Combined Pharmacotherapy for Cannabis Dependency

Cannabis use disorders remain the most common illicit drug use disorder and options for
treatment remain limited. Compared to other abusable substances, there has been little
investigation of pharmacotherapies for cannabis dependence and no effective pharmacotherapy
for cannabis dependence has yet to been developed. The development of effective cannabis
dependence pharmacotherapy is an important unmet public health need. Agonist pharmacotherapy
strategies have been effective for other substance use disorders (e.g., opioid and nicotine
use disorders) and the endocannabinoid system represents a promising target for agonist
pharmacotherapy with dronabinol. Lofexidine, a noradrenergic system suppressant, is effective
in treating opioid withdrawal and shows promise as a cannabis use disorder pharmacotherapy.
Haney et al. (2008) found that the combination of lofexidine and dronabinol (Lofex-Dro) was
superior to placebo, lofexidine alone, or dronabinol alone in improving sleep and other
cannabis withdrawal symptoms. Further, reduction in craving and relapse was greater for this
combined pharmacotherapy relative to either medication alone or placebo. The proposed
protocol is a 2 group, double blind, placebo-controlled outpatient study of the safety and
efficacy of the combination of dronabinol and lofexidine for the treatment of cannabis
dependence. We plan to enroll 180 subjects in a 12-week trial. The primary hypothesis is that
dronabinol will act as an agonist treatment while lofexidine will suppress craving- and
cue-induced related stress such that the combination will act in a complementary manner to
induce prolonged abstinence from marijuana.

Inclusion Criteria:

1. Men and women between the ages of 18-60 who meet DSM-IV criteria for current marijuana
dependence

2. Individuals must report using marijuana at least 5 days a week and have a positive
urine test for THC on the day of study entry.

3. Individual must describe marijuana as their primary drug of abuse.

4. Individuals must be capable of giving informed consent and capable of complying with
study procedures.

Exclusion Criteria:

1. Meets DSM-IV-TR criteria for schizophrenia, schizoaffective illness, psychotic
disorder other than transient psychosis due to drug abuse, major depression, bipolar
illness or psychiatric disorders (other than substance abuse) which require
psychiatric intervention.

2. Individuals who are medically unstable based on laboratory tests, electrocardiogram,
medical history, physical examination that would make participation hazardous

3. Individuals with liver enzyme function tests greater than three times normal

4. Individuals with a history of seizure disorder

5. Individuals with current suicidal risk.

6. Individuals who are cognitively impaired

7. Bradycardia (< 50 beats/minute), hypotension (sitting or standing BP < 90/50), or
symptoms attributable to low BP (i.e. lightheadedness or dizziness on standing).

8. Nursing mothers and pregnant women. Women of child bearing age will be included in the
study provided that they are not pregnant, based on the results of a blood pregnancy
test drawn at the time of screening. They must also agree to use a method of
contraception with proven efficacy and agree not to become pregnant during the study.
To confirm this, urine pregnancy tests will be repeated monthly. Women will be
provided a full explanation of the potential dangers of pregnancy while on the study
medication. If a woman becomes pregnant, the study medication will be discontinued.

9. Individuals who are physiologically dependent on any other drugs (excluding nicotine)
that would require a medical intervention

10. Individuals with known sensitivity to dronabinol or lofexidine

11. Individuals with coronary vascular disease as indicated by history or suspected by
abnormal ECG or history of cardiac symptoms

12. Individuals currently being treated with an alpha-2 agonist antihypertensive
medication

13. Individuals currently being prescribed a psychotropic medication (including sleep
medication). However, medication for depression is allowed if stable for at least 1
month.

14. Individuals who have a job that even mild intoxication would be hazardous (e.g.,
firefighter, bus driver)

15. Individuals who are court-mandated to treatment.