By the 1960s, this "psychotomimetic" theory had been largely abandoned, and mescaline itself was mostly replaced by LSD, which produced similar effects at a tiny fraction of the dose.
|
|
Coming close to achieving the modern listicle, Micro-Gram's jam-packed issue #4 lists 15 "Psychotomimetic Agents and Other Substances Affecting the Mind," including ayahuasca ("produces frenzy, visions, psycho-eroticism, and sleep"), and morning glory seeds.
|
|
A drug with psychotomimetic (also known as psychotogenic) actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to just hallucinations. Psychotomimesis is the onset of psychotic symptoms following the administration of such a drug. Some drugs of the opioid class have psychotomimetic effects. Particularly, mixed kappa receptor agonist mu receptor antagonist opioid analgesics can cause dose-related psychotomimesis.
|
|
This adverse effect, incidence 1–2%, limits their use. Pentazocine and butorphanol fall under this opioid class. There is evidence that cannabinoids are psychotomimetic, especially delta-9-tetrahydrocannabinol (THC). D'Souza et al.
|
|
The clinical use of these drugs may be limited by side effects such as amnesia and psychotomimetic symptoms, but these could be an advantage for some indications, or conversely mGluR5 positive modulators may have nootropic effects.
|
|
Jentsch was born on April 9, 1972, in Seguin, Texas. He studied behavioural biology at Johns Hopkins University. He moved to Yale University for his graduate studies, where he specialised in neurobiology. Here he worked on the biochemical changes associated with the abuse of psychotomimetic and stimulant drugs.
|
|
Chapter 6 in Natural Products in Medicinal Chemistry, Volume 60 of Methods and Principles in Medicinal Chemistry. Ed. Stephen Hanessian. John Wiley & Sons, 2013. In clinical trials, it had relatively long duration, good absorption, and provided strong pain relief but produced psychotomimetic effects via KOR activation, so its development was not continued.
|
|
Early studies of DET as well as other psychedelics were mainly focused on their presumed psychotomimetic properties. Researchers theorized that abnormal metabolites of endogenous chemicals such as tryptamine, serotonin, and tryptophan could be the explanation for mental disorders such as schizophrenia, or psychosis. With the progression of science and pharmacological understanding, this belief has been dismissed by most researchers.
|
|
Other weak partial agonists of the glycine site of the NMDA receptor such as rapastinel (GLYX-13) and apimostinel (NRX-1074) are now viewed for the development of new drugs with antidepressant and analgesic effects without obvious psychotomimetic activities.J. Moskal, D. Leander, R. Burch (2010). Unlocking the Therapeutic Potential of the NMDA Receptor. Drug Discovery & Development News.
|
|
Evidence for the use of Cannabis based medicines is limited, low-moderate quality evidence suggests a benefit in pain intensity, sleep quality and psychological distress. The use of Cannabis has to be weighed against the negative psychotomimetic effects that may impact quality of life. Therefore cannabis is not recommended as a mainstream treatment but may have a place for treatment refractory cases.
|
|
Metaescaline entry in PiHKAL Metaescaline produces mental insights, entactogenic, MDMA-like effects, and TOMSO-like activation. Little data exists about the pharmacological properties, metabolism, and toxicity of metaescaline, though it has been studied to a limited extent in comparison with other related compounds.Jacob P 3rd, Shulgin AT. Sulfur analogues of psychotomimetic agents. 3. Ethyl homologues of mescaline and their monothio analogues.
|
|
Starting in 1956, Isbell and associates published studies on LSD, psilocybin, psilocin, DMT, bufotenine, morning glory seeds (ololiuqui), and mescaline; these substances were sometimes described as "psychotomimetic". LSD and psilocybin for many of the experiments was supplied by Sandoz Pharmaceuticals (both of these substances were legal at the time). According to a 1986 interview with Isbell, the psychedelics research was initiated by an explicit CIA request.
|
|
Link R. Swanson divides scientific frameworks for understanding psychedelic experiences into two waves. In the first wave he includes model psychosis theory (the psychotomimetic paradigm), filtration theory, and psychoanalytic theory. Aldous Huxley was a proponent of filtration theory. In his book The Doors of Perception, he presents the idea of a mental reducing valve in order to explain the significance of the psychedelic experience.
|
|
Alazocine was one of the early members of the benzomorphan family of opioid analgesics to be investigated. It was first described in the scientific literature in 1961. Its development resulted from nalorphine (N-allylnormorphine), a potent analgesic and opioid antagonist with similar pharmacology which had been introduced in the mid-1950s. Alazocine was found to produce strong psychotomimetic effects in humans, and it was not further developed for clinical use.
|
|
As such, it may have improved and prolonged efficaciousness and greater tolerability in comparison to currently available opioid analgesics. As an agonist of the κ-opioid receptor, cebranopadol may have the capacity to produce psychotomimetic effects, dysphoria, and other adverse reactions at sufficiently high doses, a property which could potentially limit its practical clinical dosage range, but would likely reduce the occurrence of patients taking more than their prescribed dose.
|
|
Asimadoline (EMD-61753) is an experimental drug which acts as a peripherally selective κ-opioid receptor (KOR) agonist. Because of its low penetration across the blood–brain barrier, asimadoline lacks the psychotomimetic effects of centrally acting KOR agonists, and consequently was thought to have potential for medical use. It has been studied as a possible treatment for irritable bowel syndrome, with reasonable efficacy seen in clinical trials, but it has never been approved or marketed.
|
|
Alteration in the expression, distribution, autoregulation, and prevalence of specific glutamate heterodimers alters relative levels of paired G proteins to the heterodimer- forming glutamate receptor in question. Namely: 5HT2A and mGlu2 form a dimer which mediates psychotomimetic and entheogenic effects of psychedelics; as such this receptor is of interest in schizophrenia. Agonists at either constituent receptor may modulate the other receptor allosterically; e.g. glutamate-dependent signaling via mGlu2 may modulate 5HT2A-ergic activity.
|
|
Lanicemine (AZD6765) is a low-trapping NMDA receptor antagonist that was under development by AstraZeneca for the management of severe and treatment- resistant depression. Lanicemine differs from ketamine in that it is a low- trapping NMDA receptor antagonist, showing similar rapid-acting antidepressant effects to ketamine in clinical trials but with little or no psychotomimetic side effects. However, lanicemine did not meet study endpoints, and its development was terminated by AstraZeneca in 2013.
|
|
In an open-label, add-on, single-day, acute-dose small clinical study, pentazocine was found to rapidly and substantially reduce symptoms of mania in individuals with bipolar disorder that were in the manic phase of the condition. It was postulated that the efficacy observed was due to κ-opioid receptor activation-mediated amelioration of hyperdopaminergia in the reward pathways. Minimal sedation and no side effects including psychotomimetic effects or worsening of psychosis were observed at the dose administered.
|
|
Anandamide, an endocannabinoid, is an a7 nicotinic antagonist. Cigarettes, consumed far out of proportion by schizophrenics, contain nornitrosonicotine; a potent a7 antagonist. This may indicate a7 pentameter excess as a causative factor, or possibly as a method of self- medication to combat antipsychotic side effects. Cannabidiol, a FAAH inhibitor, increases levels in anandamide and may have antipsychotic effect; though results are mixed here as anandamide also is a cannabinoid and as such displays some psychotomimetic effect.
|
|
Apimostinel is intended by Naurex as an improved, follow-up drug to rapastinel. Similarly to rapastinel, apimostinel is an amidated tetrapeptide, and has almost an identical chemical structure to rapastinel, but has been structurally modified via the addition of a benzyl group. The drug has shown rapid antidepressant effects in pre-clinical models of depression. In addition, similarly to rapastinel, it is well tolerated and lacks the schizophrenia-like psychotomimetic effects of other NMDA receptor antagonists such as ketamine.
|
|
421 cases, or 82 percent, involved psychotomimetic drugs like GHB, a common date rape drug, and one alleged to have been used at the Burning Sun. On May 30, SMPA reported to have arrested nearly 4,000 people at 148 entertainment establishments on drug related charges in the three month crackdown after the scandal started. Some 920 of those were detained; 886 for drug related crimes, 23 for sexual assault or rape while under the influence of drugs, and 11 for taking illegal videos during drug use.
|
|
BZ was invented by the Swiss pharmaceutical company Hoffman-LaRoche in 1951. The company was investigating anti-spasmodic agents, similar to tropine, for treating gastrointestinal ailments when the chemical was discovered. It was then investigated for possible use in ulcer treatment, but was found unsuitable. At this time the United States military investigated it along with a wide range of possible nonlethal, psychoactive and psychotomimetic incapacitating agents including psychedelic drugs such as LSD and THC, dissociative drugs such as ketamine and phencyclidine, potent opioids such as fentanyl, as well as several glycolate anticholinergics.
|
|
Arylcyclohexylamines varyingly possess NMDA receptor antagonistic, dopamine reuptake inhibitory, and μ-opioid receptor agonistic properties. Additionally, σ receptor agonistic, nACh receptor antagonistic, and D2 receptor agonistic actions have been reported for some of these agents. Antagonism of the NMDA receptor confers anesthetic, anticonvulsant, neuroprotective, and dissociative effects; blockade of the dopamine transporter mediates stimulant and euphoriant effects as well as psychosis in high amounts; and activation of the μ-opioid receptor causes analgesic and euphoriant effects. Stimulation of the σ and D2 receptors may also contribute to hallucinogenic and psychotomimetic effects.
|
|
However, NMDA antagonists like dizocilpine have largely failed to show safety in clinical trials, possibly due to inhibition of NMDA receptor function that is necessary for normal neuronal function. Since dizocilpine is a particularly strong NMDA receptor antagonist, this drug is particularly likely to have psychotomimetic side effects (such as hallucinations) that result from NMDA receptor blockade. Dizocilpine had a promising future as a neuroprotective agent until neurotoxic-like effects, called Olney's Lesions, were seen in certain brain regions of lab rats. Merck, a drug company, promptly dropped development of dizocilpine.
|
|
Several small-scale studies (involving 15 or fewer test subjects) conducted in the 1950s and 1960s reported that adrenochrome triggered psychotic reactions such as thought disorder and derealization. Researchers Abram Hoffer and Humphry Osmond claimed that adrenochrome is a neurotoxic, psychotomimetic substance and may play a role in schizophrenia and other mental illnesses. In what they called the "adrenochrome hypothesis", they speculated that megadoses of vitamin C and niacin could cure schizophrenia by reducing brain adrenochrome. The treatment of schizophrenia with such potent anti-oxidants is highly contested.
|
|
He graduated M.B., B.Chir. (Cantab) in 1945. After two years as a Surgeon-Lieutenant in the R.N.V.R. as ship's doctor on H.M.S. Porlock Bay based in Bermuda, he completed his basic medical postgraduate training at Addenbrooke's Hospital, Cambridge, before selecting neuropsychiatry for a speciality. Two weeks into his first psychiatric residency at St. George's Hospital, London (20), noting the close chemical relation between the psychotomimetic drug mescaline and the neurotransmitter catecholamines, he suggested that schizophrenia might be caused by some abnormality in catecholamine metabolism that produced a mescaline-like substance in the brain.
|
|
Levorphanol's exceptionally high analgesic efficacy in the treatment of neuropathic pain is also conferred by its action on serotonin and norepinephrine transporters, similar to the opioids tramadol and tapentadol, and mutually complements the analgesic effect of its NMDA receptor antagonism. Levorphanol shows a high rate of psychotomimetic side effects such as hallucinations and delirium, which have been attributed to its binding to and activation of the KOR. At the same time however, activation of this receptor as well as of the DOR have been determined to contribute to its analgesic effects.
|
|
Alterations in production of endogenous NMDA antagonists such as agmatine and kyenurenic acid have been shown in schizophrenia. Deficit in NMDA activity produces psychotomimetic effects, though it remains to be seen if the blockade of NMDA via these agents is causative or actually mimetic of patterns resultant from monoaminergic disruption. AMPA, the most widely distributed receptor in the brain, mediates long term potentiation via activity-dependent modulation of AMPA density. GluR1 subunit-containing AMPA receptors are Ca2+ permeable while GluR2/3 subunit-positive receptors are nearly impermeable to calcium ions.
|
|
During postdoctoral studies at the Australian National University with David Curtis, he helped establish the role of glutamate as a central neurotransmitter and characterised its actions between AMPA, N-Methyl-D-aspartic acid (NMDA) and kainate receptor subtypes. At the Royal Veterinary College, Lodge linked his interests in anaesthesia and glutamate receptors by making the key discovery that the dissociative anaesthetics, ketamine and phencyclidine, selectively blocked NMDA receptors. He related NMDA receptor antagonism to psychotomimetic effects. This provided a basis for the glutamate hypothesis of schizophrenia and redirected pharmaceutical search for schizophrenia therapies.
|
|
In 1973, the American Psychiatric Association reported methodological flaws in Hoffer's work on niacin as a schizophrenia treatment and referred to follow-up studies that did not confirm any benefits of the treatment. Multiple additional studies in the United States, Canada, and Australia similarly failed to find benefits of megavitamin therapy to treat schizophrenia. The adrenochrome theory of schizophrenia waned, despite some evidence that it may be psychotomimetic, as adrenochrome was not detectable in people with schizophrenia. In the early 2000s, interest was renewed by the discovery that adrenochrome may be produced normally as an intermediate in the formation of neuromelanin.
|
|
It is described as a "high-impact" AMPAR PAM, unlike so-called "low-impact" AMPAR PAMs like CX-516 and its cogener farampator (CX-691, ORG-24448). In animals, low doses of BIIB-104 have been found to enhance cognition and memory, whereas higher doses produce motor coordination disruptions and convulsions. The same effects, as well as neurotoxicity at higher doses, have been observed with orthosteric and other high-impact allosteric AMPAR activators. In healthy volunteers, BIIB-104 has been found to significantly reduce ketamine-induced deficits in verbal learning and working memory without attenuating ketamine- induced psychotomimetic effects.
|
|
Alazocine (developmental code name -10047), also known more commonly as N-allylnormetazocine (NANM), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. In addition to its opioid activity, the drug is a sigma receptor agonist, and has been used widely in scientific research in studies of this receptor. Alazocine is described as a potent analgesic, psychotomimetic or hallucinogen, and morphine or opioid antagonist. Moreover, one of its enantiomers was the first compound that was found to selectively label the σ1 receptor, and led to the discovery and characterization of the receptor.
|
|
Human studies examining the benefit of combining opioid treatment with NMDA receptor antagonism have yielded mixed results, and few conclusions can be drawn until larger studies are conducted. Targeting the NMDA receptors in areas of potential pathology (such as the dorsal horn of the spinal cord) is a challenge considering their widespread presence throughout the spinal cord and brain, and the profound psychotomimetic side effects associated with known NMDA receptor antagonists may limit their clinical potential as adjuvants to the treatment of pain. Gliosis due to the TLR4 agonist effects of opioids has also been implicated in both hyperalgesia and tolerance.
|
|
Research into the use of cyclazocine for the treatment of bipolar patients with depression was undertaken by Fink and colleagues (1970). It showed that 8 out of 10 patients experienced moderate improvement. Research during the 1960s and 1970s into the possible use of cyclazocine for management of pain, and later for assisting treatment of narcotic addiction was severely hampered by the drug's psychotomimetic, dysphoric, and hallucinatory effects. The dysphoric/anxiety inducing effects the drug correlate with increasing dosage and would likely reduce the risk of abuse in the same manner as other opioids which preferentially act on the KOR versus the DOR.
|
|
Unlike other KOR agonists, nalfurafine does not produce hallucinogenic effects in humans. Single intramuscular injections of up to 30 µg are well tolerated by humans, whereas a dose of 40 µg produced "moderate behavioral/psychological side effects" (possibly referring to sedation), though apparently did not produce any psychotomimetic or dysphoric effects. In rodents, a low dose of nalfurafine (10–40 µg/kg) was found not to produce conditioned place preference or aversion, though a high dose (80 µg/kg) did induce significant place aversion. The most common side effect of low-dose nalfurafine seen in clinical trials was insomnia (observed in 10–15% of patients), with few other adverse effects observed.
|
|
Levallorphan was also used in combination with opioid analgesics to reduce their side effects, mainly in obstetrics, and a very small dose of levallorphan used alongside a full agonist of the MOR can produce greater analgesia than when the latter is used by itself. The combination of levallorphan with pethidine (meperidine) was indeed used so frequently, a standardized formulation was made available, known as Pethilorfan. As an agonist of the KOR, levallorphan can produce severe mental reactions at sufficient doses including hallucinations, dissociation, and other psychotomimetic effects, dysphoria, anxiety, confusion, dizziness, disorientation, derealization, feelings of drunkenness, delusions, paranoia, and bizarre, unusual, or disturbing dreams.
|
|
Licostinel (INN) (code name ACEA-1021) is a competitive, silent antagonist of the glycine site of the NMDA receptor (Kb = 5 nM). It was under investigation by Acea Pharmaceuticals as a neuroprotective agent for the treatment of cerebral ischemia associated with stroke and head injuries but was ultimately never marketed. In clinical trials, licostinel did not produce phencyclidine- like psychotomimetic effects at the doses tested, though transient sedation, dizziness, and nausea were observed. In addition to its actions at the NMDA receptor, licostinel also acts as an antagonist of the AMPA and kainate receptors at high concentrations (Kb = 0.9 μM and 2.5 μM, respectively).
|
|
Subsequently, other benzomorphans, such as pentazocine (an N-dimethylallylbenzomorphan), cyclazocine (an N-cyclopropylmethylbenzomorphan), and phenazocine (an N-phenylethylbenzomorphan), were developed, and some have been marketed for use as analgesics. The sigma σ1 receptor was named in 1976 and (+)-alazocine was described as its prototypical ligand. The receptor was initially thought to be an opioid receptor, and then was confused with the NMDA receptor for a time, but was ultimately distinguished from them both. The psychotomimetic effects of alazocine and the other benzomorphans were initially attributed incorrectly to agonism of the σ1 receptor; subsequent research established that the effects are in fact caused by agonism of the κ-opioid receptor and/or antagonism of the NMDA receptor.
|
|
Levomethorphan is a prodrug to levorphanol, analogously to DXM acting as a prodrug to dextrorphan or codeine behaving as a prodrug to morphine. As such, levomethorphan has similar effects to levorphanol but is less potent as it must be demethylated to the active form by liver enzymes before being able to produce its effects. As a prodrug of levorphanol, levomethorphan functions as a potent agonist of all three of the opioid receptors, μ, κ (κ1 and κ3 but notably not κ2), and δ, as an NMDA receptor antagonist, and as a serotonin-norepinephrine reuptake inhibitor. Via activation of the KOR, levomethorphan can produce dysphoria and psychotomimetic effects such as dissociation and hallucinations.
|
|
Arketamine appears to be more effective as a rapid-acting antidepressant than esketamine in preclinical research. In rodent studies, esketamine produced hyperlocomotion, prepulse inhibition deficits, and rewarding effects, while arketamine did not, in accordance with its lower potency as an NMDA receptor antagonist and dopamine reuptake inhibitor. As such, arketamine may have a lower propensity for producing psychotomimetic effects and a lower abuse potential in addition to superior antidepressant efficacy. A study conducted in mice found that ketamine's antidepressant activity is not caused by ketamine inhibiting NMDAR, but rather by sustained activation of a different glutamate receptor, the AMPA receptor, by a metabolite, (2R,6R)-hydroxynorketamine; as of 2017 it was unknown if this was happening in humans.
|
|
A retro example of psychedelia; the dancer combines 1960s fashion with modern LED lighting. The impact of psychedelic drugs on western culture in the 1960s led to semantic drift in the use of the word "psychedelic", and it is now frequently used to describe anything with abstract decoration of multiple bright colours, similar to those seen in drug-induced hallucinations. In objection to this new meaning, and to what some consider pejorative meanings of other synonyms such as "hallucinogen" and "psychotomimetic", the term "entheogen" was proposed and is seeing increasing use. However, many consider the term "entheogen" best reserved for religious and spiritual usage, such as certain Native American churches do with the peyote sacrament, and "psychedelic" left to describe those who are using these drugs for recreation, psychotherapy, physical healing, or creative problem solving.
|
|
Fenobam is an imidazole derivative developed by McNeil Laboratories in the late 1970s as a novel anxiolytic drug with an at-the-time-unidentified molecular target in the brain. Subsequently, it was determined that fenobam acts as a potent and selective negative allosteric modulator of the metabotropic glutamate receptor subtype mGluR5, and it has been used as a lead compound for the development of a range of newer mGluR5 antagonists. Fenobam has anxiolytic effects comparable to those of benzodiazepine drugs, but was never commercially marketed for the treatment of anxiety due to dose-limiting side effects such as amnesia and psychotomimetic symptoms. Following the discovery of its activity as a potent negative allosteric modulator of mGluR5, fenobam has been re-investigated for many applications, with its profile of combined antidepressant, anxiolytic, analgesic and anti-addictive effects potentially useful given the common co-morbidity of these symptoms.
|
|
The psychotomimetic effects produced by CI-966 are reportedly "similar to those of schizophrenia" and show "a similar phenotype to that seen with the psychotomimetics that block the effects of glutamate at the NMDA receptor", and the psychiatric effects of CI-966 were also described as resembling those seen in patients with mania in addition to schizophrenia. These research findings were responsible for the discontinuation of the clinical development of CI-966. In addition, on the basis of these findings, the drug has been characterized as a hallucinogen similarly to the potent GABAA receptor full agonist muscimol (a constituent of the hallucinogenic Amanita muscaria (fly agaric) mushrooms). In contrast to CI-966, the marketed selective GAT-1 blocker (and analogue of CI-966) tiagabine has been found at the dosages in which it has been studied and used to have far lower although non-absent potential for the same adverse effects of the former, including psychotic reactions.
|
|
It has been known since the 1980s that buprenorphine binds to at high affinity and antagonizes the KOR. Through activation of the KOR, dynorphins, opioid peptides that are the endogenous ligands of the KOR and that can, in many regards, be figuratively thought of as functional inverses of the morphine-like, euphoric and stress-inhibiting endorphins, induce dysphoria and stress-like responses in both animals and humans, as well as psychotomimetic effects in humans, and are thought to be essential for the mediation of the dysphoric aspects of stress. In addition, dynorphins are believed to be critically involved in producing the changes in neuroplasticity evoked by chronic stress that lead to the development of depressive and anxiety disorders, increased drug-seeking behavior, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In support of this, in knockout mice lacking the genes encoding the KOR and/or prodynorphin (the endogenous precursor of the dynorphins), many of the usual effects of exposure to chronic stress are completely absent, such as increased immobility in the forced swimming test (a widely employed assay of depressive- like behavior) and increased conditioned place preference for cocaine (a measure of the rewarding properties and addictive susceptibility to cocaine).
|
|