The purpose of this study is to see if Lofexidine in combination with Marinol is superior to placebo in achieving abstinence, reducing cannabis use and reducing withdrawal in cannabis-dependent patients seeking treatment for their marijuana use.

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.

12 weeks of trial or participants length of participation