Pharmacology of Psychedelics and Psychoactive Inhalants

Question 1

Differentiate delusions, hallucinations, and illusions, and identify which are most commonly caused by psychedelic drugs

Answer 1

Delusion: Fixed, false belief unresponsive to logic; Paranoia is a common manifestation
Hallucination: A false perception arising from internal stimuli; Creates a false reality
Illusion: A misperception of external stimuli; Distorts reality
Psychedelics rarely produce frank hallucinations at doses commonly used

Question 2

Differentiate between classical psychedelics and dissociative psychedelics based upon their mechanism of action and clinical effects

Answer 2

Classical psychedelics: derivatives of phenethylamine, derivatives of tyramine
Dissociative pscyhedelics: phencyclidine, ketamine, muscimol

Question 3

Derivatives of the structure of phenethylamine

Answer 3

mescaline, MDA, MDMA

Question 4

Derivatives of the structure of tryptamine

Answer 4

DMT, 5-MeO-DiPT, LSD, Ibogaine

Question 5

Naturally occurring classical psychedelic drugs

Answer 5

Dimethyltryptamine (DMT)
5-MeODMT is a derivative of DMT that is 5-6x more potent
Psilocybin is a pro-drug of psilocin; rapid dephosphorylation of psiclocybin to psilocin

Question 6

Mescaline combines mechanism of action of

Answer 6

LSD and MDMA; low potency drug, long lasting, cross tolerance to LSD - suspected interaction with serotonin system
from phenethylamine: amphetamine like - MDMA, bath salts; increases release of 5-HT>DA, NE; empathogens/entactogens - more hallucinogenic than stimulatory

Question 7

Most classical psychedelics are agonists of

Answer 7

the 5-HT2A receptor
* Pretreatment with 5-HT2A antagonists blocks psychedelic effects
* Exception: MDMA stimulates 5-HT release

Question 8

Dissociative psychedelics are antagonists of

Answer 8

NMDA receptors
inhibition of GABA release and disinhibition of glutamate release; non-competitive antagonist, enter channel when its open
NMDAR primarily postsynaptic and can also bind glycine

Question 9

Prominent NMDA receptor antagonists

Answer 9

ionotropic glutamate receptors
ketamine
dextromethorphan

Question 10

Ionotropic glutamate receptors

Answer 10

• NMDA receptor antagonist
• Induce anesthesia and analgesia

Question 11

Ketamine

Answer 11

• Racemic mixture, S(+) is more active
• Fast and short acting (10-60 min)
• Esketamine recently FDA approved for treatment resistant depression
• Used in opioid tolerant patients for chronic pain

Question 12

Dextromethorphan

Answer 12

• Also serotonin reuptake inhibitor
• Abused by ~4% high schoolers
• Doses for cough suppression are
  <60 mg, while 100 – 600 mg are used to induce “high”

Question 13

Phencyclidine

Answer 13

• NMDA antagonist: More potent than ketamine; Also dopamine D2 receptor agonist
• Cigarette dipped in liquid PCP: Nicotine or marijuana cigarette; Effect 4-6hrs
• People often unaware of cannabis laced with PCP
• Severe dissociation and analgesia: Self-mutilation without recognition (dissociation)
• Provokes psychotic reactions
• Misuse associated with violence and suicide

Question 14

Muscimol

Answer 14

ibotenic acid –> decarboxylation to muscimol
Muscimol is an agonist of GABAA channels and can induce dissociative psychedelic effects. In contrast, benzodiazepines and alcohol of allosteric modulators

Question 15

5-dimension altered states of conciousness

Answer 15

visionary restructuralization: sensory illusions
oceanic boundlessness: highly pleasurable state of self dissolution
anxious ego-dissolution: thought disorder leading to unpleasant state (bad trip)

Question 16

Describe the acute and long-term adverse effects of psychedelic drug use

Answer 16

short term physiologic, acute dysphoric reaction, psychotic reaction
* Rapid development of tolerance–third consecutive day, marked attenuation of effect
* Frequent use can lead to mood changes
* No evidence of addictive potential

Question 17

Short-term physiologic

Answer 17

Tachycardia
Hypertension
Tremors
Dry mouth
Nausea
Hyperthermia

Question 18

Acute dysphoric reaction

Answer 18

Terrifying thoughts
Fear of insanity
Fear of losing
control
Fear of death

Question 19

Psychotic reaction

Answer 19

Flashbacks (hallucinogen persisting perception disorder)
Enduring changes in personality
Exacerbate underlying psychotic
disorder
Instigate prolonged psychotic disorder
Rate of psychosis after LSD 1 to 5%

Question 20

Describe current interest in psychedelics as psychotherapeutics

Answer 20

potential therapeutic uses:
* Cancer-related psychological distress
* PTSD
* Depression
* Substance Use Disorder (Alcohol)

Question 21

Identify the primary psychoactive inhalants and their mechanism of action

Answer 21

Liquids, aerosol, gases, nitrites
inhalants can be misused in multiple ways:
* Volatile solvents (toluene, glue, kerosene, gasoline)
* Aerosols, gases, sprays
* Nitrites (poppers), and nitrous oxide.
* Hydrocarbons, ketones
sniffing, huffing, bagging, dusting

Question 22

Alkyl Nitrites

Answer 22

• Commonly sold as ‘poppers’
• Marketed as cleaning solutions and
  room deodorizers
• Nitric oxide release results in smooth
  muscle relaxation
• Relaxes anal sphincter, enhanced
  erections, euphoria
• Highest abuse among gay men (25x)
• Methemoglobinemia (low oxygen) is greatest risk

Question 23

Volatile Solvents

Answer 23

Volatile solvents are liquid at RT and evaporate readily when exposed to air
Toluene: model glues, correction fluids, lacquer thinners, plastic cements, spray paints; most characterized, alters the activity of a wide range of ion channels
Acetone: nail polish remover, model glue, rubber cements
Benzene: cleaning fluids, rubber cements, tire tube repair kits
Butane: cigarette lighters, hair spray, spray paint
Highest frequency of use among adolescents, especially in isolated communities (access driven?)

Question 24

Clinical effects of volatile solvents

Answer 24

Acute effects: locomotor sitmulation, euphoria, exhiliration
high dose: CNS depression, slurred speech, disorientation, weakness, sedation

Question 25

Describe the adverse effects of psychoactive
inhalant misuse

Answer 25

asphyxiation, suffocation, convulsions/seizures, coma, choking, fatal injury

Question 26

Asphyxiation

Answer 26

from repeated inhalations that lead to high concentrations of inhaled fumes, which displace available oxygen in the lungs

Question 27

Suffocation

Answer 27

from blocking air from entering the lungs when inhaling fumes from a plastic bag placed over the head

Question 28

Convulsions/seizures

Answer 28

from abnormal electrical discharges in the brain

Question 29

Coma

Answer 29

from the brain shutting down all but the most vital functions

Question 30

Choking

Answer 30

from inhalation of vomit after inhalant use

Question 31

Fatal injury

Answer 31

from accidents, including motor vehicle fatalities, suffered while intoxicated

Question 32

Sudden sniffing death syndrome

Answer 32

development of fatal arrhythmias within minutes of inhalation
Compulsiveuse
Neurotoxicity - neurodegeneration with people who use it chronically