DBM - Chapter 15 - Psychedelics and Dissociative Anesthetics

psychedelics

psychoactive substance that causes perceptual changes, visual hallucinations, altered awareness of mind and body, and cognitive distortions without producing toxic delirium

mescaline

least potent hallucinogen

native to US southwest and northern Mexico » found in several species of cactus

psilocybin

prodrug, converted to psilocin (psychoactive agent)

alkaloid with hallucinogenic properties

lysergic acid diethyl amide (LSD-25)

very potent and orally active - single dose in crystalline form is barely visible

larger amounts dissolved in water, single-dose units applied to sheet of paper that is divided into “tabs”

most potent hallucinogen

ayahuasca (and DMT)

orally active tryptamine-based hallucinogen

high concentration of b-carboline alkaloids

• potent MAO-A inhibitors

• protect DMT from degradation in liver and gut

onset of effects delayed for up to an hour, persist for about 4 hours

potency of hallucinogens

LSD: most potent; mescaline: least potent

effects begin 30-90 minutes after ingestion

LSD trip » 6-12 hours

DMT (smoked) » felt within seconds, peaks over minutes, gone within an hour

structure of psychedelics

most have either serotonin-like or catecholamine-like structure

serotonin-like (indoleamine): LSD, psilocybin, psilocin, DMT, synthetic tryptamines

phenethylamine hallucinogens: mescaline (similar to NE and AMPH)

psychedelic receptors

LSD » high affinity binding to eight different 5-HT receptor subtypes

phenylethylamines » bind to 5-HT receptors, commonly 5-HT_2A and 5-HT_2C

• suggests central role for these receptors in producing hallucinations

psychedelics and neural plasticity

5-HT_2A receptor-stimulating psychedelics produce:rapid increases in dendritic complexity, number of dendritic spines, and synapse number

hypothesized to contribute to rapid antidepressant effects of this class of psychedelics

psychedelic dependence and tolerance

do not have high abuse potential » no withdrawal, not reinforcing

dependence does occur in small number of use

most produce rapid tolerance with repeated use » down-regulation of 5-HT_2A

negative effects of psychedelics

“bad trip” » acute anxiety/panic, impossible to predict

flashbacks » re-experiencing after drug use has stopped

psychotic reaction » usually individuals with psychotic disorder or symptoms before taking the drug (can last weeks or months)

hallucinogen persisting perception disorder (HPPD)

rare disorder involving repeated flashbacks » re-experiencing the psychedelic after drug use has stopped

phencyclidine (PCP)

developed as an anesthetic » no respiratory depression

atypical pt response » catatonic-like state, motor rigidity, some blurred vision and dizziness, hallucinations and severe agitation

ketamine

developed as safer alternative to PCP » less potent, shorter-acting

anesthetic for certain procedures » used by veterinarians as general sedative

injectable liquid converted to a powder » smoked or snorted

half-life of 2.5 hrs

PCP and ketamine method of action

noncompetitive antagonists of NMDA receptors

binding site inside receptor ion channel

blockade in cortex and hippocampus » contributes to cognitive defects

effects of PCP

subjective effects: feeling detached from the body, floating sensation, numbness, dream-like state

affective reactions: drowsiness, apathy, loneliness, negativism, hostility

• posible euphoria/inebriation

cognitive disorganization » difficulty concentrating, abstract thinking, halting speech

similar to symptoms of schizophrenia » psychotomimetic

PCP and ketamine - abuse potential

highly reinforcing in primates, high abuse potential

both activate midbrain DA cell firing, stimulate DA release

chronic use of PCP or ketamine

urological problems

deficits in memory

gray- and white-matter abnormalities in chronic ketamine users

• bilateral frontal and left temporoparietal reductions

repeated high dose ketamine administration causes apoptotic cell death

ketamine as an antidepressant

rapid (within hours) reduction in depression for 65-70% of treatment-resistant (TR) patients

subanesthetic doses

effect lasts weeks (plasma half-life is 2.5 hrs)

ketamine as an antidepressant - neurobiology

chronic stress » excess extracellular glutamate » dendritic retraction, reduced arborization and spine density

24 hrs post-treatment » sub-anesthetic dose of ketamine reverses chronic stress-induced structural deficits

• rapid induction of BDNF

• increased synaptogenesis and spine density

• similar, but much faster effecters to traditional antidepressants

disinhibition hypothesis

antagonism of NMDARs on GABAergic interneurons » no GABA release

no inhibition of pyramidal glutamatergic neurons » glutamate release and downstream effects of glutamate

activation of post-synaptic AMPARs » Ca²⁺ influx » Ca²⁺-dependent BDNF release from post-synaptic membrane

dextromethorphan

metabolized to dextrorphan

antitussive agent: low doses » suppresses cough reflexes

high doses » noncompetitive antagonist of NMDA

• similar effects to classic hallucinogens

can be extracted from cough syrup and repackaged in pills