{"id":14724,"date":"2018-07-12T18:57:08","date_gmt":"2018-07-12T18:57:08","guid":{"rendered":"https:\/\/drugprevent.org.uk\/ppp\/?p=14724"},"modified":"2018-11-01T19:08:01","modified_gmt":"2018-11-01T19:08:01","slug":"an-update-on-safety-and-side-effects-of-cannabidiol-a-review-of-clinical-data-and-relevant-animal-studies","status":"publish","type":"post","link":"https:\/\/drugprevent.org.uk\/ppp\/2018\/07\/an-update-on-safety-and-side-effects-of-cannabidiol-a-review-of-clinical-data-and-relevant-animal-studies\/","title":{"rendered":"An Update On Safety And Side Effects Of Cannabidiol: A Review Of Clinical Data And Relevant Animal Studies"},"content":{"rendered":"
\n

by Kerstin Iffland<\/a>\u00a0and\u00a0<\/span>Franjo Grotenhermen<\/a><\/p>\n

<\/div>\n<\/div>\n
\n

Introduction:<\/strong>\u00a0This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs.<\/span><\/p>\n

\n

Results:<\/strong>\u00a0In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite\/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients’ compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam’s side effects.<\/span><\/p>\n

Conclusion:<\/strong>\u00a0This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking.<\/span><\/p>\n<\/div>\n

Keywords:<\/strong>\u2002:\u00a0<\/strong>cannabidiol, cannabinoids, medical uses, safety, side effects, toxicity<\/span><\/span><\/div>\n<\/div>\n
\n
<\/div>\n

Introduction<\/span><\/h2>\n

Since several years, other pharmacologically relevant constituents of the Cannabis plant, apart from \u03949-THC, have come into the focus of research and legislation. The most prominent of those is cannabidiol (CBD). In contrast to \u03949-THC, it is nonintoxicating, but exerts a number of beneficial pharmacological effects. For instance, it is anxiolytic, anti-inflammatory, antiemetic, and antipsychotic. Moreover, neuroprotective properties have been shown.1<\/a>,2<\/a><\/sup>\u00a0Consequently, it could be used at high doses for the treatment of a variety of conditions ranging in psychiatric disorders such as schizophrenia and dementia, as well as diabetes and nausea.1<\/a>,2<\/a><\/sup><\/span><\/p>\n

At lower doses, it has physiological effects that promote and maintain health, including antioxidative, anti-inflammatory, and neuroprotection effects. For instance, CBD is more effective than vitamin C and E as a neuroprotective antioxidant and can ameliorate skin conditions such as acne.3<\/a>,4<\/a><\/sup><\/span><\/p>\n

The comprehensive review of 132 original studies by Bergamaschi et al. describes the safety profile of CBD, mentioning several properties: catalepsy is not induced and physiological parameters are not altered (heart rate, blood pressure, and body temperature). Moreover, psychological and psychomotor functions are not adversely affected. The same holds true for gastrointestinal transit, food intake, and absence of toxicity for nontransformed cells. Chronic use and high doses of up to 1500\u2009mg per day have been repeatedly shown to be well tolerated by humans.1<\/a><\/sup><\/span><\/p>\n

Nonetheless, some side effects have been reported for CBD, but mainly\u00a0in vitro<\/em>\u00a0or in animal studies. They include alterations of cell viability, reduced fertilization capacity, and inhibition of hepatic drug metabolism and drug transporters (e.g., p-glycoprotein).1<\/a><\/sup>Consequently, more human studies have to be conducted to see if these effects also occur in humans. In these studies, a large enough number of subjects have to be enrolled to analyze long-term safety aspects and CBD possible interactions with other substances.<\/span><\/p>\n

This review will build on the clinical studies mentioned by Bergamaschi et al. and will update their survey with new studies published until September 2016.<\/span><\/p>\n<\/div>\n

\n
<\/div>\n

Relevant Preclinical Studies<\/span><\/h2>\n

Before we discuss relevant animal research on CBD possible effects on various parameters, several important differences between route of administration and pharmacokinetics between human and animal studies have to be mentioned. First, CBD has been studied in humans using oral administration or inhalation. Administration in rodents often occures either via intraperitoneal injection or via the oral route. Second, the plasma levels reached via oral administration in rodents and humans can differ. Both these observations can lead to differing active blood concentrations of CBD.1<\/a>,5<\/a>,6<\/a><\/sup><\/span><\/p>\n

In addition, it is possible that CBD targets differ between humans and animals. Therefore, the same blood concentration might still lead to different effects. Even if the targets, to which CBD binds, are the same in both studied animals and humans, for example, the affinity or duration of CBD binding to its targets might differ and consequently alter its effects.<\/span><\/p>\n

The following study, which showed a positive effect of CBD on obsessive compulsive behavior in mice and reported no side effects, exemplifies the existing pharmacokinetic differences.5<\/a><\/sup>\u00a0When mice and humans are given the same CBD dose, more of the compound becomes available in the mouse organism. This higher bioavailability, in turn, can cause larger CBD effects.<\/span><\/p>\n

Deiana et al. administered 120\u2009mg\/kg CBD either orally or intraperitoneally and measured peak plasma levels.5<\/a><\/sup>\u00a0The group of mice, which received oral CBD, had plasma levels of 2.2\u2009\u03bcg\/ml CBD. In contrast, i.p. injections resulted in peak plasma levels of 14.3\u2009\u03bcg\/ml. Administering 10\u2009mg\/kg oral CBD to humans leads to blood levels of 0.01\u2009\u03bcg\/ml.6<\/a><\/sup>\u00a0This corresponds to human blood levels of 0.12\u2009\u03bcg\/ml, when 120\u2009mg\/kg CBD was given to humans. This calculation was performed assuming the pharmacokinetics of a hydrophilic compound, for simplicity’s sake. We are aware that the actual levels of the lipophilic CBD will vary.<\/span><\/p>\n

A second caveat of preclinical studies is that supraphysiological concentrations of compounds are often used. This means that the observed effects, for instance, are not caused by a specific binding of CBD to one of its receptors but are due to unspecific binding following the high compound concentration, which can inactivate the receptor or transporter.<\/span><\/p>\n

The following example and calculations will demonstrate this.\u00a0In vitro<\/em>\u00a0studies have shown that CBD inhibits the ABC transporters P-gp (P glycoprotein also referred to as ATP-binding cassette subfamily B member 1=ABCB1<\/em>; 3\u2013100\u2009\u03bcM CBD) and Bcrp (Breast Cancer Resistance Protein; also referred to as\u00a0ABCG2<\/em>=ATP-binding cassette subfamily G member 2).7<\/a><\/sup>\u00a0After 3 days, the P-gp protein expression was altered in leukemia cells. This can have several implications because various anticancer drugs also bind to these membrane-bound, energy-dependent efflux transporters.1<\/a><\/sup>\u00a0The used CBD concentrations are supraphysiological, however, 3\u2009\u03bcM CBD approximately corresponds to plasma concentrations of 1\u2009\u03bcg\/ml. On the contrary, a 700\u2009mg CBD oral dose reached a plasma level of 10\u2009ng\/ml.6<\/a><\/sup>\u00a0This means that to reach a 1\u2009\u03bcg\/ml plasma concentration, one would need to administer considerably higher doses of oral CBD. The highest ever applied CBD dose was 1500\u2009mg.1<\/a><\/sup>Consequently, more research is warranted, where the CBD effect on ABC transporters is analyzed using CBD concentrations of, for example, 0.03\u20130.06\u2009\u03bcM. The rationale behind suggesting these concentrations is that studies summarized by Bih et al. on CBD effect on ABCC1 and ABCG2 in SF9 human cells showed that a CBD concentration of 0.08\u2009\u03bcM elicited the first effect.7<\/a><\/sup><\/span><\/p>\n

Using the pharmacokinetic relationships mentioned above, one would need to administer an oral CBD dose of 2100\u2009mg CBD to affect ABCC1 and ABCG2. We used 10\u2009ng\/ml for these calculations and the ones in\u00a0Table 1<\/a>,6<\/a>,8<\/a><\/sup>\u00a0based on a 6-week trial using a daily oral administration of 700\u2009mg CBD, leading to mean plasma levels of 6\u201311\u2009ng\/ml, which reflects the most realistic scenario of CBD administration in patients.6<\/a><\/sup>\u00a0That these levels seem to be reproducible, and that chronic CBD administration does not lead to elevated mean blood concentrations, was shown by another study. A single dose of 600\u2009mg led to reduced anxiety and mean CBD blood concentrations of 4.7\u201317\u2009ng\/ml.9<\/a><\/sup><\/span><\/p>\n

\n

Table 1.<\/span><\/h3>\n
\n

Inhibition of Human Metabolic Enzymes by Exogenous Cannabinoids\u00a0In Vitro<\/em>\u00a0and the Extrapolated Levels of Oral Daily CBD Administration in Humans Needed to Reach These\u00a0In Vitro<\/em>\u00a0Concentrations (Adapted)6<\/a>,8<\/a><\/sup><\/strong><\/span><\/p>\n<\/div>\n

\n\n\n\n\n\n\n
CYP-450 isoform<\/span><\/th>\n1A1<\/span><\/th>\n1A2<\/span><\/th>\n1B1<\/span><\/th>\n2A6<\/span><\/th>\n2B6<\/span><\/th>\n2C9<\/span><\/th>\n2D6<\/span><\/th>\n3A4<\/span><\/th>\n3A5<\/span><\/th>\n3A7<\/span><\/th>\n<\/tr>\n<\/thead>\n
CBD (in \u03bcM)<\/span><\/td>\n0.2<\/span><\/td>\n2.7<\/span><\/td>\n3.6<\/span><\/td>\n55.0<\/span><\/td>\n0.7<\/span><\/td>\n0.9\u20139.9<\/span><\/td>\n1.2\u20132.7<\/span><\/td>\n1.0<\/span><\/td>\n0.2<\/span><\/td>\n12.3<\/span><\/td>\n<\/tr>\n
a<\/sup>Extrapolated oral daily CBD doses to reach the levels above (in mg)<\/span><\/td>\n4900<\/span><\/td>\n63,000<\/span><\/td>\n84,000<\/span><\/td>\n1.28 Mio.<\/span><\/td>\nCa. 16,000<\/span><\/td>\n21,000\u2013231,000<\/span><\/td>\n28,000\u201363,000<\/span><\/td>\nCa. 23,000<\/span><\/td>\n4900<\/span><\/td>\n0.29 Mio.<\/span><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n