Hallucinogens Flashcards
(13 cards)
Hallucinogens
Hallucination is also described as ‘wandering of the mind’
Hallucinogens include:
- Deliriants: scopolamine (hyoscine), hyoscyamine, amanita species
- Dissociatives: ketamine, PCP
- Oneirogens, which induce dream-like states: salvinorin A, ibogaine
- Psychedelics, ‘mind manifesting’ drugs: psilocybin, LSD, ayahuasca, mescaline
Molecular targets of hallucinogens include:
- GABAA receptor agonists/PAMs
- NMDA receptor antagonists
- Muscarinic receptor antagonists
- 5HT2A receptor agonists
GABA-A agonists - Amanita metabolites
Orthosteric agonists at GABAA receptors include GABA, the endogenous agonist, and muscimol, a natural compound.
Muscimol was previously used as a sedative and antiemetic, but it has hallucinogenic action and is not currently in clinical use.
Bicuculine is an antagonist. It has no clinical use as it causes seizures, but it can be used to model epilepsy.
The enzyme glutamic acid decarboxylase converts glutamic acid (glutamate) to gamma-aminobutyric acid (GABA). The major excitatory and inhibitory neurotransmitters in the CNS are a single enzymatic step away.
Amanita species are deliriants.
Ibotenic acid (ibotenate) from Amanita species is converted to muscimol by glutamic acid decarboxylase in the liver.
Muscimol crosses the BBB and activates GABA-A receptors and inhibits GABA transporters and GABA transaminase. This causes a decrease in neuronal signalling.
It is neuroprotective
Oral doses >5 mg show psychotropic/behavioural effects.
Ibotenate can however also cross the BBB. It has excitatory effects, activating NMDA and metabotropic glutamate receptors, causing excitotoxicity and convulsions.
Oral doses >50 mg in humans show psychotropic/behavioural effects.
15-30 minutes following oral intake of Amanita muscaria there is an onset of nausea, vomiting, diarrhoea, sweating and salivation → purgative effects.
This is followed by:
- Dry mouth, hyperthermia, pupillodilation and light sensitivity
- Euphoria, hyperactivity, delirium, hallucinations
- Muscle twitching (not convulsions)
- ‘Mystical experiences’
Effects peak 2-3 h following ingestion and recovery takes 8 h.
Traditionally, tribal rituals would involve the shaman consuming the amanita muscaria mushroom, and the rest of the men of the tribe would consume his urine. The shaman would experience the initial side effects, but the rest of the men would only experience the hallucination, so it was seen as a sacrificial act.
Amanita phalloides (death cap mushroom) intoxication can result in death. These mushrooms contain Phalloidin and Amanitin, which are hepatotoxic, causing cholestasis, centri-lobular hepatocellular necrosis and intra-hepatic haemorrhage.
Muscarinic receptor antagonists - Solanaceae
The family Solanaceae are nightshades.
There are multiple genuses including:
- Atropa - e.g. Atropa belladonna (deadly nightshade)
- Hysocamus - e.g. Hysocamus niger (henbane)
- Solanum - e.g. Solanum tuberosum (potato), Solanum lycopersicum (tomato), Solanum melongena (aubergine), Solanum dulcamara (woody nightshade)
The Solanacaceae family produces tropane alkaloids, such as atropine, hyoscine/scopolamine and hyoscyamine. These are deliriants.
Tropane alkaloids can be extracted using an alkaline solution, usually ammonia.
Scopolamine was used in the US as a ‘truth serum’ to extract information by torture as it causes anxiety, blurred vision, dizziness, dry mouth, tachycardia, seizures, etc.
Benzatropine is a synthetic tropane alkaloid synthesised in 1953.
Atropa belladonna (deadly nightshade) was named by Linneas in 1753
- Atropa - without turning/inflexible
- Belladonna - pretty lady, reflecting the cosmetic use from Ancient Egypt to the Renaissance → used for beautification as they would cause pupil dilation, which was seen as an attractive trait
Atropa belladonna contains the tropane alkaloids atropine, hyoscyamine and scopolamine. These have anti-inflammatory, anticholinergic, antispasmodic, mydriatic, analgesic, anticonvulsant, and antimicrobial properties.
- Atropine is used as an antispasmodic agent and an analgesic for gastrointestinal spasms and biliary and hepatic colic.
- Scopolamine is a potent antidepressant and anxiolytic and a treatment for motion sickness.
Atropa can cause unpredictable hallucinations and higher doses can lead to delirium. Historically, it has been associated with occult practices and was said to be used by witches and sorcerers for potions.
Solanaceae-derived alkaloids were used as poisons in the Ancient World from 4000 BCE. They were also used in combination with opium as an anaesthetic.
In Medieval Europe, they were reported to be a component of Pharmaka diabolics or ‘flying ointments’ due to association with witches.
Members of this family evoke classical antimuscarinic effects:
- Tachycardia, dry mouth, blurred vision, restlessness, coma, death
- Centrally-mediated euphoria and hallucinations, as well as agitation and anxiety → suggested to have indirect effects on 5-HT neurotransmission through cholinergic modulation, which is what leads to hallucinogenic effects
- Delirium: similarities with sleepwalking and fugue states.
These compounds are abused in low income countries and deprieved areas of the developed world.
NMDA antagonists - Phencyclidine
Phencyclidine, also known as PCP and angel dust, functions as an open channel blocker of the NMDA glutamate receptor, reducing excitatory neurotransmission.
It is a dissociative drug.
Originally developed as an anaesthetic in 1953 and then withdrawn in 1965.
Non-medicinal use began in 1967 with hospital admissions for schizophrenia-like symptoms in San Francisco. This is consistent with the glutamatergic hypofunction hypothesis of schizophrenia. It can induce the positive and negative symptoms of schizophrenia, as well as significant cognitive deficits.
PCP use can also cause several adverse physiological events including tachycardia, elevated BP, rhabdomyolysis, seizure, memory loss, coma, elevated body temperature, and death.
Unregulated use as pills (PeaCe Pill), snorted, injected (Wack) or smoked (sprayed on herbs/Cannabis or by dipping cigarettes)
Combined with MDMA, referred to as elephant flipping or Pikachu.
NMDA antagonists - Ketamine
Keamine is also known as vitamin K, special K, Ket or cat valium.
It also functions as an open channel blocker of NMDA receptors.
Originally synthesised in 1964 and FDA approved in 1970 as an anaesthetic for use in humans and animals.
Non-medicinal use began in the mid-1970s
Higher doses elicit a ‘K-hole’ experience, combining dissociation with hallucinations
Nasal spray of S-ketamine was approved by FDA in 2019 as an adjunct for treatment-resistant depression.
- Ketamine increases the number and function of spines in the prefrontal cortex, improving neuroplasticity.
- Its mechanism of action in depression is not well understood but may involve mammalian target of rapamycin (mTOR) signalling and BDNF.
5-HT and hallucinogens
5-HT was identified in 1953
There are 14 known serotonin receptors
The 5-HT2 family is important for psychoactivity
5HT2A agonists - Psilocybin
Psilocybin is a prodrug of psilocin, naturally occuring in Psilocybe fungi species, known as ‘shrooms’ or ‘magic mushrooms’, as well as a few other species. These have worldwide distribution and can be dried and eaten or prepared as a decoction.
These compounds are psychedelics.
The mushrooms originate from prehistory (>6000 y).
The compound was isolated in 1958 by Albert Hofmann.
There was widespread use in the US in the 1970s, causing psilocybin to be scheduled as a schedule I compound.
Psilocybin is an entheogen, a psychoactive substance used in spiritual, mystical or religious contexts. It causes sensory hallucinations and synaesthesia.
The response is context sensitive - its effects depend a lot on your mood an environment, affecting the ‘trip’
Psilocin’s psychoactive properties are mainly attributed to its partial agonism at the 5-HT2A receptor. Psilocin also acts as a partial agonist at 5-HT1A receptors and has activity at other receptors, influencing the psychedelic experience.
The mushrooms have been decriminalized in many states, including Oregon and Colorado, since 2020. This correlates to more relaxed attitudes towards cannabis consumption in these states.
Psilocybin may be a useful therapeutic, showing positive results in the treatment of neurotic disorders, alcoholism, addiction, depression in terminally ill cancer patients, OCD, anxiety, and even cluster headaches.
The stigma imposed on entheogens has negatively impacted Indigenous communities by undermining their cultural and religious practices.
5HT2A agonists - LSD
Lysergic acid diethylamide (LSD), also known as just ‘acid’ is a synthetic 5HT2A agonist synthesised in 1938 by Albert Hofmann.
LSD is a psychedelic.
Hofmann ingested the compound and recorded its effects. He had a pleasant experience: “intoxicated-like condition” with “kaleidoscopic play of colors”.
He followed this up with a more deliberate consumption in his laboratory, keeping a record of the effects. When he left the lab and went home, the effects were different. He reported visual disturbances and flashing lights, vertigo, facial distortions of those present, phases of unrest and paralysis, heaviness of the limbs and body, an out of body experience and incoherent babbling.
Effects may therefore be context-dependent.
He reported complete recollection of all of these events, implying no loss of memory.
Wider testing of LSD generated the following results:
- Otherwise healthy individuals reported psychological effects
- Psychiatric patients appeared resistant.
Most analogues are less active or inactive, except for LSZ, known as ‘Ethlad’ or ‘Al-lad’.
LSD binding shows an unusual configuration and very slow kinetics, acting almost as an irreversible 5-HT2A agonist.
LSD also causes unusual conformational changes in the 5-HT2B receptor. There is an exaggerated TM6 movement and ICL2/ICL3 conformational change.
These differences may play a role in setting LSD apart from other closely related compounds in terms of its psychoactivity.
LSD has a similar structure to 5-HT.
Acutely, it induces feelings of bliss, audiovisual synaesthesia, altered perceptions, and mystical experiences, as well as increased feelings of closeness to others, openness, trust, suggestibility, and emotional empathy.
Research suggests LSD is physiologically safe, non-addictive, and has a low incidence of adverse effects in controlled experiments.
LSD has potential therapeutic value, with promising results from pilot trials for depression, anxiety and addictions.
LSD was found to have analgesic action in gravely ill patients, and they displayed a disregard for their situations, and freely talked about their impending death.
Kary Mullis won the 1993 Nobel Prize in Chemistry for the invention of PCR. He consumed a lot of LSD and regarded the psychoactive experiences offered by these higher than any lecture he ever attended and also wondered if he would have been creative enough to invent PCR without LSD. He however held many controversial opinions: didn’t believe in climate change, questioned the link between HIV and AIDS, believed in the paranormal.
5HT2A agonists - Methyltryptamines
α-Methyltryptamine (AMT) is a psychedelic also called ‘spirals’ in the US. It is not as common in the UK.
20-30 mg elicits MDMA-like effects, causing euphoria, increased empathy and psychedelic effects, but also bruxism, anxiety and tachycardia.
N,N-Dimethyltryptamine (DMT) is a widespread metabolite of AMT.
It is also a natural component of ayahuasca, together with harmine.
Ayahuasca is a concoction of boiled Banisteriopsis caapi vine with leaves of the Psychotria viridis shrub, consumed socially as a ceremonial/shamanic spiritual medicine.
When an outsider experiences this in the Amazon, they get a spirit guide which talks you through the expectations before you take the ayahuasca and during the experience.
This causes visual hallucinations and an altered perceptions of reality
- A ‘shared ayahuasca world’ - people report ‘meeting’ their future children or ancestors
This is followed by a ‘purge’
DMT interacts with various receptors in the brain. The hallucinogenic effects of DMT are believed to result primarily from agonism of the 5-HT2A receptor and are modulated by mGlu2/3 receptors.
DMT has demonstrated potent anti-inflammatory properties through activation of the sigma-1 receptor, a chaperone protein at the endoplasmic reticulum that modulates calcium signalling through the IP3 receptor.
Ibogaine
Ibogaine comes from the West African iboga plant root.
Ibogaine is an oneirogen, a drug which induces dream-like states
Low doses are used to reduce fatigue.
Higher doses induce hallucinations and are used for spiritual rituals.
Ibogaine was isolated in 1901.
It was marketed in France as a stimulant and antidepressant.
In the 1960s, it was promoted in the US as a treatment for opioid addiction after reports of heroin addicts experiencing relief from opiate withdrawal symptoms.
It shows broad binding to multiple receptors, including opioid, 5-HT, DA, NMDA, mAChRs and nAChRs.
Hallucinations are 5-HT2A-mediated.
Ibogaine can cause dose-dependent adverse effects, including tremors, neurotoxicity, and cardiovascular problems.
Ibogaine is a Schedule I drug in the US and UK, with no recognized therapeutic use, but it is unregulated in most countries and it is legal for prescription use in Brazil and New Zealand for the treatment of addiction.
- Studies showed ibogaine reduces morphine self-administration and dopamine release in rats.
- Ibogaine causes side effects, but this led to the development of analogs like 18-methoxycoronaridine (18-MC), which retains anti-craving properties with fewer adverse effects.
5HT2A agonists - *Mescaline
Mescaline is a psychedelic with a long history of use (>6000 y).
It is an alkaloid found in high concentrations in certain cacti species like peyote and wachuma. The use of these cacti has spread geographically, with peyote being used in the Native American Church and wachuma spreading for psychotherapeutic and recreational purposes.
The structure of mescaline was established in 1919.
Mescaline’s effects are mainly due to its action as a 5-HT2A serotonin receptor agonist, but it also binds to 5-HT1A and α2A receptors.
Studies have shown that mescaline can induce visual changes, alter sensory experiences, and affect motor behaviour.
*Salvinorin A
Salvinorin A is the main active compound present in Salvia divinorum, a plant from the mint family.
It is an oneirogen, a drug which induces dream-like states.
Common street names include Shepherdess’s Herb, Diviner’s Sage, Sally-D, and Magic Mint.
Salvia divinorum preparations, such as green tea from beaten leaves, were used in shamanic rituals by Mazatecs when magic mushrooms were not available. The species name divinorum refers to its divinatory purposes in identifying illnesses or finding guilty parties.
Salvinorin A activates kappa opioid receptors (KOR) but not 5-HT2A receptors, unlike classic hallucinogens.
Experiences after consumption include dysphoria, depersonalization, out-of-body experiences, colorful visions, and hallucinations.
Can be smoked or vapourized for more rapid effects.
Data on hallucinogens
Rate of consumption of hallucinogens in the UK has been fairly constant over the last 25 years (8-9%).
However, the rate of ketamine consumption has increased from 1 to 4%, probably due to increased access.
~7% of the population uses magic mushrooms. Use has gone up in the 20th century
It is difficult to pick up deaths caused by hallucinogens as a primary contributor, but, for example, the hallucinogen AMT causes less deaths than the downer GHB, and it is responsible for <10 deaths per year, often being reported as 0 in a given year.
AMT does not have a large impact on deaths in the UK compared to other psychoactive substances.
Most of these substances are classified as schedule I/ class A, but they do not seem to be very deadly, so what is the rationale behind this decision?
