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

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