AP L4T1: Pharmacological management of Cannabis Withdrawal

Before diving into cannabis withdrawal and intoxication, we’ll briefly recap the neurobiology of cannabis use disorder. If you’ve already completed our Primer on Cannabis Use Disorder, this will be familiar. If not, we encourage you to explore the “Primer on Cannabis Use Disorder” certificate module for comprehensive coverage

In-depth learning for CANNABIS

🌿 Primer On Cannabis Use Disorder⚕️

Let us take a recap to learn more about Neurobiology of Cannabis

Cannabis and CB Receptors

CB1 receptor

CB2 receptors

Most common G-protein–coupled receptor in the Brain.

Found largely within the periphery of the brain, including cells of the immune system.

 It has a major role in the behavioural effects of cannabis and THC across a range of species, including reward, subjective effects, and the development of dependence and withdrawal, including the maintenance of chronic marijuana smoking in humans.

Anti-inflammatory, Analgesic, Anticonvulsant,  Antipsychotic Antioxidant, and  neuroprotective properties 

chronic Neuroadaptation

Neurobiology of Cannabis Dependence

  • The consumption of cannabis directly targets the body’s natural endogenous endocannabinoid (eCB) system, which comprises the receptors that mediate the direct actions of cannabinoids, as well as the eCB lipid ligands (arachidonoyl ethanolamide, also called anandamide; and 2-arachidonoylglycerol, also called 2-AG) and the associated enzymes responsible for their synthesis and degradation10. 
  • The Gi/Go-protein-coupled cannabinoid receptor subtype 1 (CB1R) is the predominant form in the brain that mediates the psychoactive effects of cannabis. 

Video clip on Cannabinoids and followed by Recap questions

CANNABIS WITHDRAWAL

Approximately 50% of people who are dependent on cannabis will experience cannabis withdrawal syndrome.

Cannabis withdrawal was first recognised by the DSM in the Fifth Edition (2013) (DSM-V) and adopted by the United States in the International Classification of Diseases, Tenth Revision (2015) (ICD-10).

Cannabis withdrawal is defined by DSM-5-TR as the following:

  • Cessation of cannabis use that has been heavy and prolonged (ie, usually daily or almost daily use over a period of at least a few months).
  • Three or more of the following signs and symptoms develop within approximately 1 week after cessation of heavy, prolonged use:
    • Irritability, anger or aggression
    • Nervousness or anxiety
    • Sleep difficulty (ie, insomnia, disturbing dreams)
    • Decreased appetite or weight loss
    • Restlessness
    • Depressed mood
  • At least one of the following physical symptoms causing significant discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, or headache
  • The signs or symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance.

The DSM-5 does not include “craving” as a symptom of cannabis withdrawal, though this particular symptom has generally been identified as an important factor in CUD.

Cannabis withdrawal is clinically significant because of the unpleasant symptoms that can interfere with daily functioning in addition to serving as a negative reinforcer driving relapse and ongoing use of cannabis (Allsop et al, 2012).

Progress of Cannabis Withdrawal

Cannabis withdrawal symptoms typically begin 24–48 hours after cessation, peak between 2–6 days, and generally subside to baseline levels within 1–3 weeks (though individuals with prolonged, heavy use may experience persistent symptoms such as sleep disturbances, low mood, and cravings for more than three weeks).

Severity of withdrawal depends on the amount, frequency and potency of cannabis use.

Biologically, there is evidence that cannabis withdrawal is associated with the downregulation of brain cannabinoid-1 (CB-1) receptors as a result of chronic use. When cessation (or relative cessation) of activity at CB-1 receptors occurs, the deficiency results in interference with neurotransmitter systems, leading to the above-mentioned symptoms (Bonnet and Preuss, 2017).

Management OF CANNABIS WITHDRAWAL

Symptomatic management coupled with psychoeducation and counselling is the recommended treatment for managing cannabis withdrawal symptoms.

No medication is approved by the U.S. FDA (or any national regulatory authority) for the treatment of marijuana withdrawal. However, some medications may be used to manage certain symptoms of withdrawal.

CANNABINOID AGONIST REPLACEMENT (First-line)

Medication

Evidence

Mechanism

Dosing

Indications & Timeline

Nabiximols
(THC/CBD)

⭐⭐⭐
Best Evidence

Partial CB1 agonist – controlled cannabinoid replacement

2.7mg THC + 2.5mg CBD per spray. Start 2-4 sprays/day, max 32 sprays/day

For: All withdrawal symptoms, cravings

Timeline: Days 1-14, tapered over 12 weeks

Dronabinol

⭐⭐⭐
Good Evidence

Synthetic delta-9-THC – CB1 receptor agonist

20-40mg/day in divided doses. Start low, titrate based on response

For: General withdrawal symptoms, irritability, sleep

Timeline: Days 1-14, gradual taper

SYMPTOMATIC TREATMENT

Medication

Evidence

Mechanism

Dosing

Indications & Timeline

Gabapentin

⭐⭐
Limited Evidence

Modulates calcium channels, reduces neural excitability

300-900mg/day in divided doses

For: Anxiety, restlessness, insomnia

Note: Abuse potential, sedation common

Quetiapine

⭐
Very Limited

Atypical antipsychotic with sedative properties

25-100mg at bedtime

For: Severe insomnia, agitation (not first-line)

Timeline: Short-term only (3-7 days)

ADJUNCTIVE/SUPPORTIVE

Medication

Evidence

Mechanism

Dosing

Indications & Timeline

SSRIs
(e.g., Fluoxetine)

⭐
Minimal Evidence

Serotonin reuptake inhibition

Standard antidepressant doses

For: Pre-existing depression/anxiety

Note: Delayed onset (2-4 weeks), not for acute withdrawal

Behavioral Support & Sleep Hygiene

⭐⭐⭐
Essential

Non-pharmacological management

Daily: CBT, motivational interviewing, sleep hygiene, exercise

For: All withdrawal symptoms

Note: Should accompany any pharmacotherapy

Evidence Quality Legend

⭐⭐⭐ Good Evidence – Multiple RCTs and systematic reviews support efficacy

⭐⭐ Limited Evidence – Some supporting studies, plausible mechanism

⭐ Minimal Evidence – Case reports or theoretical basis only

Treatment Strategy

Goal: Symptom relief during detoxification to prevent relapse

Approach:

  • First-line: Cannabinoid agonist replacement therapy (Nabiximols or Dronabinol)
  • Adjunctive: Symptomatic treatment for specific symptoms (anxiety, insomnia)
  • Essential: Psychosocial support + CBT must accompany pharmacotherapy

Dronabinol

Dronabinol has shown benefit in reducing withdrawal symptoms and improving treatment retention, it has not demonstrated superiority over placebo in reducing cannabis use or promoting abstinence in outpatient treatment trials

FDA approved for AIDS Anorexia

Dronabinol, an orally bioavailable synthetic form of delta-9-tetrahydrocannabinol (THC), has FDA indications for the treatment of anorexia associated with AIDS and second-line treatment for nausea and vomiting associated with cancer chemotherapy.

Learn More

Evidence

• Levin et al. (2011): A randomized, double-blind, placebo-controlled trial of 156 cannabis-dependent individuals (122 randomized) found that dronabinol (up to 40 mg/day) was superior to placebo in promoting retention in treatment and reducing withdrawal symptoms. However, there was no significant difference between treatment groups in the proportion of participants who achieved sustained abstinence or reduced marijuana use.
• Levin et al. (2016): A randomized, double-blind, placebo-controlled trial testing dronabinol (20 mg three times daily) combined with lofexidine (0.6 mg three times daily) versus placebo in 156 cannabis-dependent adults (122 randomized). Both groups showed reductions in cannabis use, but there was no significant advantage of the active medication over placebo in promoting abstinence.
• A 2022 systematic review of randomized controlled trials found that dronabinol showed promise in reducing withdrawal symptoms and improving treatment retention, but demonstrated limited therapeutic potential in reducing cannabis use or achieving abstinence.

Learn More

Dose and Side-effects

In trials, dosages between 30-90 mg per day in divided doses have been tested. Higher doses well tolerated

Common adverse reactions include asthenia, abdominal pain, nausea, vomiting, palpitations, tachycardia, vasodilation, diarrhea, and fecal incontinence.

Learn More

Dronabinol

Dronabinol has shown benefit in reducing withdrawal symptoms and improving treatment retention, it has not demonstrated superiority over placebo in reducing cannabis use or promoting abstinence in outpatient treatment trials.

Dronabinol, an orally bioavailable synthetic form of delta-9-tetrahydrocannabinol (THC), has FDA indications for the treatment of anorexia associated with AIDS and second-line treatment for nausea and vomiting associated with cancer chemotherapy.

  • Levin et al. (2011): A randomized, double-blind, placebo-controlled trial of 156 cannabis-dependent individuals (122 randomized) found that dronabinol (up to 40 mg/day) was superior to placebo in promoting retention in treatment and reducing withdrawal symptoms. However, there was no significant difference between treatment groups in the proportion of participants who achieved sustained abstinence or reduced marijuana use.
  • Levin et al. (2016): A randomized, double-blind, placebo-controlled trial testing dronabinol (20 mg three times daily) combined with lofexidine (0.6 mg three times daily) versus placebo in 156 cannabis-dependent adults (122 randomized). Both groups showed reductions in cannabis use, but there was no significant advantage of the active medication over placebo in promoting abstinence.
  • A 2022 systematic review of randomized controlled trials found that dronabinol showed promise in reducing withdrawal symptoms and improving treatment retention, but demonstrated limited therapeutic potential in reducing cannabis use or achieving abstinence.

In trials, dosages between 30-90 mg per day in divided doses have been tested. Higher doses well tolerated.

Common adverse reactions include asthenia, abdominal pain, nausea, vomiting, palpitations, tachycardia, vasodilation, diarrhea, and fecal incontinence.

CANNABINOID AGONIST APPROACHES

Agonist approaches have been considered in the treatment of CUD given the success of conceptually similar treatments for nicotine and opioid use disorders.

Dronabinol, an orally bioavailable synthetic form of delta-9-tetrahydrocannabinol (THC), which has FDA indications for the treatment of anorexia associated with AIDS and second-line treatment for nausea and vomiting associated with cancer chemotherapy.

EVIDENCE in cannabis withdrawal- A randomized, double-blind, placebo-controlled trial by Trigo, J. M., et al. (2016) of 40 cannabis-dependent individuals found that dronabinol reduced withdrawal severity and increased retention in treatment compared to placebo.

A 2018 systematic review and meta-analysis of randomized controlled trials on the use of cannabinoids for the treatment of cannabis withdrawal found that while dronabinol showed promise in reducing withdrawal symptoms, the evidence was limited by the small number of studies and the high risk of bias.

Dose– No optimal therapeutic range has been established. In trials, dosage between 30-90 mg in divided dosage have been tried.

Common adverse reactions include asthenia, abdominal pain, nausea, vomiting, palpitations, tachycardia, vasodilation, diarrhoea, fecal incontinence.

There is no evidence of abuse or diversion of dronabinol till date. Dronabinol is a Schedule III drug, available by prescription, considered to be non-narcotic and to have a low risk of physical or mental dependence.

While some studies have shown promising results, the evidence on the use of dronabinol for cannabis withdrawal is still inconclusive. More research is needed to determine the optimal dose and duration of treatment, as well as to compare the effectiveness of dronabinol to other medications or behavioral therapies for cannabis withdrawal.

Nabilone is another synthetic form of THC that has been studied for its potential to alleviate symptoms of cannabis withdrawal.

A randomized, double-blind, placebo-controlled trial by Haney et al. (2013) in 40 cannabis-dependent individuals found that nabilone was effective in reducing withdrawal symptoms and cannabis use, and improving sleep quality, compared to placebo. The study authors suggested that nabilone may be a useful treatment for individuals with more severe withdrawal symptoms. Study results can’t be generalized- small sample size, high drop-out rate, small duration of study.

It is likely that nabilone’s properties as a long-acting and slow-onset-of-action agonist may make it less likely to have the abuse liability of smoked cannabis.

A systematic review and meta-analysis of randomized controlled trials by Gueye, A. B., et al. (2018) found that while nabilone showed promise in reducing withdrawal symptoms and improving treatment retention, the evidence was limited by the small number of studies and the high risk of bias.

Nabiximols, which is a mouth spray containing a combination of tetrahydrocannabinol (THC), which would provide the agonist action,and cannabidiol (CBD), a cannabinoid with proposed effects on attenuating paranoia,euphoria, anxiety, and depression been studied for its potential in managing cannabis withdrawal symptoms.

A study by Allsop et al (2014) found that nabixmols significantly reduced the overall severity of cannabis withdrawal compared to placebo during inpatient admission, including reductions in symptoms of irritability, depression, and craving, with limited but positive improvements in sleep, anxiety, appetite, physical symptoms, and restlessness.

Nabixmols further reduced the time course of withdrawal symptoms during the inpatient admission by almost 2 days

Freeman et al, 2020 found that while nabiximols was associated with reduced cannabis use and improved withdrawal symptoms in some studies, the evidence overall was limited and inconsistent.

Overall, while there is some evidence to suggest that nabiximols may be effective in managing cannabis withdrawal symptoms, more research is needed to understand better its potential benefits and risks, as well as the optimal dosing and duration of treatment.

In summary, medications with CB-1 receptor agonism may be effective in treating cannabis withdrawal, but need further research studies

Apart from the above medications, adjuvant medications for specific symptoms can also be given as a general approach:

SleeplessnessSleep hygiene + Mirtazapine/ Trazodone/ Promethazine/ Zolpidem/ Diazepam
Anxiety, restlessnessBenzodiazepines
HeadacheParacetamol
Nausea, vomitingPromethazine/ Dronabinol + Gastro-protective measures
Decreased appetiteNutritional support + Mirtazapine / Dronabinol
IrritabilityPsychoeducation + Benzodiazepines

Summary

Management of Cannabis Withdrawal syndrome

Often it is self-limiting and rarely need any intevention

There is no approved medication for Cannabis withdrawal syndrome.

Among moderate-severe cannabis use disorder, dronabinol (oral synthetic THC, 30, 40, or 60 mg daily), gabapentin (1,200 mg daily in divided doses), and nabiximols ( THC+ CBD sublingual spray), significantly reduced cannabis withdrawal symptoms

Synthetic cannabis withdrawal

Synthetic cannabis withdrawal has not been well-studied, but experience to date indicates the approximate time course:
Onset: Hours (can be as little as 1 hour)
Peak:  approximately day 2
Duration: approximately 1 week 
Physical symptoms: The most common and unique are palpitations, shortness of breath, chest pain, and Tachycardia, among others.
There is no specific pharmacotherapy

let us reflect on this scenario and explore

Thanks to Dr Aarti Singh, MD Resident NIMHANS for assisting in the above case scenario.

Now let us reflect on the above learning before we enter into next and last topic.

Let us practice