Tetrahydrocannabinol
From Wikipedia, the free encyclopedia
Tetrahydrocannabinol
 |
 |
| Systematic (IUPAC) name |
| (−)-(6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol |
| Clinical data |
| Licence data |
US FDA:link |
| Pregnancy cat. |
|
| Legal status |
|
|
|
8–10% (Relatively low risk of tolerance)[2] |
| Routes |
Orally, local/topical, transdermal sublingual, smoked (or vaporized) |
| Pharmacokinetic data |
| Bioavailability |
10–35% (inhalation), 6–20% (oral)[3] |
| Protein binding |
97–99%[3][4][5] |
| Metabolism |
Mostly hepatic by CYP2C[3] |
| Half-life |
1.6–59 h,[3] 25–36 h (orally administered dronabinol) |
| Excretion |
65–80% (faeces), 20–35% (urine) as acid metabolites[3] |
| Identifiers |
| CAS number |
1972-08-3  |
| ATC code |
A04AD10 |
| PubChem |
CID 16078 |
| IUPHAR ligand |
2424 |
| DrugBank |
DB00470 |
| ChemSpider |
15266 |
| UNII |
7J8897W37S |
| ChEBI |
CHEBI:66964  |
| ChEMBL |
CHEMBL465 |
| Synonyms |
Dronabinol |
| Chemical data |
| Formula |
C21H30O2 |
| Mol. mass |
314.469 g/mol |
|
|
|
|
| Physical data |
| Boiling point |
250 °C (482 °F)
(range: 250–400 °C)[7] |
| Solubility in water |
0.0028,[6] (23 °C) mg/mL (20 °C) |
| Spec. rot |
-152° (ethanol) |
|
Tetrahydrocannabinol (
THC), or more precisely its main isomer
(−)-trans-Δ9-tetrahydrocannabinol (
(6aR,10aR)-delta-9-tetrahydrocannabinol), is the principal
psychoactive constituent (or
cannabinoid) of the
cannabis plant. First isolated in 1964 by Israeli scientists
Raphael Mechoulam and Yechiel Gaoni at the
Weizmann Institute of Science[8][9][10] it is a water-clear glassy solid when cold, which becomes
viscous and sticky if warmed. A
pharmaceutical formulation of (−)-
trans-Δ
9-tetrahydrocannabinol, known by its
INN dronabinol, is available by prescription in the U.S. and Canada under the brand name
Marinol. An
aromatic terpenoid, THC has a very low solubility in water, but good solubility in most organic
solvents, specifically
lipids and
alcohols.
[6]
Like most pharmacologically-active
secondary metabolites of plants, THC in
cannabis is assumed to be involved in
self-defense, perhaps against
herbivores.
[11] THC also possesses high
UV-B (280–315 nm) absorption properties, which, it has been speculated, could protect the plant from harmful UV radiation exposure.
[12][13][14]
Tetrahydrocannabinol with double bond isomers and their stereoisomers is one of only three cannabinoids scheduled by
Convention on Psychotropic Substances (the other two are
dimethylheptylpyran and
parahexyl). Cannabis as a plant is scheduled by the
Single Convention on Narcotic Drugs (Schedule I and IV).
Effects
THC has mild to moderate
analgesic effects, and
cannabis can be used to treat pain by altering transmitter release on
dorsal root ganglion of the
spinal cord and in the
periaqueductal gray.
[15]
Other effects include relaxation, alteration of visual, auditory, and
olfactory senses, fatigue, and appetite stimulation. THC has marked
antiemetic properties. It may acutely reduce aggression and increase aggression during withdrawal.
[16]
Due to its partial agonistic activity, THC appears to result in greater
downregulation of cannabinoid receptors than
endocannabinoids,
further limiting its efficacy over other cannabinoids. While tolerance
may limit the maximal effects of certain drugs, evidence suggests that
tolerance develops irregularly for different effects with greater
resistance for primary over side-effects, and may actually serve to
enhance the drug's therapeutic window.
[17]
However, this form of tolerance appears to be irregular throughout
mouse brain areas. THC, as well as other cannabinoids that contain a
phenol group, possesses mild
antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced
excitotoxicity.
[18]
Appetite and taste
It has long been known that, in humans, cannabis increases appetite
and consumption of food. The mechanism for appetite stimulation in
subjects is believed to result from activity in the gastro-hypothalamic
axis. CB1 activity in the hunger centers in the hypothalamus increases
the palatability of food when levels of a hunger hormone
ghrelin increase prior to consuming a meal. After
chyme is passed into the
duodenum, signaling
hormones such as
cholecystokinin and
leptin
are released, causing reduction in gastric emptying and transmission of
satiety signals to the hypothalamus.
Cannabinoid activity is reduced
through the satiety signals induced by leptin release.
A study in mice suggested that based on the connection between palatable food and stimulation of
dopamine (DA) transmission in the shell of the
nucleus accumbens
(NAc), cannabis may not only stimulate taste, but possibly the hedonic
(pleasure) value of food as well. The study later demonstrates habitual
use of THC lessening this heightened pleasure response, indicating a
possible similarity in humans.
[19]
The inconsistency between DA habituation and enduring appetite observed
after THC application suggests that cannabis-induced appetite
stimulation is not only mediated by enhanced pleasure from palatable
food, but through THC stimulation of another appetitive response as
well.
Chemistry
Discovery and structure identification
The discovery of THC by team of researchers from
Hebrew University
Pharmacy School was first described in "Isolation, structure and
partial synthesis of an active constituent of hashish", published in the
Journal of the American Chemical Society in 1964.
[8] Research was also published in the academic journal
Science, with "Marijuana chemistry" by
Raphael Mechoulam in June 1970,
[20]
In the latter, the team of researchers from Hebrew University and Tel
Aviv University experimented on monkeys to isolate the active compounds
in
hashish.
Their results provided evidence that, except for tetrahydrocannabinol,
no other major active compounds were present in hashish.
Isomerism
| 7 double bond isomers and their 30 stereoisomers |
| Dibenzopyran numbering |
Monoterpenoid numbering |
Number of stereoisomers |
Natural occurrence |
Convention on Psychotropic Substances Schedule |
Structure |
| Short name |
Chiral centers |
Full name |
Short name |
Chiral centers |
| Δ6a,7-tetrahydrocannabinol |
9 and 10a |
8,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol |
Δ4-tetrahydrocannabinol |
1 and 3 |
4 |
No |
Schedule I |
 |
| Δ7-tetrahydrocannabinol |
6a, 9 and 10a |
6a,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol |
Δ5-tetrahydrocannabinol |
1, 3 and 4 |
8 |
No |
Schedule I |
 |
| Δ8-tetrahydrocannabinol |
6a and 10a |
6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol |
Δ6-tetrahydrocannabinol |
3 and 4 |
4 |
Yes |
Schedule I |
 |
| Δ9,11-tetrahydrocannabinol |
6a and 10a |
6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-9-methylene-3-pentyl-6H-dibenzo[b,d]pyran-1-ol |
Δ1,7-tetrahydrocannabinol |
3 and 4 |
4 |
No |
Schedule I |
 |
| Δ9-tetrahydrocannabinol |
6a and 10a |
6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol |
Δ1-tetrahydrocannabinol |
3 and 4 |
4 |
Yes |
Schedule II |
 |
| Δ10-tetrahydrocannabinol |
6a and 9 |
6a,7,8,9-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol |
Δ2-tetrahydrocannabinol |
1 and 4 |
4 |
No |
Schedule I |
 |
| Δ6a,10a-tetrahydrocannabinol |
9 |
7,8,9,10-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol |
Δ3-tetrahydrocannabinol |
1 |
2 |
No |
Schedule I |
 |
| 4 stereoisomers of Δ9-tetrahydrocannabinol |
| Names |
Description |
Natural occurrence |
Structure |
| (−)-trans-Δ9-tetrahydrocannabinol |
(6aR,10aR)-Δ9-tetrahydrocannabinol |
levorotary trans |
Yes |
 |
| (−)-cis-Δ9-tetrahydrocannabinol |
(6aS,10aR)-Δ9-tetrahydrocannabinol |
levorotary cis |
Yes |
 |
| (+)-trans-Δ9-tetrahydrocannabinol |
(6aS,10aS)-Δ9-tetrahydrocannabinol |
dextrorotary trans |
No |
 |
| (+)-cis-Δ9-tetrahydrocannabinol |
(6aR,10aS)-Δ9-tetrahydrocannabinol |
dextrorotary cis |
No |
 |
Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6H-benzo[c]chromen-1-ol.
3D rendering of the THC molecule
A hybrid
Cannabis strain (
White Widow) flower coated with
trichomes, which contain more THC than any other part of the plant
Closeup of THC-filled trichomes on a Cannabis sativa leaf
Medical uses
In April 2014 the
American Academy of Neurology
published a systematic review of the efficacy and safety of medical
marijuana and marijuana-derived products in certain neurological
disorders.
[21]
The review identified 34 studies meeting inclusion criteria, of which 8
were rated as Class I quality. The study found evidence supporting the
effectiveness of cannabis extracts and THC in treating certain symptoms
of multiple sclerosis, but found insufficient evidence to determine the
effectiveness of cannabis products in treating several other
neurological diseases.
Multiple sclerosis symptoms
-
- Spasticity. Based on the results of 3 high quality trials and
5 of lower quality, oral cannabis extract was rated as effective, and
THC as probably effective, for improving patient's subjective experience
of spasticity. Oral cannabis extract and THC both were rated as
possibly effective for improving objective measures of spasticity.[21]
-
- Centrally mediated pain and painful spasms. Based on the
results of 4 high quality trials and 4 low quality trials, oral cannabis
extract was rated as effective, and THC as probably effective in
treating central pain and painful spasms.[21]
-
- Bladder dysfunction. Based on a single high quality study,
oral cannabis extract and THC were rated as probably ineffective for
controlling bladder complaints in multiple sclerosis[21]
Neurodegenerative disorders
-
- Huntington disease. No reliable conclusions could be drawn
regarding the effectiveness of THC or oral cannabis extract in treating
the symptoms of Huntington disease as the available trials were too
small to reliably detect any difference[21]
-
- Parkinson disease. Based on a single study, oral cannabis
extract was rated probably ineffective in treating levodopa-induced
dyskinesia in Parkinson disease.[21]
-
- Alzheimer's disease. A 2011 Cochrane Review found
insufficient evidence to conclude whether cannabis products have any
utility in the treatment of Alzheimer's disease.[22]
Other neurological disorders
-
- Tourette syndrome. The available data was determined to be
insufficient to allow reliable conclusions to be drawn regarding the
effectiveness of oral cannabis extract or THC in controlling tics.[21]
-
- Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.[21]
-
- Epilepsy. Data was considered insufficient to judge the utility of cannabis products in reducing seizure frequency or severity.[21]
Other studies in humans
Evidence suggests that THC helps alleviate symptoms suffered both by
AIDS patients, and by cancer patients undergoing
chemotherapy, by increasing appetite and decreasing nausea.
[23][24][25][26] It has also been shown to assist some
glaucoma patients
[citation needed] by reducing pressure within the eye, and is used in the form of cannabis by a number of
multiple sclerosis patients, who use it to alleviate
neuropathic pain and
spasticity. The
National Multiple Sclerosis Society is currently supporting further research into these uses.
[27] Studies in humans have been limited by federal and state laws criminalizing marijuana.
In August 2009 a
phase IV clinical trial by the
Hadassah Medical Center in Jerusalem, Israel started to investigate the effects of THC on
post-traumatic stress disorders.
[28]
Research on THC has shown that the
cannabinoid receptors are responsible for mediated inhibition of dopamine release in the
retina.
[29]
Several studies have been conducted with spinal injury patients and
THC. Decreased tremor occurred in 2/5 patients in a 1986 double-blind,
placebo-controlled crossover study.
[30]
Studies in animals and in vitro
A two-year study in which rats and mice were force-fed
tetrahydrocannabinol dissolved in corn oil showed reduced body mass,
enhanced survival rates, and decreased tumor incidences in several
sites, mainly organs under hormonal control. It also caused
testicular atrophy and uterine and ovarian
hypoplasia, as well as hyperactivity and convulsions immediately after administration, of which the onset and frequency were dose related.
[31]
Research in rats indicates that THC prevents
hydroperoxide-induced
oxidative damage as well as or better than other
antioxidants in a chemical (
Fenton reaction) system and
neuronal cultures.
[32] In mice low doses of Δ
9-THC reduces the progression of
atherosclerosis.
[33]
Instead, recent studies with synthetic cannabinoids show that activation of CB1 receptors can facilitate
neurogenesis,
[34] as well as neuroprotection, in animals
[35]
This, along with research into the CB2 receptor (throughout the immune
system), has given the case for medical marijuana more support.
[36][37] THC is both a CB1 and CB2 agonist.
[38]
Adverse effects
Acute toxicity
There has never been a documented human fatality solely from overdosing on tetrahydrocannabinol or cannabis in its natural form.
[39] However, numerous reports have suggested an association of cannabis smoking with an increased risk of
myocardial infarction.
[40][41] Information about the
toxicity
of THC is primarily based on results from animal studies. The toxicity
depends on the route of administration and the laboratory animal.
The estimated lethal dose of intravenous dronabinol in humans is 30 mg/kg,
[42]
meaning lethality is unlikely. The typical medicinal dosage
administered is two 2.5 mg capsules daily; for an 80 kg man (~170 lb). A
lethal dose for such a person would be 960 of those capsules infused
intravenously. Non-fatal overdoses have occurred: "Significant CNS
symptoms in antiemetic studies followed oral doses of 0.4 mg/kg
(28 mg/70 kg) of dronabinol capsules."
[42]
-
- A meta analysis of cannabis and THC clinical trials conducted by the
American Academy of Neurology found that of 1619 persons treated with
cannabis products (including some treated with smoked cannabis and
nabiximols), 6.9% discontinued due to side effects, compared to 2.2% of
1,118 treated with placebo. Detailed information regarding side effects
was not available from all trials, but nausea, increased weakness,
behavioral or mood changes, suicidal ideation, hallucinations,
dizziness, and vasovagal symptoms, fatigue, and feelings of intoxication
were each described as side effects in at least 2 trials. There was a
single death rated by the investigator as "possibly related" to
treatment. This person had a seizure followed by aspiration pneumonia.
The paper does not describe whether this was one of the patients from
the epilepsy trials.[21]
Cognitive effects
Its status as an illegal drug in most countries can make research difficult; for instance in the United States where the
National Institute on Drug Abuse was the only legal source of cannabis for researchers until it recently became legalized in Colorado and Washington state.
[43]
A 2011 systematic review evaluated published studies of the acute and
long-term cognitive effects of cannabis. THC intoxication is well
established to impair cognitive functioning on an acute basis, including
effects on the ability to plan, organize, solve problems, make
decisions, and control impulses. The extent of this impact may be
greater in novice users, and paradoxically, those habituated to high
level ingestion may have reduced cognition during withdrawal. Studies of
long-term effects on cognition have provided conflicting results, with
some studies finding no difference between long-term abstainers and
never-users and others finding long term deficits. The discrepancies
between studies may reflect greater long term effects among heavier
users relative to occasional users, and greater duration of effect among
those with heavy use as adolescents compared to later in life.
[44]
A second systematic review focused on neuroimaging studies found little
evidence supporting an effect of cannabis use on brain structure and
function.
[45]
A 2003 meta analysis concluded that any long term cognitive effects
were relatively modest in magnitude and limited to certain aspects of
learning and memory.
[46]
Impact on psychosis
A 2007 meta analysis concluded that cannabis use reduced the average
age of onset of psychosis by 2.7 years relative to non-cannabis use.
[47]
A 2005 meta analysis concluded that adolescent use of cannabis
increases the risk of psychosis, and that the risk is dose-related.
[48]
A 2004 literature review on the subject concluded that cannabis use is
associated with a two-fold increase in the risk of psychosis, but that
cannabis use is "neither necessary nor sufficient" to cause psychosis.
[49]
A French review from 2009 came to a conclusion that cannabis use,
particularly that before age 15, was a factor in the development of
schizophrenic disorders.
[50]
Some studies have suggested that cannabis users have a greater risk of developing
psychosis than non-users. This risk is most pronounced in cases with an existing risk of psychotic disorder.
[51][52] A 2005 paper from the
Dunedin study suggested an increased risk in the development of psychosis linked to polymorphisms in the
COMT gene.
[53]
However, a more recent study cast doubt on the proposed connection
between this gene and the effects of cannabis on the development of
psychosis.
[54]
A 2008 German review reported that cannabis was a causal factor in
some cases of schizophrenia and stressed the need for better education
among the public due to increasingly relaxed access to cannabis.
[55]
Other potential long-term effects
A 2008
National Institutes of Health
study of 19 chronic heavy marijuana users with cardiac and cerebral
abnormalities (averaging 28 g to 272 g (1 to 9+ oz) weekly) and 24
controls found elevated levels of
apolipoprotein C-III (apoC-III) in the chronic smokers.
[56] An increase in apoC-III levels induces the development of
hypertriglyceridemia.
Detection in body fluids
THC, 11-OH-THC and THC-COOH can be detected and quantitated in blood, urine, hair, oral fluid or sweat using a combination of
immunoassay and
chromatographic
techniques as part of a drug use testing program or in a forensic
investigation of a traffic or other criminal offense or suspicious
death.
[57][58][59]
Interactions
The effects of the drug can be reduced by the CB
1 receptor inverse agonist
rimonabant (SR141716A) as well as
opioid receptor antagonists (opioid blockers)
naloxone and
naloxonazine.
[19][60] The
α7 nicotinic receptor antagonist
methyllycaconitine can block self-administration of THC in rates comparable to the effects of
varenicline on nicotine administration.
[61]
Cannabidiol,
the second most abundant cannabinoid found in cannabis, is an indirect
antagonist against cannabinoid agonists; thus reducing the effects of
anandamide and THC agonism on the
CB1 and
CB2 receptors.
Mechanism of action
The
pharmacological actions of THC result from its partial
agonist activity at the
cannabinoid receptor CB1 (K
i=10nM
[62]), located mainly in the
central nervous system, and the
CB2 receptor (K
i=24nM
[62]), mainly expressed in cells of the
immune system.
[18] The psychoactive effects of THC are primarily mediated by its activation of CB
1G-protein coupled receptors, which result in a decrease in the concentration of the second messenger molecule
cAMP through inhibition of
adenylate cyclase.
[15]
The presence of these specialized cannabinoid receptors in the
brain led researchers to the discovery of
endocannabinoids, such as
anandamide and 2-arachidonoyl glyceride (
2-AG). THC targets receptors in a manner far less selective than endocannabinoid molecules released during
retrograde signaling,
as the drug has a relatively low cannabinoid receptor efficacy and
affinity. In populations of low cannabinoid receptor density, THC may
act to antagonize endogenous agonists that possess greater receptor
efficacy.
[17] THC is a
lipophilic molecule
[63] and may bind non-specifically to a variety of entities in the brain and body, such as
adipose tissue (fat).
[64][65]
THC, similarly to cannabidiol, albeit less potently, is an
allosteric modulator of the
μ- and
δ-opioid receptors.
[66]
Pharmacokinetics
THC is metabolized mainly to
11-OH-THC by the body. This
metabolite is still psychoactive and is further oxidized to
11-nor-9-carboxy-THC
(THC-COOH). In humans and animals, more than 100 metabolites could be
identified, but 11-OH-THC and THC-COOH are the dominating metabolites.
Metabolism occurs mainly in the liver by
cytochrome P450 enzymes
CYP2C9,
CYP2C19, and
CYP3A4.
[67] More than 55% of THC is excreted in the
feces and ~20% in the
urine. The main metabolite in urine is the ester of
glucuronic acid and THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.
[68]
Biosynthesis
Biosynthesis of THC
In the
cannabis plant, THC occurs mainly as
tetrahydrocannabinolic acid (THCA, 2-COOH-THC).
Geranyl pyrophosphate and
olivetolic acid react, catalysed by an
enzyme to produce
cannabigerolic acid,
[69] which is cyclized by the enzyme
THC acid synthase to give THCA. Over time, or when heated, THCA is
decarboxylated, producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid
humulone in
hops.
[70][71]
Natural occurrence
Cannabis indica may have a
CBD:THC ratio 4–5 times that of
Cannabis sativa.
[citation needed]
Chemical synthesis
Total chemical syntheses largely depend on carefully controlled acid catalyzed condensation of selected
monoterpenes with
olivetol. If
citral is used only racemic product. The condensation is acid catalyzed, but 0.0005 N hydrogen chloride only affords a 12% yield.
∴ 1%
boron trifluoride is used as the catalyst.
Since isomerization of Δ
1THC to virtually inactive Δ
6THC takes place readily in acid or upon heating, the cyclizations must be carefully controlled.
Optically active
verbenol can be used instead of
citral.
Marinol
Dronabinol is the
INN for a pure
isomer of THC, (–)-
trans-Δ
9-tetrahydrocannabinol,
[75] which is the main isomer found in cannabis. It is sold as Marinol (a registered trademark of
Solvay Pharmaceuticals).
Dronabinol is also marketed, sold, and distributed by PAR
Pharmaceutical Companies under the terms of a license and distribution
agreement with SVC pharma LP, an affiliate of Rhodes Technologies.
Synthesized THC may be generally referred to as
dronabinol. It is available as a prescription drug (under Marinol
[76]) in several countries including the
United States and
Germany. In the United States, Marinol is a
Schedule III
drug, available by prescription, considered to be non-narcotic and to
have a low risk of physical or mental dependence. Efforts to get
cannabis rescheduled as analogous to Marinol have not succeeded thus
far, though a
2002 petition has been accepted by the
DEA.
As a result of the rescheduling of Marinol from Schedule II to Schedule
III, refills are now permitted for this substance. Marinol has been
approved by the
U.S. Food and Drug Administration (FDA) in the treatment of
anorexia in
AIDS patients, as well as for refractory
nausea and
vomiting of patients undergoing
chemotherapy, which has raised much controversy
[citation needed] as to why natural THC is still a
schedule I drug.
[77]
An overdose usually presents with lethargy, decreased motor
coordination, slurred speech, and postural hypotension. The FDA
estimates the lethal human dose of intravenous dronabinol to be 30 mg/kg
(2100 mg/ 70 kg).
[78]
An analog of dronabinol,
nabilone, is available commercially in Canada under the trade name Cesamet, manufactured by
Valeant Pharmaceuticals. Cesamet has also received FDA approval and began marketing in the U.S. in 2006. Nabilone is a
Schedule II drug.
[79]
Comparisons with medical marijuana
Female cannabis plants contain more than 60 cannabinoids, including
cannabidiol (CBD), thought to be the major
anticonvulsant that helps
multiple sclerosis patients;
[80] and
cannabichromene (CBC), an
anti-inflammatory which may contribute to the
pain-killing effect of cannabis.
[81]
It takes over one hour for Marinol to reach full systemic effect,
[82] compared to seconds or minutes for
smoked or
vaporized cannabis.
[83]
Some patients accustomed to inhaling just enough cannabis smoke to
manage symptoms have complained of too-intense intoxication from
Marinol's predetermined dosages
[citation needed].
Many patients have said that Marinol produces a more acute psychedelic
effect than cannabis, and it has been speculated that this disparity can
be explained by the moderating effect of the many non-THC cannabinoids
present in cannabis.
[citation needed] For that reason, alternative THC-containing medications based on botanical extracts of the cannabis plant such as
nabiximols are being developed.
Mark Kleiman,
director of the Drug Policy Analysis Program at UCLA's School of Public
Affairs said of Marinol, "It wasn't any fun and made the user feel bad,
so it could be approved without any fear that it would penetrate the
recreational market, and then used as a club with which to beat back the
advocates of whole cannabis as a medicine."
[84]
Mr. Kleiman's opinion notwithstanding, clinical trials comparing the
use of cannabis extracts with Marinol in the treatment of cancer
cachexia have demonstrated equal efficacy and well-being among patients
in the two treatment arms.
[85] United States federal law currently registers dronabinol as a
Schedule III controlled substance, but all other cannabinoids remain
Schedule I, except synthetics like
nabilone.
[86]
Regulatory history
Since at least 1986, the trend has been for THC in general, and
especially the Marinol preparation, to be downgraded to less and less
stringently-controlled schedules of controlled substances, in the U.S.
and throughout the rest of the world.
On May 13, 1986, the
Drug Enforcement Administration
(DEA) issued a Final Rule and Statement of Policy authorizing the
"Rescheduling of Synthetic Dronabinol in Sesame Oil and Encapsulated in
Soft Gelatin Capsules From Schedule I to Schedule II" (DEA 51 FR
17476-78). This permitted medical use of Marinol, albeit with the severe
restrictions associated with Schedule II status.
[87] For instance, refills of Marinol prescriptions were not permitted. At its 1045th meeting, on April 29, 1991, the
Commission on Narcotic Drugs, in accordance with article 2, paragraphs 5 and 6, of the
Convention on Psychotropic Substances, decided that Δ
9-tetrahydrocannabinol (also referred to as Δ
9-THC)
and its stereochemical variants should be transferred from Schedule I
to Schedule II of that Convention. This released Marinol from the
restrictions imposed by Article 7 of the Convention (See also
United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances).
[citation needed]
An article published in the April–June 1998 issue of the
Journal of Psychoactive Drugs
found that "Healthcare professionals have detected no indication of
scrip-chasing or doctor-shopping among the patients for whom they have
prescribed dronabinol". The authors state that Marinol has a low
potential for abuse.
[88]
In 1999, Marinol was rescheduled from Schedule II to III of the
Controlled Substances Act, reflecting a finding that THC had a potential for abuse less than that of
cocaine and
heroin. This rescheduling constituted part of the argument for a 2002 petition for
removal of cannabis from Schedule I of the Controlled Substances Act, in which petitioner
Jon Gettman
noted, "Cannabis is a natural source of dronabinol (THC), the
ingredient of Marinol, a Schedule III drug. There are no grounds to
schedule cannabis in a more restrictive schedule than Marinol".
[89]
At its 33rd meeting, in 2003, the
World Health Organization Expert Committee on Drug Dependence recommended transferring THC to
Schedule IV of the Convention, citing its medical uses and low abuse potential.
[90]
