Serotonergic Psychedelic

Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic hallucinogens or serotonergic hallucinogens, the term ''psychedelic'' is sometimes used more broadly to include various other types of hallucinogens as well, such as those which are atypical or adjacent to psychedelia like salvia and MDMA, respectively.

Classic psychedelics generally cause specific psychological, visual, and auditory changes, and oftentimes a substantially altered state of consciousness. They have had the largest influence on science and culture, and include mescaline, LSD, psilocybin, and DMT. There are a large number of both naturally occurring and synthetic serotonergic psychedelics.

Most psychedelic drugs fall into one of the three families of chemical compounds: tryptamines, phenethylamines, or lysergamides. They produce their psychedelic effects by binding to and activating a receptor in the brain called the serotonin 5-HT_2A receptor. By activating serotonin 5-HT_2A receptors, they modulate the activity of key circuits in the brain involved with sensory perception and cognition. However, the exact nature of how psychedelics induce changes in perception and cognition via the serotonin 5-HT_2A receptor is still unknown. The psychedelic experience is often compared to non-ordinary forms of consciousness such as those experienced in meditation, mystical experiences, and near-death experiences, which also appear to be partially underpinned by altered default mode network activity. The phenomenon of ego death is often described as a key feature of the psychedelic experience.

Many psychedelic drugs are illegal to possess without lawful authorisation, exemption or license worldwide under the UN conventions, with occasional exceptions for religious use or research contexts. Despite these controls, recreational use of psychedelics is common. There is also a long history of use of naturally occurring psychedelics as entheogens dating back thousands of years. Legal barriers have made the scientific study of psychedelics more difficult. Research has been conducted, however, and studies show that psychedelics are physiologically safe and rarely lead to addiction. Studies conducted using psilocybin in a psychotherapeutic setting reveal that psychedelic drugs may assist with treating depression, anxiety, alcohol addiction, and nicotine addiction. Although further research is needed, existing results suggest that psychedelics could be effective treatments for certain mental health conditions. A 2022 survey by YouGov found that 28% of Americans had used a psychedelic at some point in their life.

Examples

* LSD (lysergic acid diethylamide) is a derivative of lysergic acid, which is obtained from the hydrolysis of ergotamine. Ergotamine is an alkaloid found in the fungus '' Claviceps purpurea'' (ergot), which primarily infects rye. LSD is both the prototypical psychedelic and the prototypical lysergamide. As a lysergamide, LSD contains both a tryptamine and phenethylamine group within its structure. Uniquely among psychedelics, LSD agonises dopamine receptors as well as serotonin receptors.
* Psilocin (4-HO-DMT) is the dephosphorylated active metabolite of the indole alkaloid psilocybin and a substituted tryptamine, which is produced by hundreds of species of psilocybin-containing mushrooms. Of the classical psychedelics, psilocybin has attracted the greatest academic interest regarding its ability to manifest mystical experiences, although all psychedelics are capable of doing so to variable degrees. 4-AcO-DMT (''O''-acetylpsilocin or psilacetin) is a synthetic acetylated analogue of psilocin and is a prodrug of psilocin similarly to psilocybin.
* Mescaline (3,4,5-trimethoxyphenethylamine) is a phenethylamine alkaloid found in various species of cacti, the best-known of these being peyote (''Lophophora williamsii'') and the San Pedro cactus (''Trichocereus macrogonus'' var. ''pachanoi'', syn. ''Echinopsis pachanoi''). Mescaline has effects comparable to those of LSD and psilocybin. Ceremonial San Pedro use seems to be characterized by relatively strong spiritual experiences, and low incidence of challenging experiences.
* DMT (''N'',''N''-dimethyltryptamine) is an indole alkaloid found in various species of plants. Traditionally, it is consumed by tribes in South America in the form of ayahuasca. A brew is used that consists of DMT-containing plants as well as plants containing MAOIs, specifically harmaline, which allows DMT to be consumed orally without being rendered inactive by monoamine oxidase enzymes in the digestive system. A pharmaceutical version of ayahuasca is called pharmahuasca. In the Western world, DMT is more commonly consumed via the vaporisation of freebase DMT. Whereas ayahuasca typically lasts for several hours, inhalation has an onset measured in seconds and has effects measured in minutes, being much more intense. Particularly in vaporised form, DMT has the ability to cause users to enter a hallucinatory realm fully detached from reality, being typically characterised by hyperbolic geometry, and described as defying visual or verbal description. Users have also reported encountering and communicating with entities within this hallucinatory state. DMT is the archetypal substituted tryptamine, being the structural scaffold of psilocybin and, to a lesser extent, the lysergamides.
* 2C-B (2,5-dimethoxy-4-bromophenethylamine) is a substituted phenethylamine first synthesized in 1974 by Alexander Shulgin. 2C-B is both a psychedelic and a mild entactogen, with its psychedelic effects increasing and its entactogenic effects decreasing with dosage. 2C-B is the most well-known compound in the 2C family, their general structure being discovered as a result of modifying the structure of mescaline. It is also the most widely used synthetic phenethylamine psychedelic.

MDMA ("ecstasy") is sometimes said to also have weak psychedelic effects, but it acts and is classified mainly as an entactogen rather than as a hallucinogen. Certain related drugs like MDA and MMDA have greater psychedelic effects however.

Uses

Recreational

Recreational use of psychedelics has been common since the psychedelic era of the mid-1960s and continues to play a role in various festivals and events, including Burning Man. A survey published in 2013 found that 13.4% of American adults had used a psychedelic.

A June 2024 report by the RAND Corporation suggests psilocybin mushrooms may be the most prevalent psychedelic drug among adults in the United States. The RAND national survey indicated that 3.1% of U.S. adults reported using psilocybin in the past year. Roughly 12% of respondents acknowledged lifetime use of psilocybin, while a similar percentage reported having used LSD at some point in their lives. MDMA, also known as ecstasy, showed a lower prevalence of use at 7.6%. Notably, less than 1% of U.S. adults reported using any psychedelic drugs within the past month.

Traditional

A number of frequently mentioned or traditional psychedelics such as '' Ayahuasca'' (which contains DMT), San Pedro, Peyote, and Peruvian torch (which all contain mescaline), Psilocybe mushrooms (which contain psilocin/psilocybin) and '' Tabernanthe iboga'' (which contains the unique psychedelic ibogaine) all have a long and extensive history of spiritual, shamanic and traditional usage by indigenous peoples in various world regions, particularly in Latin America, but also Gabon, Africa in the case of iboga. Different countries and/or regions have come to be associated with traditional or spiritual use of particular psychedelics, such as the ancient and entheogenic use of psilocybe mushrooms by the native Mazatec people of Oaxaca, Mexico or the use of the ayahuasca brew in the Amazon basin, particularly in Peru for spiritual and physical healing as well as for religious festivals. Peyote has also been used for several thousand years in the Rio Grande Valley in North America by native tribes as an entheogen. In the Andean region of South America, the San Pedro cactus ( ''Trichocereus macrogonus'' var. ''pachanoi'', syn. ''Echinopsis pachanoi'') has a long history of use, possibly as a traditional medicine. Archaeological studies have found evidence of use going back two thousand years, to Moche culture, Nazca culture, and Chavín culture. Although authorities of the Roman Catholic church attempted to suppress its use after the Spanish conquest, this failed, as shown by the Christian element in the common name "San Pedro cactus" – Saint Peter cactus. The name has its origin in the belief that just as St Peter holds the keys to heaven, the effects of the cactus allow users "to reach heaven while still on earth." In 2022, the Peruvian Ministry of Culture declared the traditional use of San Pedro cactus in northern Peru as cultural heritage.

Although people of Western culture have tended to use psychedelics for either psychotherapeutic or recreational reasons, most indigenous cultures, particularly in South America, have seemingly tended to use psychedelics for more supernatural reasons such as divination. This can often be related to "healing" or health as well but typically in the context of finding out what is wrong with the individual, such as using psychedelic states to "identify" a disease and/or its cause, locate lost objects, and identify a victim or even perpetrator of sorcery. In some cultures and regions, even psychedelics themselves, such as ayahuasca and the psychedelic lichen of eastern Ecuador ('' Dictyonema huaorani'') that supposedly contains both 5-MeO-DMT and psilocybin, have also been used by witches and sorcerers to conduct their malicious magic, similarly to nightshade deliriants like '' brugmansia'' and '' latua''.

Medical

Psychedelic therapy (or psychedelic-assisted therapy) is the proposed use of psychedelic drugs to treat mental disorders. As of 2021, psychedelic drugs are controlled substances in most countries and psychedelic therapy is not legally available outside clinical trials, with some exceptions.

The procedure for psychedelic therapy differs from that of therapies using conventional psychiatric medications. While conventional medications are usually taken without supervision at least once daily, in contemporary psychedelic therapy the drug is administered in a single session (or sometimes up to three sessions) in a therapeutic context. The therapeutic team prepares the patient for the experience beforehand and helps them integrate insights from the drug experience afterwards. After ingesting the drug, the patient normally wears eyeshades and listens to music to facilitate focus on the psychedelic experience, with the therapeutic team interrupting only to provide reassurance if adverse effects such as anxiety or disorientation arise.

As of 2022, the body of high-quality evidence on psychedelic therapy remains relatively small and more, larger studies are needed to reliably show the effectiveness and safety of psychedelic therapy's various forms and applications. On the basis of favorable early results, ongoing research is examining proposed psychedelic therapies for conditions including major depressive disorder, and anxiety and depression linked to terminal illness. The United States Food and Drug Administration has granted breakthrough therapy status, which expedites the assessment of promising drug therapies for potential approval, to psilocybin therapy for treatment-resistant depression and major depressive disorder.

It has been proposed that psychedelics used for therapeutic purposes may act as active "super placebos".

Microdosing

Psychedelic microdosing is the practice of using sub-threshold doses ( microdoses) of psychedelics in an attempt to improve creativity, boost physical energy level, emotional balance, increase performance on problems-solving tasks and to treat anxiety, depression and addiction. The practice of microdosing has become more widespread in the 21st century with more people claiming long-term benefits from the practice.

A 2022 study recognized signatures of psilocybin microdosing in natural language and concluded that low amount of psychedelics have potential for application, and ecological observation of microdosing schedules.

Dosage

The table below provides doses of major serotonergic psychedelics as well as the entactogen and mild psychedelic MDMA ("ecstasy") that have been determined on the basis of clinical studies. Other dosage schemes have also been reported.

In the case of dried psilocybin-containing mushrooms, microdoses are 0.1g to 0.3g and psychedelic doses are 1.0g to 3.5–5.0g. The preceding 1.0 to 5.0g range corresponds to psilocybin doses of about 10 to 50mg. Psilocybin-containing mushrooms vary in their psilocybin and psilocin content, but are typically around 1% of the dried weight of the mushrooms (in terms of total or combined psilocybin and psilocin content). Psilocybin and psilocin are similar in potency and dose but psilocin is about 1.4-fold more active, this being related to the difference in molecular weight between the two compounds.

Some psychedelics, such as 2C-B, 2C-E, and 4-HO-DiPT, have been said to have steep dose–response curves, meaning that the difference in dose between a light experience and an overwhelming disconnection from reality can be small.

Effects

Psychedelic effects

Although several attempts have been made, starting in the 19th and 20th centuries, to define common phenomenological structures of the effects produced by classic psychedelics, a universally accepted taxonomy does not yet exist. At lower doses, features of psychedelic experiences include sensory alterations, such as the warping of surfaces, shape suggestibility, pareidolia, and color variations. Users often report intense colors that they have not previously experienced, and repetitive geometric shapes or form constants are common as well. Higher doses often cause intense and fundamental alterations of sensory (notably visual) perception, such as synesthesia or the experience of additional spatial or temporal dimensions. Tryptamines are well documented to cause classic psychedelic states, such as increased empathy, visual distortions (drifting, morphing, breathing, melting of various surfaces and objects), auditory hallucinations, ego dissolution or ego death with high enough dose, mystical, transpersonal and spiritual experiences, autonomous "entity" encounters, time distortion, closed eye hallucinations and complete detachment from reality with a high enough dose. Luis Luna describes psychedelic experiences as having a distinctly gnosis-like quality, and says that they offer "learning experiences that elevate consciousness and can make a profound contribution to personal development." Czech psychiatrist Stanislav Grof studied the effects of psychedelics like LSD early in his career and said of the experience, that it commonly includes "complex revelatory insights into the nature of existence… typically accompanied by a sense of certainty that this knowledge is ultimately more relevant and 'real' than the perceptions and beliefs we share in everyday life." Traditionally, the standard model for the subjective phenomenological effects of psychedelics has typically been based on LSD, with anything that is considered "psychedelic" evidently being compared to it and its specific effects.

Good trips are reportedly deeply pleasurable, and typically involve intense joy or euphoria, a greater appreciation for life, reduced anxiety, a sense of spiritual enlightenment, and a sense of belonging or interconnectedness with the universe. Negative experiences, colloquially known as "bad trips," evoke an array of dark emotions, such as irrational fear, anxiety, panic, paranoia, dread, distrustfulness, hopelessness, and even suicidal ideation. While it is impossible to predict when a bad trip will occur, one's mood, surroundings, sleep, hydration, social setting, and other factors can be controlled (colloquially referred to as " set and setting") to minimize the risk of a bad trip. The concept of "set and setting" also generally appears to be more applicable to psychedelics than to other types of hallucinogens such as deliriants, hypnotics and dissociative anesthetics.

Psychedelics include naturally occurring tryptamines like psilocybin and DMT, the naturally occurring phenethylamine mescaline, and naturally occurring lysergamides like ergine (lysergic acid amide; LSA), as well as synthetic analogues and derivatives like LSD and 2C-B. Many of these psychedelics cause remarkably similar effects, despite their different chemical structures. However, many users anecdotally report that the three major families have subjectively different qualities in the "feel" of the experience, which are difficult to describe. There can also be very substantial differences between the drugs; for instance, 5-MeO-DMT rarely produces the visual effects typical of other psychedelics. As additional examples, DiPT is said to primarily affect the auditory sense, 2C-T-17 and ASR-3001 (5-MeO-iPALT) are said to produce psychedelic effects on thinking or "head space" with few or no visuals, and ''N''-methyltryptamine (NMT) has been said to be a primarily spatial psychedelic.

The visuals of psychedelics have been reproduced in video and image form using artificial intelligence.

Some rare individuals do not experience hallucinogenic effects with serotonergic psychedelics.

Other psychoactive effects

Some psychedelics have been associated with other psychoactive effects in addition to their hallucinogenic effects. For example, psychedelics like LSD and DOM have been described as having mild stimulant and/or " psychic-energizing" (i.e., acute antidepressant) effects. Some psychedelics and related drugs, like DOET (low doses), Ariadne, and ASR-2001 (2CB-5PrO), have been investigated specifically for such effects. 2C-B has been said to have mild entactogenic effects at low doses.

Some drugs, such as MDxx compounds like MDMA and MDA as well as α-alkyltryptamines like α-methyltryptamine (AMT), are entactogens and/or stimulants acting at monoamine transporters in addition to having varying degrees of psychedelic effects.

Psychedelic afterglows

Psychedelics are associated with an afterglow, also known as positive subacute or post-experience effects, which may last days or even weeks after the psychedelic experience. These effects include reduction in psychopathology and increased well-being, mood, mindfulness, social functioning, spirituality, and executive functioning, and positive behavioral changes. They also include mixed changes in personality, values, attitudes, creativity, and flexibility, as well as adverse effects like headaches, sleep disturbances, and sometimes increased psychological distress. The afterglow period has been associated with changes in brain function, neuroplasticity, and immune system function. Both psychological and pharmacological effects may be involved in the afterglow phenomenon.

In 1898, the English writer and intellectual Havelock Ellis reported a heightened perceptual sensitivity to "the more delicate phenomena of light and shade and color" for a prolonged period of time after his exposure to mescaline. The term "psychedelic afterglow" was first formally coined in the 1960s. Albert Hofmann, the discoverer of LSD, said the following about the aftermath of his first full LSD experience in his 1980 book ''LSD: My Problem Child'':

During a speech on his 100th birthday in 2006, Hofmann additionally said of LSD:

Adverse effects

Despite the contrary perception of much of the public, psychedelic drugs are not addictive and are physiologically safe.

Risks do exist during an unsupervised psychedelic experience, however; Ira Byock wrote in 2018 in the '' Journal of Palliative Medicine'' that psilocybin is safe when administered to a properly screened patient and supervised by a qualified professional with appropriate set and setting. However, he called for an "abundance of caution" because in the absence of these conditions a range of negative reactions is possible, including "fear, a prolonged sense of dread, or full panic." He notes that driving or even walking in public can be dangerous during a psychedelic experience because of impaired hand-eye coordination and fine motor control. In some cases, individuals taking psychedelics have performed dangerous or fatal acts because they believed they possessed superhuman powers.

Psilocybin-induced states of mind share features with states experienced in psychosis, and while a causal relationship between psilocybin and the onset of psychosis has not been established as of 2011, researchers have called for investigation of the relationship. Many of the persistent negative perceptions of psychological risks are unsupported by the currently available scientific evidence, with the majority of reported adverse effects not being observed in a regulated and/or medical context. A population study on associations between psychedelic use and mental illness published in 2013 found no evidence that psychedelic use was associated with increased prevalence of any mental illness. In any case, induction of psychosis has been associated with psychedelics in small percentages of individuals, and the rates appear to be higher in people with schizophrenia.

Using psychedelics poses certain risks of re-experiencing of the drug's effects, including flashbacks and hallucinogen persisting perception disorder (HPPD). These non-psychotic effects are poorly studied, but the permanent symptoms (also called "endless trip") are considered to be rare.

Serotonergic psychedelics are agonists not only of the serotonin 5-HT_2A receptor but also of the serotonin 5-HT_2B receptor and other serotonin receptors. A potential risk of frequent repeated use of serotonergic psychedelics is cardiac fibrosis and valvulopathy caused by serotonin 5-HT_2B receptor activation. However, single high doses or widely spaced doses (e.g., months) are widely thought to be safe and concerns about cardiac toxicity apply more to chronic psychedelic microdosing or very frequent use (e.g., weekly). Selective serotonin 5-HT_2A receptor agonists that do not activate the serotonin 5-HT_2B receptor or other serotonin receptors, such as 25CN-NBOH, DMBMPP, and LPH-5, have been developed and are being studied. Selective serotonin 5-HT_2A receptor agonists are expected to avoid the cardiac risks of serotonin 5-HT_2B receptor activation.

Overdose

There have been a handful of cases of fatal overdose with LSD, psilocybin, and mescaline. There have also been cases of death with dimethyltryptamine (DMT), 5-MeO-DMT, 2C-B, Bromo-DragonFLY, NBOMes like 25I-NBOMe, and other psychedelics. LSD and psilocybin appear to have very wide margins of safety with overdose, whereas mescaline and 2C-B have much narrower margins, and NBOMes appear to be especially toxic and uniquely linked to serotonin syndrome-type symptoms. In terms of extrapolated human lethal doses based on animal studies and human case reports, lethal doses of psychedelics relative to typical recreational doses are estimated to be 1,000-fold for LSD, 200-fold for psilocybin, 50-fold for oral DMT (as ayahuasca), and 24-fold for mescaline. Estimates for other psychedelics, like 5-MeO-DMT and 2C-B, could not be made.

Interactions

Serotonin 5-HT_2A receptor antagonist

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