Lecture 20: Hallucinogens

Question 1

What are hallucinogens?

Answer 1

a hallucinogen is a psychoactive agent that causes changes in perception (hallucinations)

also associated with substantial changes in thoughts, emotions, consciousness

most hallucinogen drugs alter function of monoaminergic (especially serotonin) or glutamatergic systems

Question 2

What are the four classes of hallucinogens?

Answer 2

classical psychedelics
dissociative agents
deliriants
oneirogens

differ based on mechanism of action and effects

Question 3

What are classical psychedelics?

Answer 3

include drugs with perception-altering psychedelic effects

include drugs such as lysergic acid diethyl amide (LSD), psilocybin, and dimethyltryptamine (DMT)

common mechanism of action at the serotonin 5HT2a receptor

Question 4

What are lysergamides?

Answer 4

LSD was discovered accidentally by Sandoz pharmacologist Dr. Albert Hofmann in 1938

ergot alkaloids are compounds that are produced by a fungus that grows on rye

they were known to be good vasoconstrictors, so potential treatment for cardiovascular diseases, like migraine

pure ergot derivative not very stable in solution, so Dr. Hofmann tried to chemically manipulate to make more stable

ended up making lysergic acid diethylamide (LSD, aka acid) which he discovered was highly hallucinogenic

Question 5

What is the mechanism of LSD?

Answer 5

LSD has over fifty known targets including several serotonin (5HT) receptors

Hallucinogenic effects mediated by 5HT-2a receptors

LSD is a high affinity partial agonist at 5HT-2a receptors

Question 6

How do we know 5HT-2a activation responsible for hallucination?

Answer 6

transgenic mouse model lacking these receptors (knockout) do not show hallucinogenic like behavior (head bobs) to LSD

not all 5HT2a agonists are hallucinogenic

Question 7

Why are not all 5HT-2a agonists are hallucinogenic?

Answer 7

biased agonism

LSD activates phospholipase C (as do other hallucinogenic serotonin agonists)

non-hallucinogenic 5HT2a agonists activate beta-arrestin signaling over PLC signaling

Question 8

How was the LSD mechanism recently confirmed in humans?

Answer 8

pretreatment with 5HT2a antagonist (ketanserin) blocked hallucinogenic effects of LSD

Question 9

What are the effects of LSD?

Answer 9

dilated pupils, increases heart rate and blood pressure

distortion of sensory perception (wavering images and distortion of size); hallucinations ranging from simple color patterns to more complex scenes; sometimes feeling of enlightenment

adverse psychiatric effects such as anxiety, paranoid, and delusions are possible

Question 10

What is hallucinogenic persisting perception disorder?

Answer 10

distressing visual hallucinations that appear following drug use

Question 11

What is LSD tolerance?

Answer 11

single dose of LSD can lead to profound tolerance that lasts for several days

tolerance is accompanied by downregulation of 5-HT but not other receptors

cross tolerance of LSD with other hallucinogens acting at serotonin receptors (psilocybin, DMT)

Question 12

What is psilocybin?

Answer 12

contain an indole molecule (6 membered benzene ring fused to a five membered pyrrole ring) with an amine group

structural homology to serotonin

naturally occurring hallucinogen compound produced by psilocybin mushrooms

used by humans in religious ceremonies for thousands of years

Question 13

What are the effects of psilocybin?

Answer 13

when ingested, causes euphoria, visual and mental hallucinations, changes in perception and distorted sense of time, spiritual experiences

adverse reactions of nausea and panic attacks

Question 14

In what way is psilocybin a prodrug?

Answer 14

produced as a prodrug (psilocybin)

rapidly dephosphorylated to psilocin in the body

partial agonist at 5HT receptors; high affinity for the 5HT-2b and 5HT-2c receptors, with lower affinity at the 5HT-2a receptor

like LSD, hallucinogenic effects through 5-HT2a

Question 15

What are dissociative hallucinogens?

Answer 15

dissociative hallucinogens distort perception of sight and sound and produce feelings of detachment from the environment or self

can lead to depersonalization (out of body experiences)

often associated with analgesia

Question 16

What is phencyclidine?

Answer 16

phencyclidine (aka angel dust) is a NMDA receptor antagonist (like ketamine)

also acts as an inhibitor at the dopamine transporter (DAT), so increases synaptic levels of dopamine

one of the few hallucinogenic drugs that are self-administered in animals (addiction liability)

was originally marketed as an anesthetic medication (since replaced by ketamine)

Question 17

What are the effects of phencyclidine?

Answer 17

produces changes in body image, loss of ego boundaries, paranoia and depersonalization

alter mood states in an unpredictable fashion (some become detached other animated or aggressive)

Question 18

What are deliriant hallucinogens?

Answer 18

induce a state of delirium characterized by extreme confusion and inability to control ones actions

both deliriant hallucinogens and psychedelics (like LSD) can produce visual and auditory hallucinations

but imagery associated with deliriant hallucinations often perceived as real and users may not be aware they are in a state of drug-altered consciousness (low lucidity)

users lack the metacognitive capacity to identify the experience and its content as a dream

tend to block muscarinic acetylcholine receptors (anticholinergic)

Question 19

What is Datura stramonium?

Answer 19

Datura stramonium is a widespread poisonous plant that contains tropane alkaloids such as scopolamine and atropine

atropine and scopolamine are competitive antagonists at the muscarinic cholinergic receptors

Question 20

What are the effects of Datura stramonium?

Answer 20

symptoms of Datura use include delirium, confusion, hallucinations, and loss of consciousness

many systemic effects including dry mouth, dilated pupils, muscle stiffness, tachycardia, etc.

lethal at higher doses

Question 21

How do first generation anti-histamines produce deliriant hallucinations?

Answer 21

first generation anti-histamines (like diphenhydramine) can also produce deliriant hallucinations at very high doses

related to their anti-cholinergic effects

older adults are more susceptible to the delirium effects of first-generation anti-histamines and are not recommend for use in this population

Question 22

What are oneirogens?

Answer 22

oneirogens is a substance that produces a dreamlike state of consciousness

include the hallucinogenic sage, salvia divinorum

Salvinorin A (the active ingredient in Salvia) is an agonist at the kappa opioid receptor

Question 23

What are the effects of Salvinorin A?

Answer 23

Salvinorin A produces very short acting (~5 minutes) hallucinations

include features of classical psychedelics (visual imagery), dissociative hallucinogens (depersonalization and derealization), and anticholinergic deliriants (impaired awareness of undergoing drug-induced experience, e.g. low lucidity)

characterized by an immersive dream-like state similar to REM sleep (when dreaming occur)