Pharmacology and toxicology of synthetic cannabinoid drugs

Pharmacology and

toxicology of synthetic

cannabinoid drugs of abuse

• No financial interests or other relevant conflicts to disclosure for this program.

• These studies were supported by bridging funds from the UAMS Department of Pharmacology and Toxicology, NIH / NIDA award DA039143, NIH / COBRE awards GM109005 an GM 110702, an Arkansas Alliance Research Scholars Award, and DEA / FDA contract HHSF223201610079C.

• Cannabis sativa

• > 60 cannabinoids

synthesized by plant

• Schedule I

• No (federally) recognized

medical use.

• Main psychoactive

constituent is D9-

tetrahydrocannabinol, or

D9-THC

• Also cannabinol,

cannabidiol and others

• Found primarily in

leaves and flowering

tops of cannabis plants

• The structure of D9-THC was published by Gaoni

and Mechoulam in J Am Chem Soc in 1964.

• Distribution of CB1 cannabinoid receptors (what

the textbooks say)

• Actual distribution of CB1 receptors (PET scan

with [18F]MK-9470) – most widely-expressed

GPCR in brain

• Short-term memory impairment (hippocampus)

• Decreased capacity to do complex tasks

(cortex)

• Balance and stability of stance affected

(cerebellum)

• Slowed reaction time

(basal ganglia)

• Appetite stimulation

(hypothalamus)

• Analgesic effects (spinal cord)

• 20-50 bpm increase in HR,

lasts up to 2–5 hr

• Tachycardia of 140 bpm

not uncommon

• Increased BP while lying

down, decreased while

standing

• Vasodilation of scleral

and conjunctival vessels

leads to bloodshot eyes

• CB2 cannabinoid receptors expressed on

• immune cells

• pulmonary endothelial cells

• bone

• GI system

• adipocytes

• CNS (microglia, and maybe some neuronal

expression)

• Cannabis-derived medications show promise for use

against a wide range of conditions, but unwanted

psychotropic effects, tolerance and dependence occur

with their use.

• Legitimate sellers of

“research chemicals” are

now vastly outnumbered

by illicit sites

• All links on the first 3

pages lead to sites selling

legal and illegal drugs to

anybody with a credit

card

• Packaging covered with warnings and disclaimers.

• “Not for human consumption” ?

United Nations Office on Drugs and Crime (UNODC), 2014

• More than half of all

new psychoactive

substances

worldwide are

either synthetic

cannabinoids

(“K2”) or synthetic

cathinones (“bath

salts”).

• American Association of Poison Control Centers

(AAPCC) reported handling 2,874 calls in 2010

(less than 200 the year before).

• Synthetics appeared in AR in January, 2010. Early on, all

“K2” blends contained JWH-018, with or without some

JWH-073. New synthetics have popped up since JWH-018

and JWH-073 have been scheduled.

• Variability in drug amounts found from product to product

(left) and from lot to lot within-product (right).

• Substantial variability can be quantified even within the

same package (“hot spots.”)

K2 Summit

19.9

8.9

14.4

1.4 1.1 1.2

0.0

5.0

10.0

15.0

20.0

25.0

[1] [2] [3]

Samples

mg

dru

g /

g p

lan

t

JWH-018

JWH-073

• Spread rapidly through our state, from 27 cases in July of

2010 to 91 cases in May of 2011.

9 months

• Many of these compounds are a simplification of the

WIN-55,212 structure, which had the highest affinity for

CB1 receptors, and the best selectivity for CB1 over CB2.

• High degree of structural

diversity among compounds.

• Not unusual to find 2 or more

compounds in the same sample.

• All compounds typically possess

higher affinity for and efficacy at

CB1 receptors as compared to

D9-THC, and are usually more

potent in vivo.

• In AR, more than half of

all synthetic cannabinoid

products contain JWH-

018 or its fluorinated

analogue AM2201 as the

primary psychoactive

constituent.

AM2201

(25%)

JWH-018

(6%) JWH-018,

JWH-073

(11%)

AM2201,

JWH-210

(9%)

JWH-122,

JWH-210

(3%)

Contains

AM2201

(55%)

• 597 cases containing 1484 items and 160 distinct combinations.

• 14 synthetic cannabinoid compounds detected.

• Synthetics have higher (JWH-018) or comparable (JWH-

073) CB1R affinity to D9-THC.

• Synthetics are full CB1R agonists, while D9-THC is a

partial CB1R agonist.

• Upon activation,

intracellular regions of

GPCRs are

phosphorylated, bind

regulatory proteins

known as β-arrestins

that prevent further

signaling (e.g.,

desensitization), and

are finally internalized

for recycling (e.g.,

resensitization) and/or

degradation (e.g.,

down-regulation).

• Recent normalization of medical cannabis has been

driven, in part, by its apparent efficacy in controlling

seizure in treatment-resistant epilepsy, particularly in

children.

• Reports of SCB-elicited seizure and convulsion are

increasingly common in the clinical literature.

• Tonic-clonic spasms and leg-splay observed with high

doses of synthetics, but never observed with D9-THC.

• Dose-dependent

convulsant

effects of

synthetics, but

never observed

with D9-THC.

• SCBs more

potent than

standard

chemical

convulsant PTZ.

• Convulsant effects of SCBs blocked by CB1 antagonist,

but not by diazepam (even at a dose that blocks PTZ).

• Phase 1 hydroxylated metabolites of some SCBs retain

affinity for CB1 receptors.

• These phase 1

metabolites exhibit a

range of efficacies at

CB1 receptors.

• Disruption of Phase 1 metabolism with global P450

inhibitor 1-ABT potentiates hypothermic effects of SCBs.

• Disruption of Phase 1 metabolism with global P450

inhibitor 1-ABT attenuates convulsant effects of JWH-018

but not those of 5F-AB-PINACA.

• Oxidation is involved in JWH-018 metabolism, but not

involved in 5F-AB-PINACA metabolism.

• SCBs are high-affinity full agonists at CB1 receptors.

• They elicit the same sorts of effects as THC, but those

effects are greater in magnitude with the SCBs.

• Extensive Phase 1 metabolism of some SCBs produces a

range of active hydroxylated metabolites.

• Those metabolites may be involved in some SCB-related

toxicities, including convulsant effects.

TAKE HOME

MESSAGES

Pharmacology and

toxicology of synthetic

cannabinoid drugs of abuse