Hallucinogens (Midterm II)

Question 1

hallucinogen

Answer 1

a psychoactive agent that causes changes in perceptions (hallucinations)

• associated with substantial changes in thoughts, emotions and consciousness
• most alter the function of the monoamine system (not all though! ex salvia divinorum acts on kappa opioid receptors)

Question 2

monaminergic receptors

Answer 2

5HT: 7 subtypes
-T1 and 5 are Gi, T2 is Gq, T4/6/7 are Gs, and T3 is special bc its a LGIC
NE: 3 isoforms, all GPRCs
-alpha1 is Gq, alpha2 is Gi, and beta is Gs
DA: 2 GPCR subtypes
-D1 is Gs, D2 is Gi

Question 3

monoamine synthesis

Answer 3

• DA and NE are one chemical conversion apart (with epinepherine one step further down the pathway), and are synthesized from tyrosine -> L-DOPA
• 5HT is synthesized from tryptophan
• both share a common enzyme, aromatic L amino acid decarboxylase
• once DA and 5HT are synthesized, they’re packaged into vesicles by VMAT2

Question 4

monaminergic metabolism

Answer 4

-all metabolized by MAOs (which clip off the amine group) or catechol-O-methyltransferases (COMT)

Question 5

VMAT

Answer 5

-vesicular monoaminergic transporter, pumps cytosolic NT into vesicles to be released into the synapse following action potential

Question 6

lysergamides

Answer 6

• discovered accidentally by hofmann, who was trying to chemically manipulate ergot derivatives to make them stable in solution (these are compounds produced by fungus that grows on rye, and are potent vasoconstrictors that could be useful for treating migraine)
• he ended up making lysergic acid diethyl amide (LSD), and had the first acid trip on his bike ride home

Question 7

LSD effects

Answer 7

• dilated pupils, increased heart rate and BP
• distortion of sensory perception (size, wavering of images), hallucinations ranging from simple colour patterns to complex scenes
• sometimes a feeling of enlightenment that has shown some effects for treatment resistant psychiatric conditions such as depression)
• adverse psychiatric effects such as anxiety, paranoia, delusions (a bad trip, but usually wears off with drug clearance)
• hallucinogenic persisting perception disorder (HPPD): distressing hallucinations that appear weeks, month, even years after the drug has worn off; can be deadly

Question 8

LSD mechanism

Answer 8

• LSD has over 50 known targets (determined by competition assays with radiolabelled ligands), including several 5HT receptors
• hallucinogenic effects are mediated by 5HT2a, at high LSD is a high affinity partial agonist (confirmed by observed absence of head bobbing hallucinating behaviours in 5HT2a knockout mice)
• activates phospholipase A1 instead of PLC as 5HT (biasing agonism towards hallucinations as different genes are then regulated (and explaining why 5HT doesn’t cause hallucinations at 2a))

Question 9

LSD tolerance

Answer 9

• a single dose can lead to profound tolerance that lasts for several days; if you took LSD two days in the row, you would likely see no effects the 2nd day
• tolerance is accompanied by specific downregulation of 5HT2 receptors (not others)
• this means you get cross-tolerance of LSD with other hallucinogens that act at 5HT receptors (psilocybin, DMT)

Question 10

indolamines

Answer 10

• class of hallucinogens that are all structurally homologous with 5HT (all built on an indole molecule (benzene fused to a 5-membered pyrole) with an amine group
  ex. psilocybin

Question 11

psilocybin

Answer 11

• naturally occurring hallucinogenic compound produced by psilocybin mushrooms
• used by indigenous communities in religious ceremonies for thousands of years
• when ingested, cause euphoria, visual/mental hallucinations, changes in perceptions and distorted sense of time, spiritual experiences
• adverse rxns similar to LSD (nausea, panic attacks, but also dysphoria)
• a prodrug, rapidly dephosphorylated to the active psilocin in the body; this is a partial agonist with high affinity for 5HT2b/c receptors, and lower affinity at the 2a receptor through which hallucinogenic effects are mediated

Question 12

DMT

Answer 12

(dimethyltryptamine)

• the only hallucination produced naturally by the mammalian brain, from tryptophan
• like other hallucinogens, a partial agonist at 5HT whose hallucinogenic effects are via biased 2a antagonism

Question 13

phenethylamines

Answer 13

• a diverse class of CNS of drugs that act on monoamines, some with hallucinogenic effects (mescaline, MDMA), others as CNS stimulants (amphetamine, MDMA, methyphenidate) and antidepressants (buproprion)
• all have a phenylethyamine backbone and act by modulating the monoamine system

Question 14

mescaline

Answer 14

• a naturally occurring psychedelic alkaloid from the peyote cactus; used by native americans in mexico for centuries
• synthesized from tyrosine and activates 5HT2a receptors with high affinity

Question 15

MDMA

Answer 15

-3,4-methylenedioxy methamphetamine
-a popular club drug that increased energy, empathy, pleasure and hallucinations
adverse effects: memory impairment, paranoia, insomnia, teeth grinding, blurred vision, sweating, tachycardia, addiction, and acute death due to increased body temp and dehydration
-like mescaline, structurally similar to endogenous monoamines (DA, 5HT, NA) and hallucinogenic effects are also mediated by 5HT2a activity
-induces transporter reversal or efflux, leading to increased synaptic NT conc (it is most potent at SERT, leading to hallucinogenic effects, but also acts at NET and DAT, which likely contributes to euphoric high)

Question 16

amphetamine

Answer 16

• a very potent CNS stimulant with little hallucinogenic effect (mostly caused euphoria, fatigue resistance, improved cognitive control)
• risk of addiction and psychosis (delusions, paranoia)
• like MDMA, leads to monoamine transporter efflux, but has a much greater effect on DAT and NET than SERT (hence the general absence of hallucinations))