Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

Psychopharmacology (Berl). 2008 Mar;197(1):157-68. doi: 10.1007/s00213-007-1020-8. Epub 2007 Dec 27.


Introduction: Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence.

Objectives: The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an alpha(2)-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence.

Materials and methods: Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured.

Results: THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone.

Conclusions: These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic alpha-Agonists / adverse effects
  • Adrenergic alpha-Agonists / therapeutic use*
  • Adult
  • Affect / drug effects
  • Appetite / drug effects
  • Attention / drug effects
  • Cannabinoids / toxicity*
  • Clonidine / adverse effects
  • Clonidine / analogs & derivatives*
  • Clonidine / therapeutic use
  • Double-Blind Method
  • Dronabinol / adverse effects
  • Dronabinol / therapeutic use*
  • Drug Therapy, Combination
  • Humans
  • Male
  • Marijuana Abuse / psychology
  • Marijuana Abuse / rehabilitation*
  • Mental Recall / drug effects
  • Psychomotor Performance / drug effects
  • Psychotropic Drugs / adverse effects
  • Psychotropic Drugs / therapeutic use*
  • Secondary Prevention
  • Sleep / drug effects
  • Substance Withdrawal Syndrome / psychology
  • Substance Withdrawal Syndrome / rehabilitation*


  • Adrenergic alpha-Agonists
  • Cannabinoids
  • Psychotropic Drugs
  • Dronabinol
  • Clonidine
  • lofexidine