Treatment with CBD

The need to know about potential CBD withdrawal

A large number of people have been using CBD for a variety of reasons. In addition, the FDA approved pure CBD under the trade name Epidiolex® for the treatment of certain forms of childhood epilepsy.

CBD has little to no interaction with the CB1 and CB2 receptors. Therefore, CBD has little potential to cause psychoactive effects and therefore become a drug of abuse. As a note, the psychoactive properties of THC are due to its activity at the CB1 receptor.

As a matter of fact, laboratory experiments with lab rats have not shown any withdrawal after 100 mg/kg administration of CBD for 19 days. However, there is a lack of evidence in humans about CBD withdrawal.

The clinical trial to assess CBD and withdrawal

Scientists conducted this two-part, randomized, double-blind clinical trial to assess the potential of CBD to cause withdrawal. Study participants were 30 non-obese healthy adult volunteers (about half men and half women) with no history of alcohol or drug abuse or addiction.

In the first part of the study, all participants received 750 mg of Epidiolex® for 4 weeks (about 20 mg/kg/day for a 75 kg adult). In the second part, which lasted for only 2 weeks, participants then were randomly assigned into either an experimental group or a control group. The experimental group received 750 mg of Epidiolex®, and the control group received placebo.

Only the statisticians but neither the clinicians nor the study participants knew who took the medication and who took the placebo. Study participants had follow-up visits with the clinicians once every week during the study.

Watch this 3:35 minute video by Simple Learning Pro: “Placebo Effect, Control Groups, and the Double Blind Experiment”

Assessment of withdrawal symptoms

Study staff administered the participants the so-called Cannabis Withdrawal Scale, which is an instrument designed to assess (as its name says) the severity of a person’s cannabis withdrawal. Higher scores on the scale indicate a more severe addiction to cannabis.

In addition, they used the Penn Physician Withdrawal Checklist to detect other withdrawal symptoms. Moreover, researchers also noted any possible side effects of CBD administration. For this, they took lab measurements and had the participants fill out a number of patient reported outcome questionnaires on, for example, sleepiness, depression, and suicidal thoughts.

To make sure that participants indeed to the medication, the study scientists collected and analyzed blood samples to assess CBD and THC concentrations.

CBD withdrawal results

The highest possible score on the Cannabis Withdrawal Scale is 190. After 4 weeks, participants had an average score of 9 for addiction, which means that they were not addicted at all, and 6 for negative impact, meaning their lives were not impacted because of a possible CBD addition. At the end of the study, these two already very low scores decreased even more, showing that no CBD addiction developed during the study period.

The Penn Physician Withdrawal Checklist has a highest possible score of 60. After 4 weeks, participants’ average score was 1.4, and it was 0 at the end of the study, meaning that according to this scale as well, study participants reported no signs of addiction.

The highest possible score on the Cannabis Withdrawal Scale is 190. After 4 weeks, participants had an average score of 9 for addiction, which means that they were not addicted at all, and 6 for negative impact, meaning their lives were not impacted because of a possible CBD addition. At the end of the study, these two already very low scores decreased even more, showing that no CBD addiction developed during the study period.
CBD withdrawal during the study

As the figure shows, there was no difference in withdrawal symptoms in the experimental and control groups, meaning that when participants stopped taking CBD they did not experience withdrawal. 

Blood levels of CBD during the study

When participants were taking CBD, their plasma levels showed very large differences, as they ranged from 17 to 126 ng/mL. Blood levels of THC showed only trace amounts (0.4 ng/mL). When participants in the placebo group stopped taking CBD, their CBD blood levels suddenly dropped and went back to pre-study amounts by the end of the study.

Adverse effects of taking CBD

All except one person reported some adverse effects, but only 4 said these effects were severe. There was no difference in the extent of reported side effects between the placebo and the control groups. This means that whatever side effects participants reported, were most probably due to some other reasons but not CBD.

These were the most common side effects that the participants reported:

  • Diarrhea (63%)
  • Headache (50%)
  • Abdominal pain (47%)
  • Nausea (43%)
  • Fatigue (33%)

As a note, all cases of headache occurred in the placebo group soon after CBD was stopped, in line with the timing of when cannabis withdrawal would occur.

Watch this 3:15 minute video by Amrita Akhouri: “Side effects Vs Adverse Effects”

Severe adverse effects that lead to discontinuing participation

Altogether 9 participants in the experimental CBD group and 1 participant in the control group discontinued participation due to their adverse effects. (The latter one person started showing the side effects while they were still taking CBD). Here are their stories:

  • Scientists discontinued 2 participants because their blood test results increasingly indicated signs of potential drug-induced liver injury. The two people recovered after they stopped taking CBD, and their blood panels did not indicate actual liver injury.
  • Seven participants had generalized rashes (2 severe and 5 moderate), and therefore did not continue participating. Once they stopped taking CBD, their rashes disappeared.

Medium to mild adverse effects

Heightened eosinophil levels indicating inflammation affected 8 participants, but the blood cell counts returned to normal as the study progressed. Study investigators did not consider these situations as clinically significant or indicated liver injury.

One participant reported mild palpitations, but their ECG measurements were normal, and the palpitations ended soon. Participants reported very little sleep disruptions and daytime sleepiness. Finally, there were no reports of suicidal risk (either thoughts or intentions), and depression scores were also normal.

Conclusions

  • There was no indication of withdrawal symptoms and/or addiction with regards to taking CBD in this study according to patient reported outcomes
    • Headache might be an unconfirmed potential withdrawal symptom based on the adverse event reporting
    • However, just having headache does not mean that CBD is addictive
  • CBD was moderately well tolerated
    • Even though the majority of participants reported side effects, those were not severe
  • Given that this study used 4 times the dose of Epidiolex® (20 mg/kg/day vs 5 mg/kg/day), real-life doses might lead to fewer side effects.

Reference

Taylor L, Crockett J, Tayo B, Checketts D, Sommerville K. Abrupt withdrawal of cannabidiol (CBD): A randomized trial. Epilepsy Behav. 2020 Feb 6;104(Pt A):106938.

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