pharmacology and toxicology of synthetic cannabinoid drugs
TRANSCRIPT
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.
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Pharmacology and
toxicology of synthetic
cannabinoid drugs of abuse