(THC)

delta-9-
tetrahydrocannabinol
(Δ9-THC)

Dronabinol, the active ingredient in

MARINOL® Capsules, is synthetic
(delta-9-THC) & is a naturally
occurring component of Cannabis
sativa L. (Marijuana).
 THC Synthesis - Overview
(Written in 1968 and 1969)
(Minor embellishments by Damian, 1999)
(The assumption was made that all temperatures are in degrees
Centigrade/Celslus)
• http://designer-drugs.com/pte/12.162.180.114/dcd/ch

• Under the term

tetrahydrocannabinol
(THC) we will consider
the three known
physiologically active
isomers, which differ
only in the bonding in
the left-hand ring of the
molecule.
 Organic Chemistry
• In general it has been
shown that alterations
of the molecule result
in reduction of
activity. However, by
changing the alkyl
group on the right-
hand ring (above, n-
amyl, composed of
five carbon atoms in a
straight chain) it has
been possible to
produce THC-C
variants with
enormously increased
potency and duration
of effect. The variant
described here as
THC-V is at least as
potent as LSD (dose
• Like most • THC also possesses
pharmacologicall high UV-B (280-
y-active 315 nm)
secondary absorption
metabolites of properties,
plants, THC in which, it has
cannabis is been speculated,
assumed to be could protect the
involved in self- plant from
defense, perhaps harmful UV
against radiation
herbivores. exposure.
 Legal & Production
• 1st isolated by Raphael • Dronabinol is the
Mechoulam, Yechiel
Gaoni, and Habib Edery International Nonprop
from the Weizmann (INN) for a pure
Institute of Science in
Rehovot, Israel, in 1964.
isomer of THC,
(-)-trans-Δ9-
•Marinol is a registered
trademark of
Solvay Pharmaceuticals.
tetrahydrocanna
binol, that is, the
•Dronabinol is also marketed,
sold, and distributed by PAR main isomer in
Pharmaceutical Companies
under the terms of a cannabis.
license and distribution
agreement with SVC pharma
LP, an affiliate of Rhodes
Technologies.
• Dronabinol, an
aromatic terpenoid,
is insoluble in water
[not easily ionized
at bodily pH’s] &
thusly formulated in
sesame oil. • In pure form, it is a
glassy solid when
•
cold and becomes
• pKa of 10.6 & an viscous and sticky if
octanol-water warmed.
partition coefficient: •
6,000:1 at pH 7 • Good solubility in most
organic solvents.
– Alcohol
• Used in
preparation of
(red) hash oil,
which yields
up to 60%
concentrated
cannabinoids.
– Lipids
Capsules for oral
administration are
supplied as round, soft
gelatin capsules.

Dosages are supplied in

quantities of:
2.5 mg
5.0 mg Inactive ingredients :
10 mg
FD&C Blue No. 1 (5 mg)
FD&C Red No. 40 (5 mg)
FD&C Yellow No. 6 (5 mg and 10
mg)
gelatin
glycerin
methylparaben
propylparaben
sesame oil
titanium dioxide
 Ingestion & Digestion

• Oral consumption •D u e to its h ig h lip id

and thus, a ffin ity d o se s
absorption in the d istrib u te to a ll
digestive system a re a s o f th e b o d y
is slow, a cco rd in g to
incomplete, &
erratic. b lo o d flo w
•
•
•
•Primary
• Considerable 1st accumulation in
pass, hepatic lungs, kidneys, &
metabolism. liver bile.
– desired doses
 Ingestion & Digestion
• Due to its high lipid • Only 1% of the
affinity doses administered
distribute to all dose @ peak
areas of the body blood-
according to concentration
blood flow actually enters
• Primary the brain.
accumulation in •
lungs, kidneys, &
liver bile.
•
• Effects of the drug
can be felt within
a half-hour of
taking the pill,
• Peak effect at 2 to
4 hours.
• The psychoactive
effects may last
4 to 6 hours.
• Biliary excretion is • After passing the
the major route liver it is
of elimination converted to 11-
with about half of hydroxy-delta-9-
a radio-labeled THC which
oral dose being rapidly converts
recovered from to various, less
the feces within lipid soluble,
72 hours. metabolites.
 How Marinol Alleviates Pain
• The body also has
chemicals known
• Marijuana kills pain
as
by activating
endocannabinoid
cannabinoid
s that naturally
receptors:
activate these
– regulate
same receptors:
appetite,
inflammation, – namely N-
and memory. arachidonoyl
ethanolamine
(AEA)
– 2-
arachidonoylgl
 In the Brain
• In the central nervous system, the CB2
receptor, present in cells of the immune
system. It acts as
– a partial agonist on both receptors
• The psychoactive effects of THC are
mediated by its activation of the CB1
receptor, the most abundant G protein-
coupled receptor in the brain.
•

• This implies that endogenous cannabinoids

are manufactured by the body.
– The so-called natural ligand or agonist,
anandamide, 2-arachi donyl glyceride (
 Precautions
• Capsules should be
used with caution
in patients with
cardiac disorders
because of
occasional
hypotension,
possible
hypertension,
syncope, or
tachycardia
 Relivar from Cannasat
• Relivar, a buccal tablet for •Relivar aims to deliver the
symptomatic drug in the oral cavity
management of by incorporating it into a
neuropathic pain, tablet that adheres to
contains the active the gum and releases
ingredient, dronabinol the drug in the mouth.
(or THC). Undesired The benefits are two-
psychoactivity fold:
associated with higher •       (1) promoting direct
doses of the oral absorption through the
formulation has limited gums, Relivar can
its utility for this achieve increased
indication. bioavailability and
reduce the   dose
• required for efficacy
•       (2) reducing the
• amount of drug
swallowed, and thereby
•http://www.cannasat.com/general.php?pid=6
reducing the amount of
drug directly
metabolized by the liver
•R e g u la to ry a p p ro va l in th e
U n ite d S ta te s w ill d e p e n d o n a
Fo o d a n d D ru g A d m in istra tio n
re g u la to ry p a th w a y , b a se d in
p a rt o n th e kn o w n sa fe ty
p ro file o f d ro n a b in o l, to b e
co m p le m e n te d w ith a d d itio n a l
clin ica l d a ta fo r u se in th e n e w
in d ica tio n o f n e u ro p a th ic p a in .
• Relivar has successfully
completed Proof of Concept
Phase I clinical trials for
safety and
pharmacokinetics (results
announced on April 14,
2009) which show proof of
buccal absorption, though a
combination of increased