hallucinogens

• Hallucinogens


  Induce an altered state of consciousness, characterized by distortions of perception, hallucinations or visions, ecstasy, dissolution of self boundaries and the experience of union with the world
• Hallucinogens


  Also referred to as 'psychedelics' (mind revealing/opening), 'psychotomimetic' (mimicking psychosis) or 'entheogen' (generating the divine/spiritual within)
• Classical hallucinogens


  • Plant-derived substances, such as psilocybin (from Psycocybe 'magic' mushrooms) and mescaline (from peyote cactus)
  • Synthetic drugs, such as LSD
• Classical hallucinogens


  Agonists at serotonin (5-HT), especially 5-HT2A, receptors. Altered state of consciousness is primary effect.
• Dissociative anaesthetics


  • Synthetic drugs, such as phencyclidine (PCP) and ketamine
• Dissociative anaesthetics


  Produce anaesthesia (loss of all sensation) at higher doses and altered states of consciousness at lower doses, including 'disconnection/dissociation' from environment (loss of time sense, feeling of floating/hovering weightlessly) and body (altered perception of body consistency and out of body experience). Non-competitive NMDA receptor antagonists.
• Comparison of classical hallucinogen (psilocybin) and dissociative anaesthetic (ketamine) using Five-dimensional altered states of consciousness (5DASC) rating scale
• The 5DASC rating scale has 5 primary dimensions with subdimensions: 'oceanic boundlessness', 'anxious ego-disintegration', 'visionary restructuralization', 'acoustic alterations', and 'altered vigilance'
• The importance of 'set' (expectations) and 'setting' in determining subjective experience induced by hallucinogenic drugs
• Hallucinogen effects are heavily dependent on the user's expectations ("set") and the environment ("setting")
• An individual's response to repeated administration of the same drug and dose may vary
• Classical hallucinogens


  Include plant-derived drugs, such as psilocybin and mescaline, and synthetic drugs, such as LSD, and they primarily induce altered states of consciousness
• Dissociative anaesthetics


  Are synthetic drugs, such as phencyclidine and ketamine; they produce altered states of consciousness at lower doses and anaesthesia at higher doses
• It is difficult to predict whether a user of hallucinogens will have a "good trip" or a "bad trip" because the drug effects depend very much on the user's expectations and the environment and circumstances in which the drug is taken
• Natural hallucinogens have been used for millennia, often as part of rituals
• Plant-derived hallucinogens and LSD entered Northern American and European mainstream culture in first half of 20th century
• PCP developed as anaesthetic in mid1950; ketamine synthesized as safer alternative in 1962 – still used as anaesthetic in humans and animals
• Ketamine approved as depression treatment in US in 2019
• There was substantial interest by researchers in understanding hallucinogenic drug actions and to exploit them clinically, but the classical hallucinogens became associated with 1960s counterculture and were made illegal
• MDMA (Ecstasy)


  An amphetamine with strong effects on serotonin transmission, having stimulant properties that increase alertness and 'energy, and hallucinogenic-like properties that increase sociability and talkativeness and induce an altered state of consciousness with emotional and sensual overtones
• The 'alteration of consciousness' produced by MDMA may be much weaker than the one produced by LSD
• MDMA has been suggested for use in psychotherapy (with recent focus on PTSD), but has also become notorious for use in the rave scene and ecstasy-related deaths
• Proportion of 16-59 year olds in England and Wales using LSD, magic mushrooms, and ketamine in 2017/18 was 0.4%, 0.4%, and 0.8% respectively
• David Nutt, then the Chair of the governments Advisory Council for the Misuse of Drugs (ACMD), made the provocative claim that ecstasy use may be less dangerous than horse riding
• Apart from potential distress, classical hallucinogenic drugs cause virtually no physical harm and no dependence
• Ecstasy and dissociative anaesthetics (PCP, ketamine) can cause dependence and neurodegeneration, although it is debated if typical recreational usage and doses cause neurodegeneration
• There were about 130 ecstasy-related deaths in England, Wales and Scotland in 2017, which may be related to overheating and dehydration
• Hallucinogens and MDMA are subject to severe legal restrictions in the UK, with penalties for offences such as supply, production and possession
• MDMA is a synthetic drug that induces stronger effects on serotonin transmission than other amphetamines, but does not induce stronger visual hallucinations than LSD, and has a higher potential to cause dependence than LSD
• Possession of classical hallucinogens may be punished with a prison sentence, and ketamine is still used as an anaesthetic in humans
• Classical hallucinogens are more likely to cause dependence than alcohol
• Possession of MDMA may be punished with a prison sentence
• Indoleamine hallucinogens and phenethylamine hallucinogens

  Have high affinity to serotonin (5HT) receptors, especially 5HT2A and C receptor subtypes, and their primary neuropharmacological mechanism is stimulation of 5HT receptors
• Stimulation of 5HT2A receptors is critical for the main psychological effects of indoleamine and phenethylamine hallucinogens
• Serotonin system and 5HT2A receptors

  Serotonergic raphe nuclei in the midbrain innervate large parts of the brain, including many cortical and subcortical forebrain regions. 5HT2A receptors are G protein-coupled receptors whose activation mainly has stimulatory effects on the neuron (increased transmitter release and increased activity). 5HT2A receptor activation may stimulate excitatory neurons, including in the prefrontal cortex, which may be critical for the hallucinogenic effects.
• 1. HT2A receptors mediate the subjective effects of hallucinogens
• Evidence supports that stimulation of 5HT2A receptors is critical for main psychological effects of indoleamine and phenethylamine hallucinogens
• Serotonin system and 5HT2A receptors

  G protein-coupled receptors; their activation mainly has stimulatory effects on the neuron (increased transmitter release and increased activity)
• 5HT2A receptor activation may stimulate excitatory neurons, including in the prefrontal cortex, which may be critical for the hallucinogenic effects
• 1. HT2A receptors mediate subjective effects of hallucinogens