Fighting Fire with Fire: Using agonist replacement therapy to treat cannabis addiction

Fighting Fire with Fire: Using agonist replacement therapy to treat cannabis addiction

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By: Sonja Elsaid

Pot. Weed. Skunk. Dope. Mary Jane. Call it whatever you want, cannabis, is material that contains dried leaves, flowers or fruiting tops of the plant Cannabis sativa,1 usually smoked as joints (cigarettes), or in bongs (pipes).  It can also be baked into foods, such as cakes, cookies, and the ever-magical brownies.  Worldwide, cannabis is the third most commonly used psychoactive substance after tobacco and alcohol.1 It is estimated that over 40% of Canadians have tried cannabis at least once in their lifetime.2 Cannabis consumers often seek feelings of relaxation or euphoria and they often experience changes in perception.3 Responsible for these effects is tetrahydrocannabinol (THC), the main psychoactive ingredient in Cannabis Sativa.

Sadly, it is expected that 8-12% of regular cannabis users will at some point in their lifetime develop cannabis use disorder (CUD), which can lead to cannabis addiction.1 According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) used by Canadian healthcare professionals, CUD is a recognized mental health disorder.4 Furthermore, cannabis withdrawal, which is the more severe form of CUD, can develop after the abrupt reduction or cessation of prolonged cannabis use.4 Individuals in the state of withdrawal normally experience unpleasant symptoms, such as irritability, sleep difficulty, depressed mood and restlessness.4 These unpleasant conditions not only interfere with daily functioning of these individuals, but efforts to avoid them represent the driving force for continuous cannabis abuse.Currently, the only approved therapy for cannabis withdrawal is psychotherapy.1,5 However, only 20% of those treated achieve abstinence, indicating that better treatments are needed.5

Since successes were observed with using agonist replacement therapies for treating other substance use disorders, such as using nicotine patch to help quit smoking, scientists started testing synthetic THC in subjects with cannabis withdrawal.1 The rationale for using the agonist replacement therapy was the potential to reduce  symptoms of withdrawal by providing a similar drug—synthetic THC—through a safer route of administration. Thus, instead of smoking a joint, and inhaling chemicals, synthetic THC would be ingested.1 The other benefit of this harm reducing method was to empower patients to make the necessary lifestyle changes, while distancing them from the regular substance abuse.5

One of the first synthetic THC drugs tested for cannabis addiction was dronabinol, an oral and synthetic THC.1 Initially, dronabinol was approved for treatment of anorexia, nausea, and vomiting in cancer patients.1 Early clinical trials demonstrated that dronabinol was effective in reducing cannabis smoking by 50%. However, its poor bioavailability and slow onset of action prompted scientists to test nabilone (CesametTM), a synthetic analog with better bioavailability.1,5 Like dronabinol, nabilone was originally approved for the treatment of nausea and vomiting in cancer patients.1 In clinical trials, nabilone was effective in decreasing cannabis smoking and treating symptoms of withdrawal.1 Furthermore, nabilone is long-acting and did not exhibit addictive potential likely due to its slow onset of action.5 Despite these strengths, nabilone is not approved as CUD treatment, as nabilone is still composed of THC, the substance originally derived from marijuana, which led to cannabis addiction in the first place.5 Furthermore, the medical community’s fear of prescribing THC alone for any medical condition was why researchers had to look elsewhere for more sophisticated compounds to treat CUD.5,6

The most recent variations of agonist replacement therapy is nabiximols (Sativex®), which have been prescribed for the treatment of multiple sclerosis and cancer-related pain in 15 countries.2 Nabiximols contains THC, which aims to provide the agonist replacement therapy.  However, unlike dronabinol and nabilone, nabiximols also contains cannabidiol (CBS), the other major ingredient found in marijuana.1 Importantly, CBD does not exhibit the same mind-altering properties of THC and counteracts the negative effects of THC abstinence.1 Nabiximols is administered as a buccal spray and is placed between the gums and cheek in the mouth for absorption.5 The first study was conducted on inpatients with cannabis dependence, who reported having fewer symptoms of withdrawal when treated with nabiximols.7 Furthermore, when tested in outpatients, patients taking nabiximols exhibited fewer withdrawal symptoms when abstaining from smoking cannabis.8,9  In fact, this study was conducted at the Centre of Addiction and Mental Health (CAMH) in Toronto, under the supervision of the Institute of Medical Science’s very own, Dr. Bernard Le Foll, a psychiatrist at the Addiction Division at the CAMH.  Moreover, in another study at CAMH, Dr. Le Foll and his group have demonstrated that cannabis use was reduced by 70% in those treated with nabiximols. Use of nabiximols was well tolerated and did not lead to greater incidence of abuse.9,10

Yet, despite the evidence that synthetic cannabinoids have been shown their effectiveness in treatment of cannabis addictions, Canadian and American government officials remain hesitant about giving these drugs the official indication for treatment of cannabis addictions.5  It seems that much more effort is needed for agonist replacement medications to get approved on the market.5 With the recent legalization of cannabis for recreational use in Canada, cannabis use and the number of individuals developing CUD are expected to rise, with no drugs currently indicated for treatment, except for psychotherapy.2,9 It is also worthwhile to note that psychotherapy may not be accessible to those without health insurance.

Although the use of synthetic THC and nabiximols may be controversial, the benefits of cannabis agonist replacement therapy demonstrated by its superior safety, efficacy, and potential for harm reduction far outreach the cost of fear by the medical community to use THC-containing compounds for treatment.  Unfortunately, changing the opinion of the medical community and government officials to approve cannabis-derived treatments for CUD may require more time and effort.


  1. Brezing CA, Levin FR. The Current State of Pharmacological Treatments for Cannabis Use Disorder and Withdrawal. Neuropsychopharmacology. 2018;43(1):173-94.
  2. Bonner WIA, Andkhoie M, Thompson C, et al. Patterns and factors of problematic marijuana use in the Canadian population: Evidence from three cross-sectional surveys. Can J Public Health. 2017;108(2):e110-e6.
  3. Canadian Centre on Substance Abuse. Canadian Drug Summary: Cannabis. 2018 June [10p]. Available from:
  4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC; 2013.
  5. Allsop DJ, Lintzeris N, Copeland J, et al. Cannabinoid replacement therapy (CRT): Nabiximols (Sativex) as a novel treatment for cannabis withdrawal. Clin Pharmacol Ther. 2015;97(6):571-4.
  6. CBC Radio Quirks and Quarks. Doctors’ group wants to scrap Canada’s medical cannabis program [document on the Internet]. CBC Radio; 2018 April 30 [cited 2018 Oct 20].  Available from:
  7. Allshop DJ, Copeland J, LIntzeris N, et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA. 2014;71:281-291.
  8. Trigo JM, Lagzdins D, Rehm J, et al. Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and carvings. Drug Alcohol Depend. 2016;161:298-306.
  9. Le Foll B. Oral communication 2018 Oct 17.
  10. Trigo JM, Soliman A, Quality LC, et al.  Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial. PLoS ONE 13(1): e0190768.