depressive symptoms in patients with advanced cancer. In 2016, researchers from Johns Hopkins University published a randomized, blinded, crossover study involving 51 patients with advanced cancer. A high dose of psilocybin (22 or 30 mg/70 kg) produced a significant and lasting (over 6 months) improvement in anxiety and depression symptoms, quality of life, sense of meaning in life, and optimism in 80% of patients. Simultaneously, New York University researchers published a study in 29 cancer patients treated with psilocybin (0.3 mg/kg) compared to an active placebo (niacin); psilocybin treatment also led to lasting improvements. These landmark studies garnered significant attention and clearly demonstrated to the wider community that a new era of rigorous psychedelic research had arrived.

Similarly encouraging early studies have explored psilocybin's potential in treating major depressive disorder (MDD). Placebo-controlled studies began appearing in 2021. Griffiths and colleagues administered two doses of psilocybin (20 mg/70 kg and 30 mg/70 kg, one week apart, with psychological support) to 27 MDD patients, either immediately or after a waiting period. Depression symptoms significantly improved in the psilocybin group, with little change in the wait-list group. In another study, Carhart-Harris and colleagues randomized 59 MDD patients to receive either psilocybin (25 mg, with psychological support) and a daily placebo, or a low-dose psilocybin (1 mg, with psychological support) and daily escitalopram, a common antidepressant. Both groups showed improvement; the psilocybin group tended to show greater improvement, though this difference was not statistically significant. These small but impressive studies suggest a substantial therapeutic benefit in MDD, potentially comparable to or greater than standard medications. Larger studies are needed to confirm these findings, and several are currently underway.

Treatment studies of psilocybin for numerous other conditions are in earlier stages. A preliminary study involving 10 individuals with alcohol use disorder showed that adding psilocybin to standard psychotherapy improved abstinence rates for up to 36 weeks. Results from a follow-up controlled study are anticipated soon. Studies are also ongoing for conditions such as obsessive-compulsive disorder, body dysmorphic disorder, anorexia nervosa, certain types of headaches, and various other substance use disorders. In parallel work, researchers led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have investigated the use of MDMA with structured psychotherapy for post-traumatic stress disorder (PTSD), yielding extremely promising results. In a study, 90 participants were randomly assigned to receive either MDMA or placebo, along with 12 psychotherapy sessions. Those receiving MDMA experienced a significantly greater reduction in PTSD symptoms and disability, with no major adverse events. This finding, the culmination of over two decades of dedicated work, represents one of the most promising recent advancements in PTSD treatment.

This encouraging early data, across various diagnoses, has captured the attention of regulatory bodies. Psilocybin and MDMA remain Schedule 1 drugs under federal law, meaning they are legally available only in carefully controlled research settings. However, some states and localities, like Oregon, have adopted more lenient stances towards psilocybin use, creating a complex regulatory environment. The U.S. Food and Drug Administration (FDA) has granted both psilocybin and MDMA "breakthrough therapy" status for the treatment of depression and PTSD, respectively. This designation acknowledges the promising early data and aims to accelerate the regulatory path toward approval, provided that controlled data continue to be positive. However, the legal status of these drugs has not changed, and the data are not yet sufficient for them to be approved for any medical use.

Open questions

For a more comprehensive understanding of the field's current state, interested readers can refer to several excellent review articles. There are several key questions for which clear answers are still needed. Researchers know that 5-HT2A receptors are essential for the subjective effects of psychedelics. It remains unclear whether the same or a different receptor subtype is responsible for their potential therapeutic actions. Related to this, researchers are exploring whether new psychedelic-like compounds can be designed to minimize subjective effects while retaining beneficial actions. Determining the most effective behavioral and neural measures for screening these new compounds is also a challenge. Psychedelics have been shown to promote neural plasticity. An important question is whether the new synaptic connections they form are special in some way—for example, do they strengthen particular neural pathways in the brain? Finally, the neural and behavioral consequences of microdosing (using psychedelics at sub-hallucinogenic doses) are not yet fully understood.

Summary

Current research into psychedelics stands at an interesting point. On one hand, there is significant optimism and enthusiasm, driven by positive results from small, carefully conducted studies in mood and anxiety disorders, and early findings in a range of other conditions. On the other hand, it is important to acknowledge that the work to date is still preliminary and requires validation through robust, multi-site studies. Looking ahead, a deeper understanding of the chemistry and neurobiology of psychedelics will facilitate their application and accelerate the discovery of new compounds. These advancements will hopefully fulfill the immense potential of psychedelic pharmacology for treating various neuropsychiatric disorders.

Chemistry

Psychedelic substances are categorized into three main types based on their chemical makeup: tryptamines, ergolines, and phenethylamines. Tryptamines share a core structure that resembles serotonin, a natural brain chemical. Examples include psilocybin, psilocin (which is what psilocybin turns into in the body), and DMT. Ergolines, which include LSD, were first found in a type of fungus. The phenethylamine group contains substances like mescaline and other similar compounds such as 2C-B and DOI.

Besides these traditional psychedelics, there are other compounds that cause similar mind-altering effects but work differently in the body. These include some phenethylamines like MDMA, deliriants such as muscimol, and dissociatives like ketamine and PCP. Sometimes, these are also broadly referred to as psychedelics.

Some psychedelics occur naturally in fungi, plants, and animals. For instance, psilocybin is found in many mushroom species, which ancient cultures like the Mayans and Aztecs used for healing and spiritual practices. Naturally occurring psychedelics such as mescaline (from peyote and San Pedro cactus) and DMT (in ayahuasca) may have also been important to early Indigenous peoples. Other psychedelics are synthetic, meaning they were created in a lab. MDMA was discovered in 1912, and LSD in 1943. Today, substances like psilocybin can be obtained from mushrooms, made using biological processes with bacteria or yeast, or created through chemical synthesis.

Properties

Once consumed, psychedelics undergo various chemical changes in the body. Some are "prodrugs," meaning the original substance is inactive until it is converted into an active form. For example, when psilocybin is eaten, it changes into psilocin in the gut and liver before reaching the brain. In contrast, DMT taken by mouth is quickly broken down and does not have an effect unless taken with another substance that prevents its breakdown. Depending on how they are taken, psychedelics usually act quickly. Psilocin, from psilocybin, stays in the blood for about 2.5 hours, with effects starting in 20–40 minutes, peaking around 60–90 minutes, and generally fading within 6–8 hours. Psilocin is eventually changed into more water-soluble forms and leaves the body through urine.

Psychedelics can significantly change how a person perceives things, thinks, and feels. People describe similar but also different experiences across various compounds. Studies on psilocybin, LSD, and MDMA show that psilocybin can lead to feelings of unity, a sense of timelessness, and altered perceptions, including visual changes and synesthesia (where senses mix). However, it can also cause anxiety and distress, such as a fear of losing one's sense of self. The intense experience is often remembered long after the drug wears off, with many participants considering it a very important personal event. Generally, there are minimal impacts on intellect or memory, and only minor physical side effects. The amount of the substance taken and how it is administered greatly affect the experience.

A core principle in psychedelic administration is "set and setting," which emphasizes the importance of a person's mindset (set) and the environment (setting) where the substance is taken. Research suggests that taking psychedelics in a safe, supportive environment with professional guidance can help reduce negative experiences. If used repeatedly over a few days, the body quickly develops a tolerance to psychedelics, meaning larger doses are needed for the same effect. This rapid tolerance, along with cross-tolerance between different psychedelics, might be why dependence and abuse are less common compared to many other illicit drugs. Generally, psychedelics are considered safe for the body, with low toxicity. Serious side effects are rare when administered in a controlled, supervised clinical setting.

Animal models

Because the subjective experience of altered consciousness cannot be directly observed in animals, researchers use other methods to study the effects of psychedelics. One common method is the "head-twitch response." After a psychedelic is given, animals like mice, rats, and rabbits show quick, repetitive head movements. Studies have found a link between how strongly a psychedelic causes hallucinations in humans and how much it causes head twitches in mice. Also, drugs that block psychedelic-induced hallucinations in humans also stop the head-twitch response in animals. Because of this, the head-twitch response is seen as a reliable way to gauge the hallucinatory experience, with a few known exceptions. Another common test is "drug discrimination." Animals are trained for weeks to tell the difference between a psychedelic (like LSD) and a saline solution by pressing different levers. During testing, a new compound is introduced, and its ability to act like the psychedelic is measured by which lever the animal presses. This test can precisely show how much of a drug is needed to produce an effect.

In addition to these specific psychedelic tests, a variety of general behavioral tests can be used to assess other drug effects. For example, behaviors related to depression can be studied using tests like "learned helplessness" or "sucrose preference." Psilocybin, for instance, has been shown to improve stress-related problems in mice. However, these tests were developed mainly to find traditional antidepressants, so it is debated whether they fully capture the unique effects of psychedelics. Another example is studying the pro-social effects of MDMA, which can be observed by measuring how much mice or octopuses approach others. "Fear extinction," where fear decreases after repeated exposure to a feared trigger, can model parts of therapy for post-traumatic stress disorder (PTSD) and might be useful for evaluating psychedelics in trauma-related conditions. While animal studies suggest potential benefits, it is challenging to apply these findings directly to humans due to differences in behavior and how drugs are processed in each species.

Effects on the brain

Psychedelics affect the brain at different levels: how they interact with molecules, how they change individual cells, how they impact brain circuits, and how they alter overall brain networks. At the molecular level, psychedelics activate specific serotonin receptors, especially the 5-HT2A subtype, even at very low concentrations. This binding to 5-HT2A receptors in the brain is necessary for psychedelics to alter consciousness. Evidence for this comes from studies where drugs that block 5-HT2A receptors, like ketanserin, prevent the subjective effects of psychedelics. Other serotonin receptor types likely play a role too, as most psychedelics bind to 5-HT2C receptors, and many also strongly bind to 5-HT1A receptors. Substances like MDMA are different because they primarily work by preventing serotonin from being reabsorbed in the brain. Other non-serotonin receptors may also be involved. A recent significant discovery is the detailed atomic structure of a psychedelic bound to a 5-HT2A receptor, which could help in designing new drugs.

When psychedelics bind to serotonin receptors, they activate different signaling pathways within brain cells (neurons). The main pathway involves a protein called Gαq, which then activates other proteins. There's also a separate pathway that does not involve G-proteins but uses β-arrestins instead. Some psychedelics appear to favor the β-arrestin pathway over the G-protein pathway when interacting with 5-HT2A receptors. In contrast, 5-HT1A receptors activate different signaling proteins.

These receptor interactions and signaling pathways lead to changes in the brain's structure and function, known as neural plasticity. Psychedelics can alter gene expression, including increasing the production of genes associated with neural plasticity. They also change the shape of dendrites, which are parts of neurons that receive signals from other cells. In lab-grown neurons, various psychedelics have been shown to make dendrites grow more branches. In living mice, a single dose of psilocybin increased the number of dendritic spines (where signals are received) for at least a month. These lasting effects on genes and brain structure are important because they continue long after the psychedelics have left the body, suggesting long-term brain changes.

Psychedelics are expected to affect specific cell types and brain regions because serotonin receptors are not evenly distributed throughout the brain. 5-HT2A receptors are mainly found in the outer layer of the brain (neocortex), thalamus, and other specific areas. In the neocortex, most 5-HT2A receptors are on the dendrites of excitatory neurons, though some are on inhibitory neurons. Studies show that activating these receptors on dendrites increases excitatory signals. Less is known about where other serotonin receptors are located within cells. The impact of psychedelics on the firing activity of neurons has been studied in a few brain regions, like the frontal cortex, but remains largely unexplored in others.

At the level of the entire brain, the effects of psychedelics on different regions can be seen using brain imaging techniques like PET and fMRI scans. Human studies have shown that psilocybin reduces activity in certain brain areas, including the medial frontal cortex, which are part of the "default mode network." This network is a group of brain regions that are more active when a person is resting and less active when interacting with the outside world. Imaging data also suggest that under the influence of psychedelics, activity in many brain regions becomes more connected. These observations have led to interesting ideas, such as the theory that suppressing the default mode network might explain the feeling of "ego dissolution" (loss of self). However, many other tasks, illnesses, and drugs can also affect the default mode network, so it is still unclear if this effect is unique to psychedelics.

Therapeutic potential

In the 1950s and 1960s, mental health professionals explored the potential benefits of psychedelic drugs, especially LSD. While these early studies did not meet today's research standards, they showed promise for mood disorders and addiction. Unfortunately, widespread recreational use led to a strong negative reaction from society and the law, resulting in the Controlled Substances Act of 1970, which effectively halted most research into these substances' therapeutic uses. Research began to slowly resume in the late 1990s in a few places in the United States and Europe. It has significantly sped up in the last ten years, and many now believe that psychedelic medicine could mark a new era in treating mental health conditions.

Most recent clinical studies have focused on psilocybin. Much effort has gone into developing the right "set and setting" to support the dosing experience; this approach makes the therapeutic use of psychedelics unique compared to many other drug treatments in current research. Trust and understanding are built between the participant and the trained facilitators through conversations before drug administration, where treatment goals are thoroughly discussed. During the dosing session, one or two trained facilitators are present to provide support to the participant. There are variations in approach: depression studies often provide support mainly during the dosing, with a few follow-up sessions, while studies for substance use disorders integrate psychedelic administration within a multi-week course of psychotherapy.

The first modern controlled studies of psilocybin treatment, starting in 2011, investigated its use to reduce anxiety and depression in patients with advanced cancer. In 2016, researchers from Johns Hopkins University conducted a study with 51 cancer patients, comparing low and high doses of psilocybin. The high dose (22 or 30 mg/70 kg) led to a significant and lasting improvement (over 6 months) in anxiety, depression, quality of life, sense of meaning, and optimism in 80% of patients. At the same time, researchers from New York University published a study of 29 cancer patients treated with psilocybin (0.3 mg/kg) compared to an active placebo. Psilocybin treatment also resulted in lasting improvements. These important studies attracted a great deal of attention, signaling that rigorous modern research into psychedelic therapies had truly begun.

Similarly encouraging early studies have been conducted on psilocybin for major depressive disorder (MDD). Placebo-controlled studies started appearing in 2021. One study gave two doses of psilocybin (20 mg/70 kg and 30 mg/70 kg, one week apart, with psychological support) to 27 MDD patients, either immediately or after a waiting period. Depression greatly improved in the psilocybin group, with little change in the wait-list group. In another study, 59 MDD patients were randomly assigned to receive either psilocybin (25 mg, with psychological support) plus a daily placebo, or a low-dose psilocybin (1 mg, with psychological support) plus daily escitalopram, a common antidepressant. Both groups showed improvement, with a trend towards greater improvement in the psilocybin group, though this difference was not statistically significant. These studies are small but promising, suggesting a substantial benefit for MDD, possibly comparable to or even better than standard medications. Larger studies are needed to confirm these findings, and several are currently underway.

Early research on psilocybin for many other conditions is also in progress. A pilot study involving 10 individuals with alcohol use disorder showed that adding psilocybin to standard psychotherapy improved abstinence for up to 36 weeks. Results from a follow-up controlled study are expected soon. Studies are also ongoing for conditions like obsessive-compulsive disorder, body dysmorphic disorder, anorexia nervosa, and various substance use disorders. In related work, the Multidisciplinary Association for Psychedelic Studies (MAPS) has investigated MDMA combined with structured psychotherapy for post-traumatic stress disorder (PTSD), with very promising results. In a study of 90 participants, those receiving MDMA showed a significantly greater reduction in PTSD symptoms and disability compared to those on placebo, with no major side effects. This finding, after more than two decades of dedicated work, represents one of the most promising new developments in PTSD treatment in many years.

This encouraging early data, across different diagnoses, has caught the attention of regulatory bodies. Psilocybin and MDMA are still classified as Schedule 1 drugs, meaning they are legally available only in carefully controlled research settings under federal law. However, in some places, like Oregon, state and local laws have adopted a more flexible approach to psilocybin use, creating a complex legal situation. The U.S. Food and Drug Administration (FDA) has given both psilocybin and MDMA "breakthrough therapy" status for depression and PTSD, respectively. This acknowledges the promising early data and speeds up the process towards approval, provided that controlled study results continue to be positive. However, the legal status of these drugs has not changed, and the existing data are not yet enough for them to be approved for general medical use.

Open questions

For a more detailed look at the current state of the field, several excellent review articles are available. Despite the progress, several key questions remain unanswered. Researchers know that 5-HT2A receptors are essential for the subjective, mind-altering effects of psychedelics. It is not clear, however, if the same receptors, or different ones, are responsible for their potential therapeutic benefits. This leads to the question of whether new psychedelic-like compounds can be designed to minimize the mind-altering effects while keeping the beneficial actions. Identifying the most effective behavioral and neural measurements to screen these new compounds is also important. Psychedelics have been shown to promote neural plasticity, meaning they can help the brain form new connections. An important question is whether these new connections are special—for example, do they strengthen specific brain pathways? Finally, there is a need to understand the effects of microdosing, which involves taking psychedelics at doses too low to cause hallucinations, on the brain and behavior.

Summary

Current research into psychedelics is at an interesting and hopeful point. There is considerable optimism due to positive results from small, carefully conducted studies on mood and anxiety disorders, and early findings in other conditions. However, it is important to acknowledge that the work done so far is preliminary and needs validation through larger, multi-site studies. Looking forward, a deeper understanding of the chemistry and how psychedelics affect the brain will help improve their use and speed up the discovery of new compounds. These advances will hopefully help unlock the immense potential of psychedelic pharmacology for treating brain-related disorders.

Chemistry

Psychedelics are chemicals that can be grouped into three main types based on their structure. These types are tryptamines, ergolines, and phenethylamines. Tryptamines, like psilocybin (from "magic mushrooms"), psilocin, and DMT, are similar to a natural brain chemical called serotonin. Ergolines include LSD, which was first found in a fungus called ergot. Phenethylamines include drugs like mescaline (from peyote cactus) and MDMA.

There are also other types of drugs that have similar effects on the mind but work in different ways. These include MDMA, scopolamine, and ketamine. Sometimes, these are also called psychedelics under a wider meaning of the word.

Psychedelics can be found in nature, like in certain mushrooms, plants, and even some animals. For example, psilocybin is in hundreds of mushroom types, which were used for healing and spiritual reasons by old cultures like the Mayans and Aztecs. Mescaline and DMT were also important to some early Native American groups. Other psychedelics are made by people in labs. MDMA was made in 1912, and LSD in 1943. Today, chemicals like psilocybin can be taken from mushrooms, made using tiny living things in a lab, or created through chemical processes.

Properties

When psychedelics enter the body, they change in different ways. Some drugs are "prodrugs," which means they are not active until the body changes them into something that works. For example, when a person takes psilocybin by mouth, the body changes it into psilocin in the gut and liver. Psilocin then goes into the blood and affects the brain. But DMT, if taken by mouth alone, does not work because the body gets rid of it too fast. Taking DMT with certain other drugs can make it work better and last longer.

Psychedelics usually work quickly. Psilocin, from psilocybin, stays in the blood for about 2.5 hours. People start to feel its effects in 20 to 40 minutes, and the strongest effects happen between 60 to 90 minutes. These strong effects last for about an hour before they start to fade. Most effects are gone in 6 to 8 hours. If psilocybin is given directly into a vein, it works even faster and lasts only 15 to 30 minutes. The body later changes psilocin into other forms that are passed out in urine.

Psychedelics change how people sense things, think, and feel. People who have used these drugs describe both similar and different experiences across the various types. Studies have looked at psilocybin, LSD, and MDMA. For example, people say psilocybin can make them feel connected to everything, change their sense of time, and cause them to see things that are not there or mix up senses, like seeing sounds. But it can also cause worry and fear, like the feeling of losing one's sense of self. People often remember these experiences long after the drug leaves the body. In one study, people said it was a very important and meaningful experience even two months later. Usually, psychedelics do not cause lasting problems with thinking or memory, and they only slightly affect body functions like heart rate. How much drug is taken and how it is taken can greatly change its effects.

A very important idea with psychedelics is "set and setting." This means a person's mindset (set) and the place where they take the drug (setting) are very important. Studies show that taking psychedelics in a safe place with caring support can help prevent bad experiences. If people use psychedelics many days in a row, the drugs start to have less effect. The body quickly gets used to them, and this happens across different psychedelics too. This might be why people are less likely to get addicted to psychedelics compared to many other illegal drugs. Overall, psychedelics are thought to be safe for the body, with low risk of harm. Serious problems are rare when they are given in a controlled place by trained people.

Animal models

Psychedelics are known for changing how the mind works. Since we cannot ask animals what they feel, scientists use other ways to study how psychedelics affect them. One common test is called the "head-twitch response." After getting a psychedelic, animals like mice, rats, and rabbits quickly shake their heads in a special way. Scientists can record these movements. When many psychedelics were tested, the ones that caused strong hallucinations in humans also caused many head twitches in mice. Also, drugs that block hallucinations in humans also stop head twitches in animals. Because of this, the head-twitch response is a good way to guess if a drug will cause hallucinations, even though a few drugs might give wrong results.

Another common test is "drug discrimination." Animals are trained for many weeks to tell the difference between a psychedelic (like LSD) and salt water. They show what they sense by pressing one of two levers. Then, a new drug is given to them, and scientists see if the animal thinks the new drug is like the psychedelic. This test can show exactly how much of a drug is needed to cause an effect. It is often done with rats, but also with mice and monkeys.

Besides these tests for psychedelics, other general tests can be used to see how the drugs affect behavior. For example, tests like "learned helplessness" or "sucrose preference" can show behaviors like sadness. Psilocybin has been shown to help mice deal with stress. However, these tests were first used to find drugs for depression, so scientists are still figuring out if they are the best for understanding the special effects of psychedelics. Another example is studying how MDMA makes animals more social. This can be seen by how much mice (and even octopuses!) approach each other. "Fear extinction" is when fear decreases after being exposed to something scary many times. This test helps study how psychedelics might help with problems like post-traumatic stress disorder (PTSD). Overall, animal studies suggest psychedelics could have good effects, but it is hard to know if these effects will be the same in humans, as each animal acts in its own way. Also, drugs and how they are handled by the body can be different across species.

Effects on the brain

Psychedelics affect the brain in many ways: at the level of tiny parts, single cells, cell groups, and whole brain networks. At the smallest level, psychedelics work by turning on certain brain receptors called serotonin receptors, especially the 5-HT2A type. For psychedelics like tryptamines and ergolines to change a person's awareness, they must connect to these 5-HT2A receptors in the brain. We know this because other drugs that block these 5-HT2A receptors also stop the effects of psychedelics. Other types of serotonin receptors may also play a part. Most psychedelics also connect to 5-HT2C receptors, and many tryptamines and ergolines connect strongly to 5-HT1A receptors. MDMA is different because it mainly works by stopping the brain from taking back serotonin. Other receptors or groups of receptors might also be involved, but we do not know as much about them yet. Scientists have recently been able to see the structure of a 5-HT2A receptor with a psychedelic attached. This detailed view helps them use computers to guess how thousands of new drugs might connect to serotonin receptors, opening a new way to find medicines.

When psychedelics connect to serotonin receptors, they start different chemical signals inside brain cells. The main way involves a protein called Gαq. When the receptor is turned on, Gαq moves away and activates other proteins. There is also another way that does not use G-proteins, but instead uses proteins called β-arrestins. Some psychedelics seem to work in a way that favors the β-arrestin pathway over the G-protein pathway for 5-HT2A receptors. In contrast, 5-HT1A receptors work with Gi/o-proteins and activate different signals.

These connections and signals cause brain cells to change and adapt. Psychedelics can change how genes are used, even making more of certain genes that help brain cells change. Also, psychedelics change the shape of dendrites, which are parts of a brain cell that receive signals from other cells. In lab-grown brain cells, various psychedelics like LSD, DMT, and DOI have been shown to make more branches on dendrites. When scientists looked at dendrites in live mice over time, a single dose of psilocybin caused more tiny bumps (called dendritic spines) on dendrites, which are where signals come in. These changes lasted for at least a month. These lasting changes to genes and cell structure are important because they stay long after the psychedelics have left the body, showing that the brain has changed in a lasting way.

Psychedelics are expected to act on specific types of cells and in certain brain areas. This is because serotonin receptors are not found everywhere in the brain in the same amounts. 5-HT2A receptors are mostly found in areas like the neocortex (the outer layer of the brain), thalamus, and other deeper brain parts. In the neocortex, most 5-HT2A receptors are on parts of important brain cells called pyramidal neurons, which send signals. Some are also found on cells that stop signals. Studies show that giving chemicals that turn on 5-HT receptors to these cells makes them send more signals. We do not know as much about where other types of serotonin receptors are located inside cells. How psychedelics affect brain cell activity has been looked at in a few brain areas like the front part of the brain, but much more research is needed.

For the whole brain, scientists can see the effects of psychedelics using special scans like PET and fMRI. Studies in people show that psilocybin makes certain brain areas, like parts of the front and back of the brain, less active. These areas are part of the "default mode network," which is a group of brain parts that are busy when a person is resting and not focused on the outside world. Brain scans also suggest that under the influence of psychedelics, many brain areas work together more closely. These findings have led to interesting ideas, such as the thought that slowing down the default mode network might explain the feeling of losing one's sense of self. However, many things like different tasks, illnesses, and other drugs can also affect the default mode network, so it is still not clear if this effect is unique to psychedelics.

Therapeutic potential

In the 1950s and 1960s, mental health doctors studied how psychedelics, especially LSD, might help people. While these early studies were not done with today's strict rules, they showed promise for helping with sadness and addiction. Sadly, too much casual use of these drugs led to a ban in 1970, which almost stopped all research into their medical benefits. Research slowly started again in the late 1990s in a few places. Over the last ten years, it has grown a lot. Many now believe that psychedelics could start a new time for treating mental health problems. Today's research often focuses on psilocybin and how important "set and setting" are. Before giving the drug, a person talks with helpers to build trust and understand the treatment goals. During the drug session, one or two trained helpers are in the room to support the person. Some studies, like those for sadness, mostly provide support during the session and a few follow-up talks. But studies for addiction might combine the drug session with many weeks of therapy.

The first careful studies of psilocybin in modern times, starting in 2011, looked at its use to help cancer patients with their worry and sadness. In 2016, a study from Johns Hopkins University showed that a higher dose of psilocybin greatly and lastingly improved worry, sadness, quality of life, and hope in 80% of cancer patients for more than six months. At the same time, New York University published a study where psilocybin also led to lasting improvements for cancer patients. These important studies got a lot of attention and showed everyone that careful research into psychedelics as medicine had truly begun.

There have also been exciting early studies looking at psilocybin for severe sadness (major depressive disorder, or MDD). Studies comparing psilocybin to a fake drug started appearing in 2021. One study gave two doses of psilocybin with support to people with MDD. Their sadness got much better compared to a group that waited. Another study compared psilocybin with support to a small dose of psilocybin with a common antidepressant. Both groups got better, and the group getting the full psilocybin dose tended to improve more, though this was not a clear statistical difference. These studies are small but impressive. They suggest that psilocybin could help with MDD as much as or more than common medicines. Larger studies are now underway to confirm these findings.

Studies of psilocybin for many other conditions are in earlier stages. A small study with 10 people who had problems with alcohol showed that adding psilocybin to therapy helped them stop drinking for up to 36 weeks. Results from a larger, controlled study are expected soon. Studies are also happening for obsessive-compulsive disorder, body image issues, eating disorders, headaches, and other problems with drug use. In other important work, researchers have studied MDMA with therapy for post-traumatic stress disorder (PTSD). The results have been very promising. In one study, people received either MDMA or a fake drug, along with 12 therapy sessions. Those who got MDMA had much bigger and clearer reductions in their PTSD symptoms and problems in daily life, with no major bad effects. This finding, after more than 20 years of work, is one of the most hopeful new steps in treating PTSD in a long time.

This promising early information across different conditions has caught the eye of government groups. Psilocybin and MDMA are still listed as highly controlled drugs, meaning they can only be used in very strict research settings under federal law. In a few places, like Oregon, state laws have become more open to psilocybin, which makes the rules tricky. The U.S. Food and Drug Administration (FDA) has given both psilocybin and MDMA "breakthrough therapy" status for depression and PTSD. This means the FDA sees the early data as very promising and will speed up the process for approval if more studies continue to show good results. However, the legal status of these drugs has not changed yet, and there is not enough data for them to be approved for any use right now.

Open questions

We are still learning a lot about psychedelics. We know that 5-HT2A receptors are key for the mind-altering effects. But are these the same receptors, or different ones, that are responsible for the healing effects? Can we make new psychedelic-like drugs that have good effects but do not cause hallucinations? What are the best ways to test these new drugs in animals and measure their effects on the brain? Psychedelics have been shown to help brain cells make new connections. Are these new connections special in some way? Do they make certain brain pathways stronger? Finally, what happens in the brain and behavior when people take very small amounts of psychedelics (microdosing) that do not cause hallucinations?

Summary

We are at an exciting time in the study of psychedelics. On one hand, there is a lot of hope because of good results from small, careful studies on mood and worry problems, and early findings for other conditions. On the other hand, we must remember that this work is still new and needs to be confirmed by bigger studies done in many places. Looking ahead, if we learn more about how psychedelics work as chemicals and how they affect the brain, it will help us use them better and find new drugs. These advances will hopefully help unlock the big promise of psychedelics for treating brain and mental health problems.