hallucinogens (and ecstasy)

Question 1

what are hallucinogens?

Answer 1

induce altered state of consciousness

characterised by distortions of perception, hallucinations or visions, ecstasy, dissolution or self-boundaries and the experience of union with the world

sometimes referred to as “psychedelics” or “psychotomimetic” or “entheogen”

Question 2

what are classical hallucinogens?

Answer 2

plant-derived substances (psilocybin, mescaline)

synthetic drugs (LSD)

agonists at serotonin (5-HT), especially 5-HT2A, receptors

primary effect = altered state of consciousness

Question 3

what are dissociative anaesthetics?

Answer 3

synthetic drugs (phencyclidine, ketamine)

produce anaesthesia (loss of all sensation) at higher doses

produce altered states of consciousness at lower doses

“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

Question 4

what are five primary dimensions of the five-dimensional altered states of consciousness rating scale?

Answer 4

oceanic boundlessness

anxious ego-disintegration

visionary restructuralisation

acoustic alterations

altered vigilance

Question 5

what is oceanic boundlessness?

Answer 5

referring to positively experienced loss of ego boundaries

Question 6

what is anxious ego-disintegration?

Answer 6

thought disorder

loss of self-control

Question 7

what is visionary restructuralisation?

Answer 7

perceptual alterations (visual illusions and hallucinations)

altered meaning of precepts

Question 8

what are acoustic alterations?

Answer 8

hypersensitivity to sound

auditory hallucinations

Question 9

what does “set” mean?

Answer 9

expectations

Question 10

what is the importance of “set” and “setting” in determining subjective experience induced by hallucinogenic drugs?

Answer 10

psychopharmacological actions of hallucinogenic drugs may be less predictable than those of other drugs

hallucinogen effects are heavily dependent on user’s expectations (set) and environment (setting)

individual’s response to repeated administration of same drug and dose may vary

Question 11

what is the historical background of hallucinogens?

Answer 11

natural hallucinogens have been used for millennia (possibly longer than any other psychoactive drug because they are in edible mushrooms) often as part of rituals (under control of suitably experienced people)

plant-derived hallucinogens and LSD entered Northern America and European mainstream culture in first half of 20 century

PCP developed as anaesthetic in mid 1950s

ketamine synthesised as safer alternative in 1962 (still used as anaesthetic in humans, when limited anaesthesia infrastructure and support and in children which show less pronounced psychological events, and in animals)

in Europe and North America was substantial interest by researchers in understanding hallucinogenic drug actions and to exploit them clinically (using them for research to reveal mechanisms of altered states of consciousness in neuropsychiatric disorders and therapy)

especially classical hallucinogens became associated with 1960s counterculture and were made illegal

ketamine approved as depression treatment in US in 2019

Question 12

what is ecstasy (MDMA)?

Answer 12

amphetamine (stimulant) with strong effects on serotonin transmission

has stimulant properties, increasing alertness and energy

has hallucinogenic-like properties - increasing sociability and talkativeness, inducing an alerted state of consciousness

altered state of consciousness may weaker than one produced by LSD

has been suggested for use in psychotherapy (with recent focus on PTSD)

has become notorious for use in rave scene and ecstasy-related deaths

Question 13

what did a crime survey for England and Wales (2017/18) reveal about hallucinogens and MDMA?

Answer 13

proportion of 16-59 year olds using

LSD = 0.4%

magic mushrooms = 0.4%

ketamine = 0.85%

Question 14

what is the harmfulness of classical hallucinogenic drugs?

Answer 14

apart from potential distress caused by subjective experience (depending on set/setting and a particular risk in people with mental health problems)

cause otherwise virtually no physical harm and no dependence

Question 15

what is the harmfulness of ecstasy and dissociative anaesthetics?

Answer 15

cause dependence

cause neurodegeneration - debated if typical recreational usage and doses cause neurodegeneration

Question 16

how many ecstasy-related deaths are there?

Answer 16

about 130 in England, Wales and Scotland in 2017

may be related to overheating and dehydration

Question 17

what are the UK drug regulations?

Answer 17

three classes (A, B and C) - determine penalties for offences (supply, production and possession of controlled drug)

five schedules - regulate clinical use of controlled substances and their storage and labelling requirements

Question 18

what is the schedule and class of ketamine, LSD, MDMA and psilocybin?

Answer 18

ketamine = schedule 4, class C

LSD = schedule 1, class A

MDMA = schedule 1, class A

psilocybin = schedule 1, class A

Question 19

what are the two types of classical hallucinogens?

Answer 19

indoleamine hallucinogens

phenethylamine hallucinogens

Question 20

what are indoleamine hallucinogens?

Answer 20

all have indoleamine backbone (resembles serotonin)

Question 21

what are phenethylamine hallucinogens?

Answer 21

have dopamine backbone

Question 22

what are the neuropharmacological mechanisms of classical hallucinogens?

Answer 22

active serotonin (5HT2) receptors

5HT2S receptor activation is main contributor to their psychological effects

high affinity to serotonin (5HT) receptors - especially 5HT2A and C receptor subtypes; in case of phenethylamines methoxy[CH3O] groups may contribute to this

primary neuropharmacological mechanism is stimulation of 5HT receptors

substantial evidence supports that stimulation of 5HT2A receptors is critical for main psychological effects

Question 23

what is the serotonin system?

Answer 23

originates in midbrain, projecting to forebrain

serotonergic raphe nuclei in the midbrain innervate large parts of the brain, including many cortical and subcortical forebrain regions

Question 24

what are 5HT2A receptors?

Answer 24

critical for psychedelic effects

G protein-coupled receptors

activation mainly has stimulatory effects on the neuron (increased transmitter release and increased activity)

receptor activation may stimulate excitatory neurons (including in prefrontal cortex) which may be critical for hallucinogenic effects

Question 25

how do 5HT2A receptors mediate the subjective effects of hallucinogens?

Answer 25

give psychedelics to healthy volunteers measure effect it had using questionnaire combined with different other drugs which know what subtypes of receptors they act on by looking at combined effects, could find which receptors are used in animal studies, behavioural effects of classical hallucinogens are blocked by selective 5HT2A receptor antagonist

Question 26

what are the neuropharmacological mechanisms of MDMA?

Answer 26

stimulates serotonin release (probably by interaction with 5HT transporter) not a direct agonist some of MDMA's subjective effects are mediated by 5HT2A receptors stimulates dopamine release including in nucleus accumbens, thought to contribute to stimulant and rewarding/reinforcing properties

Question 27

what are the neuropharmacological mechanisms of dissociative anaesthetics?

Answer 27

primary neuropharmacological mechanism is blockade of channel pore of the NMDA-type glutamate receptor (non-competitive NMDA receptor antagonist) one prominent idea = NMDA receptor blockade increases neural excitation NMDA receptors antagonists also stimulate prefrontal cortex and nucleus accumbens dopamine release

Question 28

what is a non-competitive antagonist?

Answer 28

an antagonist that doesn't compete for binding site, binds independently

Question 29

what is the idea that the NMDA receptor blockade increases neural excitation?

Answer 29

in many brain areas, including cortical, by disinhibition disinhibition = reducing activity of inhibitory neurons may be key factor in psychological effects of dissociative anaesthetics

Question 30

what is the idea that NMDA receptors antagonists stimulate prefrontal cortex and nucleus accumbens dopamine release?

Answer 30

key driver of addictive properties mediated by increased neural excitation in cortical regions

Question 31

what is prefrontal cortical activation?

Answer 31

common neural mechanism for hallucinogenic drug effects? combine administration of drug with brain imaging methods

Question 32

what are PET studies into prefrontal cortical activation?

Answer 32

can see similar areas of activation (including in prefrontal cortex) with psilocybin and ketamine

Question 33

what is the synaptic model of neural effects for classical hallucinogens?

Answer 33

stimulate serotonin 2A receptors activate glutamate receptors in prefrontal cortex

Question 34

what is the synaptic model of neural effects in dissociative anaesthetics?

Answer 34

NMDA receptors blocked decreased activity (neurotransmitter release) means excitatory neurons are more activated

Question 35

are imaging findings in people consistent?

Answer 35

no some studies say reduced rather than increased activation

Question 36

what are the adverse effects of dissociative anaesthetics and MDMA (ecstasy)?

Answer 36

dependence neurodegeneration "ketamine bladder"/ketamine-induced ulcerative cystitis, kidney dysfunction, "k-cramps" MDMA-induced damage of serotonergic neurons

Question 37

what is dependence?

Answer 37

evidence from animal models and humans support that both dissociative anaesthetics and MDMA can cause dependence potential for dependence may be weaker than with other drugs of abuse may partly be mediated by increased mesocorticolimbic dopamine release caused by these drugs

Question 38

what is neurodegeneration?

Answer 38

brain damage studies in animal models show non-competitive NMDA receptor agonist and MDMA caused neurodegeneration MDMA-induced neurodegeneration selective to serotonergic neurons for MDMA, compelling evidence that recreational usage of drug also damages serotonergic neurons in humans

Question 39

what is "ketamine bladder"/ketamine-induced ulcerative cystitis, kidney dysfunction, "k-cramps"?

Answer 39

"ketamine bladder" = thickening of bladder wall and low bladder capacity "k-cramps" = intense abdominal pain reported in chronic ketamine users

Question 40

What has been found about MDMA-induced damage of serotonergic neurons in squirrel monkeys?

Answer 40

monkeys given high doses of ecstasy serotonergic damage found stained serotonergic fibres after 2 weeks, substantially reduced after 7 years, still a reduction - long-lasting

Question 41

what has been found about MDM-induced damage of serotonergic neurons in human recreational users?

Answer 41

meta-analysis of neuroimaging studies investigating serotonin transporter (SERT) expression in different brain regions forest plot showing effect sizes for SERT changes in different brain regions SERT expression was decreased in MDMA users in multiple brain regions (including parietal, temporal, occipital, cingulate cortices, thalamus and hippocampus) participants were heavy MDMA users so impact of moderate MDMA use remains to be examined

Question 42

what are the ethical challenges of research?

Answer 42

are risks due to adverse effects, including dependence and neurodegeneration, acceptable and do they outweigh the potential gains?

Question 43

how can hallucinogens and MDMA be used in the treatment of neuropsychiatric disorders?

Answer 43

long-standing interest in use of hallucinogens and MDMA for psychotherapy but properly controlled clinical trials have only started recently partly because of strict legal regulations of hallucinogens classical hallucinogen/MDMA-assisted psychotherapy ketamine for severe treatment-resistant depression

Question 44

what is classical hallucinogen/MDMA assisted psychotherapy?

Answer 44

drug used on one or a few occasions during psychotherapy sessions to overcome obstacles to successful psychotherapy and facilitate therapeutic experience ongoing research on psilocybin/LSD-assisted psychotherapy for substance abuse, severe depression and cancer anxiety and on MDMA-assisted psychotherapy for PTSD and alcohol-dependence encouraging preliminary findings but several limitations (including small samples, often open-label or no placebo) careful clinical supervision required because of potential for "bad trips" MDMA toxicity for serotonergic neurons is of concern although therapeutic effects of MDMA reported at substantially lower doses than those that have been shown to cause neurotoxicity

Question 45

how can ketamine be used for severe treatment-resistant depression?

Answer 45

first clinical study in 2000 reported rapid anti-depressant effect of ketamine well-controlled clinical trials support antidepressant effect of ketamine (not all patients, duration of anti-depressant effect is variable, not all patient groups may be suitable - e.g. patients with psychosis) potential adverse effect of ketamine is concern in 2019, nasal spray containing esketamine (S(+)-ketamine) was approved for treatment-resistant depression in US and Europe, including UK, but NICE has not approved it for NHS funding