Lecture 12 - Hallucinogens (and ecstasy) 2

Question 1

What are the two categories of classic hallucinogens?

Answer 1

Indoleamine hallucinogens and phenethylamine hallucinogens

Question 2

What type of backbone do indoleamine hallucinogens have?

Answer 2

Serotonin

Question 3

What type of back bone do phenethylamine hallucinogens have?

Answer 3

Dopamine and norepinephrine

Question 4

What is the primary neurological mechanism for classic hallucinogens?

Answer 4

• Indoleamine and phenethylamine hallucinogens activate serotonin (5HT2) receptors, and 5HT2A receptor activation is main contributor to their psychological effects
• High affinity to serotonin (5HT) receptors, especially 5HT2A and C receptor subtypes (in the 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 5

What is the relationship between the serotonin system and 5HT2A receptors?

Answer 5

• Serotonergic raphe nuclei in the midbrain innervate large parts of the brain, including many cortical and subcortical forebrain regions (shown by red lines in diagram)
• 5HT2A receptors are 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 (e.g. Vollenweider & Kometer, 2010)

Question 6

How do 5-HT2A receptors mediate subjective effects of hallucinogens?

Answer 6

• Study = give psychedelics to healthy volunteers and measure effect on them using questionnaires
• Ketanserin = serotonin 2A receptor antagonist (should block it). Same effect in 5-HT2A/dopamine D2 antagonist
• Dopamine D2 antagonist not as effective at blocking haloperidol group
• Studies strongly support that 5-HT2A mediates mind altering effects of hallucinogens
• Serotonin 2A receptors mediate psychedelic effects
• In animal studies, behavioural effects of classic hallucinogens are blocked by selective 5HT2A receptor antagonist (Halberstadt, 2015)

Question 7

How does ecstasy (MDMA) affect serotonin and dopamine?

Answer 7

• MDMA = 3,4-methylene-dioxymethamphetamine
• Ecstasy has a particularly strong serotonin effect
• Stimulates serotonin release (probably by interaction with 5HT transporter – responsible for getting serotonin from extracellular space to neuron) and some of MDMA’s subjective effects are mediated by 5HT2A receptors (see Liechti et al, 2000)
• Also stimulates dopamine release, including in nucleus accumbens, which is thought to contribute to stimulant and rewarding/reinforcing properties (see Bankson & Yamamoto, 2004)

Question 8

What is the primary neuropharmacological mechanism of dissociative anaesthetics?

Answer 8

• Primary neuropharmacological mechanism is blockade of the channel pore of the NMDA-type glutamate receptor (non-competitive NMDA receptor antagonist – doesn’t compete with glutamate for binding site but binds independently with the ligand)
• One prominent idea is that NMDA receptor blockade increases neural excitation in many brain areas, including cortical, areas by ‘disinhibition’, i.e. reducing the activity of inhibitory neurons. This may be a key factor in the psychological effects of dissociative anaesthetics (e.g. Vollenweider & Kometer, 2010)
• NMDA receptor antagonists also stimulate prefrontal cortex and nucleus accumbens dopamine release (e.g., Hertel et al, 1995) and this effect may be mediated by increased neural excitation in cortical regions (Moghaddam et al, 1997)

Question 9

How may hallucinogenic drug effects be explained by prefrontal cortical activation?

Answer 9

• Similar areas of activation
• Synaptic mechanisms by which drugs cause psychedelic effects (increased activation in prefrontal cortex)
• Classic hallucinogens – serotonin receptors activated, release glutamate
• Dissociative anaesthetics – neurons carry NMDA receptors, blocked by dissociative anaesthetics, GABA release reduced, so excitatory neurons are less inhibited/more activation

Question 10

Describe dependence to hallucinogens

Answer 10

• Evidence from animal models and humans supports that both dissociative anaesthetics (ketamine, PCP) and MDMA can cause dependence, although the potential for dependence may be weaker than with other drugs of abuse (amphetamines, opioids, alcohol, nicotine) (Degenhardt et al, 2010; Morgan&Curran, 2012)
• This may partly be mediated by the increased meso-corticolimbic dopamine release caused by these drugs

Question 11

Describe neurodegeneration due to hallucinogens

Answer 11

• Studies in animal models have long shown that non-competitive NMDA receptor antagonists, including PCP and ketamine (Olney, et al,1989; Cadinu et al, 2018), and MDMA (Parrott, 2013) cause neurodegeneration; MDMA-induced neurodegeneration is selective to serotonergic neurons
• For MDMA, there is compelling evidence that recreational usage of the drug also damages serotonergic neurons in humans

Question 12

What is ‘ketamine bladder’?

Answer 12

• ‘Ketamine bladder’/ketamine-induced ulcerative cystitis (thickening of bladder wall and low bladder capacity), kidney dysfunction and ‘k-cramps’ (intense abdominal pain) have also been reported in chronic ketamine users (Morgan & Curran, 2012)

Question 13

Describe MDMA-induced damage of serotonergic neurons in human recreational users

Answer 13

• 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 13

Describe MDMA induced damage of serotonergic neurons in squirrel monkeys

Answer 13

Damage of serotonergic neurons in frontal, parietal and primary visual cortices 2 weeks after injection, and some damage remains 7 years later (Hatzidimitriou et al., 1999)

Question 14

What are some ethical challenges associated with research involving MDMA administration to volunteers?

Answer 14

• Are the risks due to adverse effects, including dependence and neurodegeneration, acceptable and do they outweigh the potential gains?
• See:
• McCann, U. D., & Ricaurte, G. A. (2001). Caveat emptor: editors beware
• Lieberman, JA, & Aghajanian, GK, 1999. Caveat emptor: Researcher beware

Question 15

How may hallucinogens/ecstasy be used in the treatment of neuropsychiatric disorders

Answer 15

• Long-standing interest in use of hallucinogens and MDMA for psychotherapy, but properly controlled clinical trials have only started recently (2000-2010), partly because of the strict legal regulations of hallucinogens

Question 16

How may classic hallucinogens/MDMA assist psychotherapy?

Answer 16

• Drug is used on one or a few occasions during psychotherapy sessions to overcome obstacles to successful psychotherapy and to facilitate a 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 17

How may ketamine be used for severe treatment-resistant depression?

Answer 17

• First clinical study in 2000 reported rapid anti-depressant effect of ketamine
• Well-controlled clinical trials support antidepressant effect of ketamine, although not all patients respond, the duration of antidepressant effect is variable, and not all patient groups may be suitable (e.g., patients with psychosis)
• Potential adverse effects of ketamine are of 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