CANNABINOIDS and HALLUCINOGENS€¦ · • 1964 Gaoni and Mechoulam identify structure of THC •...
Transcript of CANNABINOIDS and HALLUCINOGENS€¦ · • 1964 Gaoni and Mechoulam identify structure of THC •...
CANNABINOIDS and
HALLUCINOGENS
Cannabinoids
Cannabis
• Most popular recreational drug in the US after alcohol and tobacco
• Possession and use illegal under federal law, but states have variable
policies on enforcement and prosecution
• Schedule I
Medical Marijuana
•Alleged efficacy in treating:
•AIDS (HIV) & AIDS
•Wasting Diseases
• Arthritis
•Crohn's Disease
• Epilepsy / Seizures
• Glaucoma
• Migraines
• Multiple Sclerosis / Muscle Spasms
• Nausea cf Chemotherapy
• Pain / Analgesia
Chemistry
▪ Various parts of the plant differ in chemical
composition
▪ Sinsemilla → seedless, unfertilized flowering tops
of female cannabis plants
▪ THC is found in the plant’s flowering or fruity tops,
leaves and resin
Cannabinoid Receptors
• 1964 Gaoni and Mechoulam identify structure of THC
• 1990’s CB1 and C are identified and characterized
• CB1: expressed mostly at nerve terminals, mediate
neurotransmitter release
• CB2: immunomodulation (eicosanoids)
Mechanism of Action
▪ THC is thought to stimulate reward circuits in the
brain and to act as a dopamine agonist
▪ THC in marijuana can bind with cannabinoid
receptors located on the presynaptic and/or
postsynaptic cell in a synapse
Effects
▪ A mixture of depressant and stimulant effects is
noted at low doses
▪ CNS depressant at high doses
▪ The endogenous cannabinoid system, which
consists of cannabinoid neurotransmitters,
receptors, metabolic enzymes and transporters
affect physiological and behavioral processes
DRE Rubric
Cannabinoid Pharmacokinetics
Smoked THC Time-Concentration Curve
Courtesy Marilyn Huestis, Borkenstein Drug Course, 2012
• THC concentrations fall:
• To about 60% of their peak within 15 minutes after the end of smoking.
• To about 20% of their peak 30 minutes after the end of smoking.
Metabolism
Pharmacokinetics
▪ THC is rapidly absorbed and distributed to tissues
▪ Counterclockwise hysteresis
▪ Delay between the effects and plasma THC concentrations
▪ THC can be measured w/in seconds of inhalation
▪ Concentrations increase rapidly
Oral Administration
▪ THC and 11-OH THC concentrations are much lower as compared to
smoked administration
▪ Degradation in the stomach and significant first-pass metabolism in the
liver
▪ Two THC peaks may be observed → enterohepatic circulation
▪ The onset, magnitude, and duration of effects general occur later
▪ The effects are lessened
Distribution
▪ Large Vd
▪ 97-99% of the drug is bound to plasma proteins
▪ Highly perfused organs are rapidly exposed to the
drug
▪ Highly lipid soluble
▪ Slow release of the drug from fat and significant
enterohepatic circulation → long drug half-life
Chemistry
▪ THC decomposes when exposed to air, heat or
light
▪ Exposure to acid can oxidize THC to cannabinol
Hallucinogens
What are they?
Hallucinogens are a diverse group of drugs that
alter perception (awareness of surrounding objects
and conditions), thoughts, and feelings. They cause
hallucinations, or sensations and images that seem
real though they are not. Hallucinogens can be
found in some plants and mushrooms (or their
extracts) or can be human-made. People have used
hallucinogens for centuries, mostly for religious
rituals.
Hallucinogens
•Hallucinogens
•LSD
•Salvia Divinorum
•Peyote
•Mescaline
•Psilocybin
•Dissociatives
•PCP
•Dextromethorphan (high doses)
•Ketamine
▪ Psychosis
▪ A loss of contact with reality
▪ Hallucinations
▪ Auditory, visual, tactile
▪ Delusional beliefs
▪ Lack of insight, paranoia
▪ Disorganized thought
▪ Pressure of speech, flight of ideas
▪ Personality changes
▪ Mania
Substance Induced Intoxication (DSM IV)
Lysergic Acid Diethylamide (LSD)
d-isomer
N
N
C
O
N
CH2CH
3
CH2CH
3
CH3
H
H
H
LSD-25, Acid, Microdot, White Lightning
LSD Metabolism
N
C
O
N
CH3CH2
CH3CH2
CH3 OOH
NH
2-oxo-3-hydroxy-LSDN
C
O
N
CH3CH2
CH3CH2
CH3 O
NH
2-oxo-LSD
N
C
O
N
CH3CH2
CH3CH2
CH3
OH
NH
13-hydroxy-LSDN
C
O
N
CH3CH2
CH3CH2
CH3
OH
NH
14-hydroxy-LSD
N
C
O
N
CH3CH2
CH3CH2
H
NH
norLSDN
C
O
N
CH3CH2
CH3CH2
CH3
NH
LSDN
C
O
N
CH3CH2
CH2CH2
CH3
HONH
N-hydroxyethyl-LSD
N
C
O
N
CH3CH2
H
CH3
NH
LAE
Other Metabolites
?
Copy right 2003
1938 - Albert Hofmann working for Sandoz Pharmaceutical, synthesizes LSD-25
1943 - Hofmann accidental exposed to LSD
“I suddenly became strangely inebriated. The external world became changed as in a
dream. Objects appeared to gain in relief; they assumed unusual dimensions; and colors
became more glowing. Even self-perception and the sense of time were changed. When
the eyes were closed, colored pictures flashed past in a quickly changing kaleidoscope.
After a few hours, the not unpleasant inebriation, which had been experienced whilst I
was fully conscious, disappeared.. What had caused this condition”?
- - Albert Hofmann
- - Laboratory Notes (1943)
LSD
▪ Normally 20 - 80 micrograms
▪ Minimal clinical perceptible dose is
20 or 25 micrograms
▪ Much lower than in the 1960’s
▪ Duration and intensity are dose
dependent
▪ Effect duration typically 6-12 hours
LSD - Dose and Effect
LSD Effects
▪ PERCEPTUAL
▪ Altered shapes and colors, visual hallucinations, distorted time sense, synesthesia
▪ SOMATIC
▪ Dizziness, weakness, tremors, nausea, tingling of skin, blurred vision
▪ COGNITIVE
▪ Large and rapid mood changes, difficulty thinking, de-personalization, dream-like feeling, trance-like state
LSD Effects
Wikipedia – LSD-25
LSD Pharmacology
▪ High affinity for pre and post synaptic
serotonin receptors
▪ 5-HT2 partial agonist/antagonist
▪ Inhibition of serotonergic effects in the
Raphe Nuclei implicated in sensory effects
▪ Some affinity for dopamine and NE
receptors systems also
LSD Pharmacokinetics
▪ Duration of effect 6-12 hours
▪ Following a 140 mcg dose
▪ Peak plasma concs of 5 ng/mL @ 1 hour
▪ Half life 3-4 hours
▪ Death attributed to LSD
▪ Postmortem blood concentration 5 ng/mL
PCP - Phencyclidine
Angel Dust
Embalming fluid
Sherm/Shermans
Killer weed
Sernyl ®
Wet
Fry
Phencyclidine - PCP
▪ Dissociative anesthetic
▪ Effects include emergent delirium
▪ Possesses both stimulant and
depressant properties
▪ Can produce hallucinations
Phencyclidine – Receptor Chemistry
▪ PCP2 receptor
▪ Part of dopamine reuptake transporter?
▪ PCP1 receptor
▪ Part of NMDA complex
PCP - Effects on Behavior
▪ User reported depressant effects
▪ Calmness, depression, psychic numbing, anergia, impaired
concentration, ataxia, sedation, analgesia
▪ Enhances alcohol and barbiturate effects
▪ User reported stimulant effects
▪ Feelings of euphoria, power, strength, invulnerability, anxiety,
insomnia, anorexia.
▪ BP, Heart Rate, temperature increase
▪ User reported hallucinogenic effects
▪ Slowed time perception, visual illusions, paranoia, religious
experiences, bizarre behavior
PCP Dose and Pharmacokinetics
▪ Typical street doses are 3 - 5 mg
▪ Laced cigarettes or marijuana cigarettes
▪ Up to 50 mg PCP
▪ PCP is well absorbed
▪ Highly lipophilic and protein binding is 65%
▪ ½ life: 7 - 46 hrs (Avg. 21 hrs.)
▪ Peak plasma levels: 1 - 4 hrs
▪ Rapidly enters brain, elimination from brain slower than blood
PCP Pharmacodynamics
▪ Peak effects are route dependent
▪ Smoking 1 min
▪ Inhalation Several min
▪ Oral 20-40 min
▪ Duration of effects
▪ Typical street high: 4-6 hr
▪ Subjective effects: 24-48 hr
DRE Rubric