Treatment with CBD

Treatment with CBD – Your Gateway to the Science of Cannabidiol

CBD safety in clinical trials

A recently published review of cannabidiol (CBD) assessed CBD safety in clinical trials. The study found identified that the majority of adverse side effects from taking CBD have only a mild to moderate impact. However, researchers recorded a number of serious adverse effects, which we discuss below.

General aspects of CBD safety in clinical trials

CBD has a complex array of actions in the body that can lead to a wide range of mild to moderate adverse effects, including:

  • gastrointestinal effects (diarrhea, nausea, vomiting),
  • central effects (sedation, drowsiness, convulsions (involuntary body movements) and fatigue), and
  • metabolic effects (increased serum aminotransferases (an indicator of cell damage in the liver), and decreased appetite)

Clinical trials have tested the effect of CBD for the treatment of Parkinson’s disease, psychosis, epilepsy, and anxiety. Studies with epileptic patients typically show that in CBD treatments, patients withdrew from treatment or the clinical trials more often, compared with taking a placebo. This suggests higher levels of adverse effects when taking CBD.

These observations are likely to be due to CBD’s interaction with other drugs that users are also taking for their condition. For epilepsy, drugs such as clobazam, valproate, stiripentol, topiramate, and levetiracetam may cause drug–drug interactions with CBD.

Serious adverse effects related to CBD

In 18 clinical trials reviewed, 7 reported serious adverse effects from taking CBD. Five of the trials were on epilepsy and two on psychosis. No trials on healthy individuals produced adverse effects. This finding strongly suggests that it was the presence of other treatment drugs that caused the effects.

In the two psychosis trials, two patients experienced strong sedation (drowsiness and relaxation), while one of the trials showed that 20% of patients involved felt “mild sedation”, compared to 5% taking a placebo. The authors concluded that CBD most likely caused the sedation directly.  Nevertheless, as the patients were taking a range of other drugs (including antipsychotics, antidepressants, anticholinergics, antconvulsants/mood stabilizers, and benzodiazepines) they could not easily assign any potential CBD interaction with a particular drug.

In a trial of 88 patients with schizophrenia, 8 patients suffered a gastrointestinal complaint with nausea, diarrhea, abdominal pain, and vomiting. Still, only one was serious enough to withdraw from the trial. It is most likely that the additives in the CBD oil formulation may be the cause.

CBD safety in epilepsy clinical trials

In trials on epileptic patients, other serious side effects when taking CBD included:

  • convulsions,
  • skin rashes,
  • diarrhea,
  • vomiting,
  • viral infection,
  • the increased concentration of antiepileptic drugs (although not exceeding therapeutic recommended levels),
  • restlessness,
  • hypercapnia (elevated carbon dioxide levels in the blood),
  • hypoxia (oxygen deprivation)
  • constipation,
  • worsening of chronic cholecystitis (inflammation of the gall bladder), and
  • pyrexia (raised body temperature)

The authors generally did not consider CBD as the primary cause of these effects. However, they implicated the impact of the complex drug–drug interactions and severe consequences of epileptic syndrome. Nevertheless, the increases in epileptic drug concentrations and the potential impairment of anticonvulsant drugs by CBD needs to be taken into account.

Other side effects

Skin rashes appear to be a common side effect in CBD trials, in some cases severe enough for withdrawal from the trial. Once again, doctors should monitor patients for rashes and have dose reduction/adjustment or end treatment if it becomes a problem. Concomitant use with the antiepileptic clobazam, which can also induce rashes, produced a notable number of cases when combined with CBD.

Gastrointestinal problems, diarrhea, and vomiting were common symptoms, and they appeared in both healthy volunteers and psychotic patients taking CBD. Nevertheless, other drugs may increase or cause vomiting too.

Watch this 1:09 minute video “Mayo Clinic Minute: Is CBD safe to use?”

Drug–drug interactions: valproate

In the five epilepsy trials, serious adverse effects were far more common. The most observed effect, causing the withdrawal of 15 patients, was elevated transaminases that were three times higher than the normal upper limit. Transaminases are important in the synthesis of amino acids to form proteins. 

The drug valproate may be the cause of the elevated transaminase levels. CBD can, in theory, interfere with the metabolism of valproate by inhibiting the enzyme CYP2C9. However, this is only a theory, since levels of valproate have not decreased in the body. Other pharmacokinetic factors may therefore have an involvement. For example, both valproate and CBD bind to plasma proteins, which may result in elevations of valproate in the body, although this needs to be researched more. 

Although drug-induced liver injury also occurred, it did not reach a “serious” level and was largely a transient short-term effect. The effects were sufficient enough, however, for the researchers to suggest that patients taking valproate and CBD should have their liver-health closely monitored.

Drug–drug interactions: clobazam

Ample information is available on the interaction between CBD and clobazam (an antiepileptic drug) or its metabolite N-desmethylclobazam. 

CBD can inhibit the activity of specific enzymes, which causes a large increase in plasma levels of N-desmethylclobazam and the CBD active metabolite 7-hydroxy-CBD. 

The FDA reports that clobazam on its own is a sedative and can cause adverse effects such as pneumonia, lethargy, and respiratory problems. When people take CBD or opioids together with clobazam, its toxicity increases, with potentially serious effects that can result in “profound sedation, respiratory depression, coma, and death”. 

When discussing the patient outcomes above, the researchers remained unconvinced that it was the addition of CBD caused the serious effects. However, they suggested that doctors closely monitor patients using both drugs for these potential conditions.

Summary

  • Recent high-quality trials have shown that most acute and prolonged (over several weeks) adverse effects of CBD are only mild to moderate.
  • Serious adverse effects are rare and include mainly sedation, lethargy, and upper respiratory tract infections. 
  • The combined use of CBD and valproate may lead to elevated transaminases. On the other hand, concomitant use of CBD and clobazam causes more sedation, lethargy, and upper respiratory tract infections. 
  • Doctors should monitor epileptic patients who use CBD together with valproate and clobazam for potential drug–drug adverse effects.

Reference

Dos Santos RG, Guimarães FS, Crippa JAS, Hallak JEC, Rossi GN, Rocha JM, Zuardi AW. Serious adverse effects of cannabidiol (CBD): a review of randomized controlled trials. Expert Opin Drug Metab Toxicol. 2020 Jun;16(6):517-526. doi: 10.1080/17425255.2020.1754793. Epub 2020 Apr 27. PMID: 32271618.

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