MARINOL (dronabinol)
Drugs

Marinol (dronabinol)

Dronabinol is the INN for a pure isomer of THC (–)-trans-Δ9-tetrahydrocannabinol, which is the main isomer found in cannabis. It is sold as Marinol.

Dronabinol has the following empirical and structural formulas:

Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil.
(http://it.wikipedia.org/wiki/Dronabinol)

CLINICAL PHARMACOLOGY

Dronabinol is an orally active cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS), including central sympathomimetic activity. Cannabinoid receptors(CB1, CB2. Both CB1 and CB2 receptors are coupled through Gi/o proteins, negatively to adenylate cyclase and positively to mitogen-activated protein kinase. CB1receptors are also coupled through Gi/o proteins to ion channels, positively to inwardly and A-type outward potassium channels, and negatively to outward potassium channels4 and to P/Q type calcium channels) have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol and other cannabinoids. The discovery of the cannabinoid receptors and of their endogenous ligands, the endocannabinoids, which, unlike THC, play a pro-homeostatic function in a tissue- and time-selective manner, offered the opportunity to develop new analgesics from synthetic inhibitors of endocannabinoid inactivation. The advantages of this approach over direct activation of cannabinoid receptors as a therapeutic strategy against neuropathic and inflammatory pain are discussed here along with its potential complications. These latter have been such that clinical success has been achieved so far more rapidly with naturally occurring THC or endocannabinoid structural analogues acting at a plethora of cannabinoid-related and -unrelated molecular targets, than with selective inhibitors of endocannabinoid enzymatic hydrolysis, thus leading to revisit the potential usefulness of "multi-target" versus "magic bullet" compounds as new analgesics.

The pharmacology of cannabinoid receptors and their ligands: an overview, 2006
(http://www.ncbi.nlm.nih.gov/pubmed/23500197) (2013)

Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB1.

Products containing synthetic cannabinoids are consumed as a surrogate for marihuana due to their non-detectability with commonly used drug tests and their strong cannabimimetic effects. Because data concerning their toxicological properties are scarce, the cytotoxic, genotoxic, immunomodulatory, and hormonal activities of four naphthoylindole compounds (JWH-018, JWH-073, JWH-122 and JWH-210) and of one benzoylindole (AM-694) were studied in human cell lines and primary cells; tetrahydrocannabinol was included as the classical non-endogenous cannabinoid receptor ligand. All compounds induced damage to the cell membranes of buccal (TR146) and breast (MCF-7) derived cells at concentrations of ≥75-100 μM. No cytotoxic responses were seen in other assays which reflect mitochondrial damage, protein synthesis, and lysosomal activities. JWH-073 and JWH-122 induced DNA migration in buccal and liver cells (HepG2) in single cell gel electrophoresis assays, while JWH-210 was only in the latter cell line active. No estrogenic activities were detected in bone marrow cells (U2-OS), but all compounds caused anti-estrogenic effects at levels between 2.1 and 23.0 μM. Furthermore, no impact on cytokine release (i.e., on IL-10, IL-6, IL-12/23p40 and TNFα levels) was seen in LPS-stimulated human PBMCs, except with JWH-210 and JWH-122 which caused a decrease of TNFα and IL-12/23p40. All toxic effects were observed with concentrations higher than those expected in body fluids of users. Since genotoxic effects are in general linear over a wide concentration range and the exposure levels may be higher in epithelial cells or in serum, further experimental work is required to find out if DNA damage takes place in drug users.

(http://www.ncbi.nlm.nih.gov/pubmed/23494106) (2013)

Pharmacodynamics

Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but occasional subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing.

Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great interpatient variability.
After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.
Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol and other cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male volunteers received 210 mg/day dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These volunteers developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.
Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of MARINOL. In studies involving patients with Acquired Immune Deficiency Syndrome (AIDS), the appetite stimulant effect of MARINOL has been sustained for up to five months in clinical trials.

Pharmacokinetics

*Absorption
90% to 95% absorbed. T max approximately 2 to 4 h.
*Distribution
10% to 20% reaches systemic circulation. Vd approximately 10 L/kg. Approximately 97% protein bound.
*Metabolism
Liver
Extensive first-pass metabolism yielding active and inactive metabolites.
*Elimination
Initial t ½ approximately 4 h. Terminal t ½ is 25 to 36 h. Cl is 0.2 L/kg/h.
Feces
Approximately 50% of dose; less than 5% unchanged drug.
Urine
10% to 15%.
*Onset
0.5 to 1 h.
*Peak
2 to 4 h.
*Duration
4 to 6 h (psychoactive effects), 24 h or longer (appetite stimulant).

(http://www.drugs.com/ppa/dronabinol.html) (2009)

INDIVIDUALIZATION OF DOSAGES

The pharmacologic effects of Dronabinol are dose-related and subject to considerable interpatient variability. Therefore, dosage individualization is critical in achieving the maximum benefit of Marinol treatment.

Appetite Stimulation: In the clinical trials, the majority of patients were treated with 5 mg/day Marinol, although the dosages ranged from 2.5 to 20 mg/day. For an adult:

1. Begin with 2.5 mg before lunch and 2.5 mg before supper. If CNS symptoms (feeling high,dizziness, confusion, somnolence) do occur, they usually resolve in 1 to 3 days with continued dosage.
   1. If CNS symptoms are severe or persistent, reduce the dose to 2.5 mg before supper. If symptoms continue to be a problem, taking the single dose in the evening or at bedtime may reduce their severity.
   2. When adverse effects are absent or minimal and further therapeutic effect is desired, increase the dose to 2.5 mg before lunch and 5 mg before supper.

The pharmacologic effects of Marinol are reversible upon treatment cessation.

The ability of Dronabinol to promote eating has been documented for many centuries, with the drug reported by its users to promote strong cravings for, and an intensification of the sensory and hedonic properties of food. These effects are now known to result from the actions of cannabinoid molecules at specific cannabinoid receptor sites within the brain, and to reflect the physiological role of their natural ligands, the endocannabinoids, in the control of appetite. Recent developments in the biochemistry and pharmacology of endocannabinoid systems have generated convincing evidence from animal models for a normal role of endocannabinoids in the control of eating motivation. The availability of specific cannabinoid receptor agonists and antagonists raises the possibility of improved therapies for disorders of eating and body weight: not only in the suppression of appetite to counter our susceptibility to the over-consumption of highly pleasurable and energy-dense foods; but also in the treatment of conditions that involve reduced appetite and weight loss.

Fig: The psychobiological appetite regulating network conceptualised as three distinct but co-ordinated domains: psychobiological and behavioural, physiological and metabolic and neurochemical brain activity. 5-HT, serotonin; AA, amino acids; AgRP, agouti-related peptide; CART, cocaine and amphetamine-regulated transcript; CCK, cholecystokinin; CRF, corticotrophin releasing factor; FFA, free fatty acids; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; GRP, gastric releasing peptide; MC, melanocortin; NPY, neuropeptide Y; NST, nucleus tractus solitarius; PYY, peptide YY; T:LNAA, tryptophan large neutral amino acid ratio (see Blundell, 1991 for detailed diagram)

(http://www.ncbi.nlm.nih.gov/pubmed/19367510) (2009)

Antiemetic: Most patients respond to 5 mg three or four times daily. Dosage may be escalated during a chemotherapy cycle or at subsequent cycles, based upon initial results. Therapy should be initiated at the lowest recommended dosage to clinical response. Administration of Marinol with phenothiazines has resulted in improved efficacy as compared to either drug alone, without additional toxicity.
# Dronabinol suppresses vomiting behavior and Fos expression in both acute and delayed phases of cisplatin-induced emesis in the least shrew. Cisplatin chemotherapy frequently causes severe vomiting in two temporally separated clusters of bouts dubbed the acute and delayed phases. Cannabinoids can inhibit the acute phase, albeit through a poorly understood mechanism. We examined the substrates of cannabinoid-mediated inhibition of both the emetic phases via immunolabeling for serotonin, Substance P, cannabinoid receptors 1 and 2 (CB, CB), and the neuronal activation marker Fos in the least shrew (Cryptotis parva). Shrews were injected with cisplatin (10mg/kg i.p.), and one of vehicle, Delta(9)-THC, or both Delta(9)-THC and the CB receptor antagonist SR141716A (2mg/kg i.p.), and monitored for vomiting. Delta(9)-THC-pretreatment caused concurrent decreases in the number of shrews expressing vomiting and Fos-immunoreactivity (Fos-IR), effects which were blocked by SR141716A-pretreatment. Acute phase vomiting induced Fos-IR in the solitary tract nucleus (NTS), dorsal motor nucleus of the vagus (DMNX), and area postrema (AP), whereas in the delayed phase Fos-IR was not induced in the AP at all, and was induced at lower levels in the other nuclei when compared to the acute phase. CB receptor-IR in the NTS was dense, punctate labeling indicative of presynaptic elements, which surrounded Fos-expressing NTS neurons. CB receptor-IR was not found in neuronal elements, but in vascular-appearing structures. All areas correlated with serotonin- and Substance P-IR. These results support published acute phase data in other species, and are the first describing Fos-IR following delayed phase emesis. The data suggest overlapping but separate mechanisms are invoked for each phase, which are sensitive to antiemetic effects of Delta(9)-THC mediated by CB receptors.

(http://www.ncbi.nlm.nih.gov/pubmed/18721829) (2009)

Chemo Trigger Zone
p=.

Pediatrics: Dronabinol is not recommended for AIDS-related anorexia in pediatric patients because it has not been studied in this population. The pediatric dosage for the treatment of chemotherapy-induced emesis is the same as in adults.

Geriatrics: Caution is advised in prescribing Marinol in elderly patients because they are generally more sensitive to the psychoactive effects of drugs. In antiemetic studies, no difference in tolerance or efficacy was apparent in patients >55 years old.

INDICATIONS AND USAGE

Dronabinol is indicated for the treatment of:

1. anorexia associated with weight loss in patients with AIDS.
2. nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

(http://www.sciencedirect.com/science/article/pii/0885392494001174) (1995)

CONTRAINDICATIONS

Dronabinol is contraindicated in any patient who has a history of hypersensitivity to any cannabinoid or sesame oil.

WARNINGS

Patients receiving treatment with dronabinol should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely.

PRECAUTIONS

General: The risk/benefit ratio of Dronabinol use should be carefully evaluated in patients with the following medical conditions because of individual variation in response and tolerance to the effects of Marinol.

Marinol should be used with caution in patients with cardiac disorders (because of occasional hypotension, possible hypertension, syncope, or tachycardia), in patients with a history of substance abuse, in patients with mania, depression or schizophrenia, in patients in terapy with sedatives, hypnotics or other psychoactive drugs, and in pregnant patients.

Patients receiving treatment with dronabinol should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely.

Patients using Marinol should be advised of possible changes in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations.

Drug Interactions: Dronabinol can be co-administered with a variety of medications (e.g., cytotoxic agents, anti-infective agents, sedatives, or opioid analgesics) without any clinically problems.

CONCOMITANT DRUG and CLINICAL EFFECTS

1. Amphetamines, cocaine, other sympathomimetic agents
   Additive hypertension, tachycardia, possibly cardiotoxicity
2. Atropine, scopolamine, antihistamines, other anticholinergic agents
   Additive or super-additive tachycardia, drowsiness
3. Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants
   Additive tachycardia, hypertension, drowsiness
4. Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants
   Additive drowsiness and CNS depression
5. Disulfiram
   A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
6. Antipyrine, barbiturates
   Decreased clearance of these agents, presumably via competitive inhibition of metabolism

ADVERSE REACTIONS

*Body as a whole: Asthenia.

*Cardiovascular: Palpitations, tachycardia, vasodilation/facial flush, conjunctivitis, hypotension.

*Digestive: Abdominal pain, nausea, vomiting, diarrhea, fecal incontinence.

*Nervous system: (Amnesia), anxiety/nervousness, (ataxia), confusion, depersonalization, dizziness, euphoria, (hallucination), paranoid reaction, somnolence, thinking abnormal, depression, nightmares, speech difficulties.

The clinical significance of the association of these events with Marinol treatment is unknown, but they are reported as alerting information for the clinician.

DRUG ABUSE AND DEPENDENCE

Dronabinol is one of the psychoactive compounds present in cannabis, and is abusable and controlled under the Controlled Substances Act. Both psychological and physiological dependence have been noted in healthy individuals receiving dronabinol, but addiction is uncommon and has only been seen after prolonged high dose administration.
Chronic abuse of cannabis has been associated with decrements in motivation, cognition, judgement, and perception. The etiology of these impairments is unknown, but may be associated with the complex process of addiction rather than an isolated effect of the drug. No such decrements in psychological, social or neurological status have been associated with the administration of dronabinol for therapeutic purposes.
In an open-label study in patients with AIDS who received Marinol for up to five months, no abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a substantial number of patients with a past history of drug abuse.
An abstinence syndrome has been reported after the abrupt discontinuation of dronabinol in volunteers receiving dosages of 210 mg/day for 12 consecutive days. Within 12 hours after discontinuation, these volunteers manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include “hot flashes”, sweating, rhinorrhea, loose stools, hiccoughs and anorexia.
These withdrawal symptoms gradually dissipated over the next 48 hours. Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol.

OVERDOSAGE

Signs and symptoms following Dronabinol intoxication include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia; following MODERATE intoxication include memory impairment, depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following SEVERE intoxication include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients with existing seizure disorders.

DOSAGE AND ADMINISTRATION

Appetite Stimulation: Initially, 2.5 mg Marinol Capsules should be administered orally twice daily, before lunch and supper.. If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day MARINOL, administered in divided oral doses. Caution should be exercised in escalating the dosage of dronabinol because of the increased frequency of dose-related adverse experiences at higher dosages.

Antiemetic: Marinol is best administered at an initial dose of 5 mg/m2, given 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6 doses/day. Caution should be exercised in dose escalation, however, as the incidence of disturbing psychiatric symptoms increases significantly at maximum dose.

(http://www.fda.gov/ohrms/dockets/dockets/05n0479/05N-0479-emc0004-04.pdf) (2004)

Discussion

Therapeutic profile on existing evidence
Tetrahydrocannabinol and nabilone are effective anti-emetics but there are no comparisons with 5-HT3 antagonists, so a role in modern anti-emetic regimes remains to be determined. Currently, only nabilone is licensed in the UK and available for prescription and research. THC (as dronabinol) has recently been rescheduled to permit prescription but remains unlicensed and must be specially imported on a named-patient basis. Delta-8-THC looks worthy of further investigation, particularly in children, and is much simpler to synthesise than THC.
Many individuals with MS have claimed a benefit from cannabis and small controlled trials support this, although effect upon posture and balance requires clarification. THC is an effective analgesic at the expense of sedation with larger doses and may have special merit in neuropathic pain. No conclusions are possible as yet about anticonvulsant potential. Some cannabinoids reduce IOP, though side-effects of products currently available limit application and effects of tolerance are uncertain. The mechanism for bronchodilation probably differs from that of [beta]2-stimulants, so synergistic combinations may be possible.
Cannabis and THC are effective appetitc stimulants. Alongside anti-emetic, analgesic, anxiolytic, hypnotic and antipyretic properties this suggests a unique role in alleviating symptoms in selected patients with cancer or AIDS. This is a compelling area for future research, although possible effects upon immune function require careful monitoring.
Optimal doses and routes of delivery have not been established. Absorption by the oral route is unreliable. Smoking the drug is generally not a viable option since advantages such as rapid onset, accurate titration of effects and reliability in patients who are vomiting have to be set against the likelihood of lung irritation or damage, and it would in any case be unacceptable to most patients. However, pending availability of more satisfactory preparations, I believe that the existing profile of efficacy and toxicity justifies the provision of a legal supply of standardised herbal material ('compassionate reefers') to patients with terminal conditions who currently obtain relief with street cannabis. Sublingual sprays or tablets, nebulisers and aerosols look promising for the future, and THC is effective by the rectal route. Many potentially active cannabinoids have yet to be investigated and the recent identification of a peripheral receptor may lead to new drugs devoid of central nervous system effects.
Cannabis arouses passion in those who support or condemn it, and few people approach the clinical literature with dispassionate objectivity. Poorly controlled research produces ambiguous results which are then interpreted according to the prejudices of the reader. Anecdotes seem to be more readily accepted when they point to adverse rather than positive effects. Yet the known adverse effects of oral cannabinoids are rarely intolerable or life-threatening, in contrast to those associated with some standard therapies. A British Medical Association survey indicated that many UK doctors believe that cannabis should once again be available on prescription.
The way forward
A Select Committee of the House of Lords recently examined the scientific information concerning medical cannabis and took verbal and written evidence from a wide range of witnesses. Their conclusion, was that, although cannabis should remain a controlled drug, the law should be changed to allow doctors to prescribe "an appropriate preparation of cannabis if they saw fit". The government rejected this recommendation on the day of publication.
Under the auspices of the Royal Pharmaceutical Society, large-scale multi-centre trials are under way to explore further the efficacy of cannabinoids in relieving spasticity and postoperative pain. A pharmaceutical company has obtained a licence to cultivate medicinal cannabis on a large scale in the UK. By selecting a specific genotype then carefully controlling all other relevant variables such as soil conditions, temperature and humidity, it is possible to obtain levels of purity in plant extracts equal or superior to those of 'pure' synthetic cannabinoids. Most of the 60 or so naturally occurring cannabinoids are present in tiny amounts, and synthetic cannabinoids such as nabilone themselves contain up to 5% impurities, some of which are of unknown identity. Whether obtained by synthetic means or by plant extraction, it is essential that cannabinoids for prescription and research in the future should demonstrate excellent purity, stability and bioavailability.
The medicinal properties of cannabis are still mainly delineated by the anecdotal reports of those who believe their symptoms are relieved by its use, and these accounts are often dismissed as wishful thinking or even mischievous. Since the conventional treatments for many of these disorders are both toxic and relatively ineffectual, a more constructive response would be to expose such claims to careful scientific examination and, in the meantime, search for a way to avoid criminalising those who seek only to assuage their own suffering.

(http://www.calgarycmmc.com/appetitestimulant.htm) (1996)

Edoardo Forcignano
Davide Michele Capone