Therapeutic Potential of Cannabidiol,Cannabidiolic Acid,and Cannabidiolic Acid Methyl Ester as Treatments for Nausea and Vomiting

Abstract

Introduction:

Nausea and vomiting are the most distressing symptoms reported by oncology patients undergoing anticancer treatment. With the currently available treatments, vomiting and especially nausea remain problematic, highlighting the need for alternative treatments.

Discussion:

Here we review in vitro and in vivo evidence for the effectiveness of the nonpsychoactive cannabinoid cannabidiol (CBD) in managing nausea and vomiting. In addition, we also review the evidence for CBD's acidic precursor, cannabidiolic acid (CBDA), and a methylated version of CBDA (CBDA-ME) in these phenomena. Finally, we explore the potential role of CBD in the treatment of cannabinoid hyperemesis syndrome.

Conclusions:

CBD has demonstrated efficacy in reducing nausea and vomiting, with CBDA and CBDA-ME being more potent. The data suggest a need for these compounds to be evaluated in clinical trials for their ability to reduce nausea and/or vomiting.

Introduction

The adverse side effects of nausea and vomiting are often reported by oncology patients undergoing chemotherapy or radiation therapy, despite the use of currently available anti-emetic treatments.¹ Nausea and vomiting severely impact the quality of life and treatment outcomes for oncology patients,² highlighting the need to properly prevent and manage these symptoms.

There are three types of chemotherapy-induced nausea and vomiting.³ Acute nausea and vomiting occurs within 24 h of the initial anticancer agent administration, whereas delayed nausea and vomiting occurs at least 24 h later (and may peak 2–3 days after administration of the anticancer agent). Improper management of the acute and delayed phases may result in the development of anticipatory nausea and vomiting. Anticipatory nausea and vomiting occurs upon arrival at the cancer clinic, which triggers an episode of nausea and/or vomiting owing to a learned association between contextual cues (e.g., sights and smells) of the clinic and the subsequent nausea and vomiting caused by the anticancer agent administered there.⁴

The neurobiology of vomiting is well characterized,⁵ whereas that of nausea is still being elucidated. Acute vomiting occurs when toxic chemotherapy agents or radiation stimulate enterochromaffin cells in the gut, causing the release of serotonin (5-HT). This serotonin then binds to intestinal vagal afferent nerves through 5-HT₃ receptors, which trigger the vomiting reflex. The delayed phase of vomiting is thought to be driven by the release of substance P from neurons in the central and peripheral nervous systems, which then binds to neurokinin-1 (NK1) receptors to induce delayed vomiting.⁶

The primary treatment options for nausea and vomiting include 5-HT₃ receptor antagonists (ondansetron [OND], dolasetron, and granisetron), NK1 receptor antagonists (aprepitant, fosaprepitant, and rolapitant), and corticosteroids (dexamethasone), often as a combination for particularly toxic chemotherapy agents.⁷ Although these medications are fairly good at managing vomiting, they are essentially ineffective in reducing acute and delayed nausea^8–10 and none are effective in reducing anticipatory nausea. For example, Sepúlveda-Vildósola et al.¹¹ reported that 72% of patients treated with a 5-HT₃ receptor antagonist achieved complete acute vomiting control, whereas only 38% achieved complete acute nausea control. Therefore, nausea (acute, delayed, and anticipatory) continues to burden oncology patients, highlighting a need for alternative treatment options, such as cannabis and cannabinoid compounds. Please refer to Maida and Daeninck for an excellent summary of the use of cannabinoids in oncology.¹²

One of the few recognized medicinal effects of the cannabis plant is the control of chemotherapy-induced nausea and vomiting, with focus on the psychoactive component Δ⁹-tetrahydrocannabinol (THC). Synthetic THC is available for the management of chemotherapy-induced nausea and vomiting in capsule form as dronabinol (Marinol^®) or nabilone (Cesamet^®). Human and animal studies suggest that although THC can be effective in reducing nausea and vomiting, it may dose-dependently produce undesirable sedative effects.¹³ For example, high doses of THC (10 mg/kg, i.p.) impair locomotor activity¹⁴ and may actually promote nausea¹⁵ in rats. The psychoactive effects of THC have led physicians to direct patients toward the use of cannabis strains with low THC content. THC and cannabidiol (CBD) are derived from the same precursor, therefore as THC content decreases in a particular cannabis strain, the other main nonpsychoactive cannabinoid CBD correspondingly increases.

CBD, first isolated from Mexican marijuana by Adams et al.,¹⁶ was later isolated with its structure established by Mechoulam et al.¹⁷ CBD (unlike THC) lacks psychoactive effects, likely because of its low affinity for activating the cannabinoid receptors (CB₁ and CB₂). CBD instead exerts its action through a variety of mechanisms, likely explaining its widespread therapeutic effects.¹⁸ CBD acts as a noncompetitive antagonist at the CB₁ receptor, and acts at the CB₂ receptor as an inverse agonist.¹⁹ It has recently been shown to act as a negative allosteric agonist of the CB₁ receptor.²⁰ In addition, CBD is an antagonist at both the G-protein-coupled receptor GPR55, and the TRPM8 channel,²¹ and as an agonist at both the nuclear PPAR-γ, and the transient receptor potential cation channel subfamily V member 1 (TRPV1) and (TRPV2) channels.²² Furthermore, CBD prevents degradation of anandamide,²² the endogenous ligand that acts at the CB₁ receptor. It is through this mechanism that CBD can exert indirect agonist effects through the CB₁ receptor. Finally, and of interest to nausea and vomiting, CBD also acts at the 5-HT_1A receptor.^23,24 At the 5-HT_1A receptor, CBD may be a positive allosteric modulator as it can enhance direct activation of the 5-HT_1A receptor.^23,24

The acidic precursor of CBD, cannabidiolic acid (CBDA),²⁵ was isolated from cannabis and its structure was reported in 1965.²⁶ CBDA is present in the fresh cannabis plant, particularly in its industrial hemp forms. CBDA gradually undergoes decarboxylation into CBD, with heating or burning of the plant material accelerating this process. Although CBDA has been shown to be more potent than CBD in animal models (reviewed hereunder), its instability²⁷ may make it a less desirable therapeutic. The more stable methyl ester version of CBDA (CBDA-ME or HU-580) has demonstrated superior potency, suggesting it may also be a possible treatment option. Here we review evidence for the effects of CBD (as well as CBDA and CBDA-ME) in alleviating nausea and vomiting, at the in vitro and in vivo levels of study, leading to human case reports.

In Vitro Effects of CBD in the Regulation of Nausea and Vomiting

The classic anti-emetic 5-HT₃ receptor antagonists, such as OND, act by reducing 5-HT transmission. This suggests that other compounds that also act by reducing 5-HT availability may be anti-nausea and/or anti-vomiting treatment candidates. A few in vitro studies examining the effect of CBD on 5-HT receptor binding have aimed to understand how CBD may exert its action to ultimately reduce 5-HT availability.

The effect of CBD on the function of mouse and human 5-HT_3A receptors expressed in frog egg cells indicates that CBD has an inhibitory effect on these receptors, reversing 5-HT-induced currents in a concentration-dependent manner with an IC₅₀=0.6 μM.²⁸ Although CBD did not change the potency of 5-HT, it did reduce its efficacy, suggesting that CBD may be acting as an allosteric modulator of 5-HT₃ receptors. The binding of CBD at the allosteric site of 5-HT₃ receptors would lead to reduced 5-HT signaling (similar to the action of a 5-HT₃ receptor antagonist). This reduction in 5-HT signal may be a mechanism contributing to CBD's anti-nausea and/or anti-vomiting effects.

The 5-HT_1A autoreceptor is another receptor in the 5-HT family that when activated results in decreased 5-HT signaling. These receptors are located on the soma and dendrites of 5-HT neurons where they exert negative feedback on subsequent firing.²⁹ Thus, activation of the 5-HT_1A autoreceptor results in the inhibition of further 5-HT release. Early evidence suggested that CBD (at the rather high concentration of 16 μM) binds to and activates human 5-HT_1A receptors transfected into ovary cells of hamsters.²³ Further examination of CBD at physiologically relevant levels suggested that CBD (100 nM, but not at 10 nM or 1 μM) enhanced the ability of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to stimulate binding in rat brainstem membranes.²⁴ Furthermore, CBD did not have a direct agonist action at the 5-HT_1A receptor, nor did it alter the rate at which 8-OH-DPAT dissociates from specific binding sites in these membranes.²⁴ These findings suggest that CBD may potentiate the action of endogenous 5-HT at the 5-HT_1A receptor, through an indirect mechanism.

In comparison with CBD, CBDA displayed greater potency at enhancing 8-OH-DPAT-induced binding, over a much wider range of concentrations (0.1–100 nM).³⁰ In addition, the more stable methyl ester version of CBDA, CBDA-ME, potently enhanced 8-OH-DPAT-induced binding to human 5-HT_1A receptors (0.01–10 nM).³¹ Of interest, the in vitro effect of CBD (as well as CBDA) has been investigated in cancer cell survival and colony-forming assays, with results suggesting that CBD treatment significantly reduced migration/invasion and viability of cancer cells and actually enhanced the cytotoxicity of anticancer drugs.^32–34 Taken together, these findings suggest that CBD, CBDA, and CBDA-ME may reduce nausea and vomiting through 5-HT_1A receptor activation, enhancing the ability of endogenous 5-HT to bind to these autoreceptors to prevent further 5-HT release. Similarly, in vitro studies suggest that CBD and CBDA may exert positive anticancer effects that may enhance the effectiveness of chemotherapeutic agents.^32–34

In Vivo Effects of CBD in the Regulation of Nausea and Vomiting

CBD's anti-emetic effects

Species capable of vomiting including shrews, ferrets, and cats, are often used in the laboratory to evaluate potential anti-emetic compounds. Common toxin-induced emetic treatments include lithium chloride (LiCl) and the chemotherapeutic agent cisplatin. A summary of CBD's anti-emetic effects in the house musk shrew (Suncus murinus) is given in Table 1.

Table 1.

Summary of in vivo anti-emetic effects of cannabidiol, cannabidiolic acid, and cannabidiolic acid methyl ester

Compound	Dose(s) tested	Effect	Reference
Toxin-induced vomiting
CBD	5, 10 mg/kg (i.p., s.c.)	Reduce	^24,35–37
	5 mg/kg (s.c., daily for 7 days)	Reduce	³⁸
	2.5 mg/kg (i.p.)	No effect	^36,39
	25, 40 mg/kg (i.p.)	Potentiate	^35,36
CBD+THC	2.5 mg/kg CBD +1 mg/kg THC (i.p.)	Reduce	³⁹
CBDA	0.1, 0.5 mg/kg (i.p.)	Reduce	³⁰
CBDA	0.05, 20 mg/kg (i.p.)	No effect	^30,39
CBDA+THC	0.05 mg/kg CBDA +1 mg/kg THC (i.p.)	Reduce	³⁹
CBDA-ME	Not yet evaluated
Motion-induced vomiting
CBD	0.5, 1, 2, 5, 10, 20, and 40 mg/kg (i.p.)	No effect	⁴⁰
CBDA	0.1, 0.5 mg/kg (i.p)	Reduce	³⁰
CBDA	0.02 mg/kg (i.p.)	No effect	³⁰
CBDA-ME	Not yet evaluated

CBD, cannabidiol; CBDA, cannabidiolic acid; CBDA-ME, cannabidiolic acid methyl ester; i.p., intraperitoneal; s.c., subcutaneous; THC, Δ⁹-tetrahydrocannabinol.

In the house musk shrew, CBD produces a biphasic effect, with low doses (5, 10 mg/kg, i.p., s.c.) suppressing,^24,35–37 and high doses (25, 40 mg/kg, i.p.) potentiating^35,36 toxin-induced vomiting. CBD's anti-emetic effects were blocked by a 5-HT_1A receptor antagonist,²⁴ but not by a CB₁ receptor antagonist.³⁶ Of importance, when CBD (5 mg/kg, s.c.) was administered daily for 7 days its anti-emetic efficacy was maintained in S. murinus.³⁸ These findings suggest anti-emetic efficacy of CBD but at a limited dose range.

CBDA (0.1 and 0.5 mg/kg, i.p.) potently reduced toxin-induced vomiting,³⁰ and recent unpublished data demonstrates that higher doses (20 mg/kg, i.p.) do not potentiate LiCl-induced vomiting. The anti-emetic effects of CBDA-ME have not been evaluated in S. murinus. Finally, enhanced anti-emetic effects were observed when an ineffective anti-emetic dose of THC (1 mg/kg, i.p.) was combined with either an ineffective anti-emetic dose of CBD (2.5 mg/kg, i.p.) or CBDA (0.05 mg/kg, i.p.).³⁹ These findings suggest that CBD and CBDA reduce toxin-induced vomiting, likely acting through 5-HT_1A receptors. CBD seems to have a narrow therapeutic window, with low/moderate doses reducing vomiting, but higher doses enhancing toxin-induced vomiting. In contrast, CBDA does not seem to enhance toxin-induced vomiting. This might suggest that lower doses of CBD or CBDA should be used to treat toxin-induced vomiting.

CBD's anti-emetic effects have also been evaluated in motion-induced vomiting in the house musk shrew with CBD (0.5, 1, 2, 5, 10, 20, and 40 mg/kg, i.p.) being ineffective,⁴⁰ but CBDA (0.1 and 0.5 mg/kg, i.p.) effectively reducing vomiting.³⁰ The ability of CBD to suppress toxin-induced but not motion-induced vomiting may be because of differential activation of neuronal pathways involved in emesis or differing degrees of the sickness they produce. Motion may be a more severe illness-inducing agent and may require more potent anti-emetic efficacy such as that offered by CBDA.

CBD's anti-nausea effects

Although rodents lack the vomiting reflex, they receive the same gut-brain signals upon administration of illness-inducing agents (such as LiCl), presumably resulting in nausea,⁴¹ making them a perfect rodent model to study nausea. Parker compiled a plethora of evidence indicating that conditioned gaping in rats—large openings of the mouth and jaw, with exposed lower incisors—first described by Grill and Norgren,⁴² is a selective measure of nausea.⁴³ Conditioned gaping responses are produced only by manipulations that produce vomiting in emetic species and prevented by treatments that reduce nausea and vomiting in other species. Illness-paired flavors can elicit conditioned gaping reactions (a rodent model of acute nausea), as do illness-paired contextual cues (a rodent model of anticipatory nausea).⁴⁴ A summary of CBD's anti-nausea effects in rats is given in Table 2, beginning with the effects in acute nausea, followed by anticipatory nausea.

Table 2.

Summary of in vivo anti-nausea (acute and anticipatory) effects of cannabidiol, cannabidiolic acid, and cannabidiolic acid methyl ester

Compound	Dose(s) tested	Effect	Reference
Acute nausea
CBD	0.5, 1 (i.p.), 2.5 (s.c.), 5 mg/kg (i.p., s.c.)	Reduce	^{24,37,38,45–47}
	5 mg/kg (s.c., daily for 7 days or weekly for 4 weeks)	Reduce	³⁸
	0.1, 20, 40 (i.p.)	No effect	⁴⁷
CBD+THC	0.1 mg/kg CBD +0.1 mg/kg THC (i.p.)	Reduce	⁴⁷
CBD +8-OH-DPAT	0.5 mg/kg CBD +0.005 mg/kg 8-OH-DPAT (s.c.)	Reduce	²⁴
CBDA	0.5, 1, 5, 10, 100 μg/kg (i.p)	Reduce	^30,49
	1 μg/kg (s.c., daily for 7 days or weekly for 4 weeks)	Reduce	³⁸
	2.5, 10, 20 μg/kg (i.g.)	Reduce	⁵⁰
	0.01, 0.1, 500, 5000 μg/kg (i.p); 0.5, 1 μg/kg (i.g.)	No effect	^{14,30,49–51}
CBDA+THC	0.01 μg/kg CBDA +0.01 mg/kg THC, 0.1 μg/kg CBDA +0.1 mg/kg THC (i.p.); 0.5 μg/kg CBDA +0.5 mg/kg THC, 1 μg/kg CBDA +1 mg/kg THC (i.g.)	Reduce	^14,50
CBDA+THCA	0.01 μg/kg CBDA +1 μg/kg THCA (i.p.)	Reduce	⁴⁷
CBDA+OND CBDA+MCP	0.1 μg/kg CBDA + 1 μg/kg OND (i.p.) 0.1 μg/kg CBDA + 0.3 mg/kg MCP (s.c.)	Reduce Reduce	⁴⁹ ⁵¹
CBDA-ME	0.1, 1 μg/kg (i.p.)	Reduce	³¹
	1 μg/kg (s.c., daily for 7 days or weekly for 4 weeks)	Reduce	³⁸
	0.01 μg/kg (i.p.)	No effect	³¹
Anticipatory nausea
CBD	1, 5 mg/kg (i.p.)	Reduce	⁵²
CBD	10 mg/kg (i.p.)	No effect	⁵²
CBDA	1, 10, 100 μg/kg (i.p.); 10 μg/kg (i.g.)	Reduce	^14,30,50,53
CBDA	0.01, 0.1, 1000 μg/kg (i.p.); 0.1, 1, 2.5 μg/kg (i.g.)	No effect	^14,50,53
CBDA+THCA	0.1 μg/kg CBDA +5 μg/kg THCA (i.p.)	Reduce	⁵³
CBDA+THC	0.01 μg/kg CBDA +0.01 mg/kg THC, 0.1 μg/kg CBDA +0.1 mg/kg THC (i.p.) 0.1 μg/kg CBDA +0.1 mg/kg THC, 1 μg/kg CBDA +1 mg/kg THC (i.g.)	No effect Reduce	¹⁴ ⁵⁰
CBDA-ME	0.01, 0.1 μg/kg (i.p.)	Reduce	³¹

8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; i.g., intragastric; MCP, metoclopramide; OND, ondansetron; THCA, tetrahydrocannabinolic acid.

In a rodent model of acute nausea, CBD (5 mg/kg, s.c. or i.p.) reduced conditioned gaping,^{24,37,38,45–47} with similar acute anti-nausea effects reported in male and female rats.³⁸ More recently, a wider therapeutic window for CBD's acute anti-nausea effect was established, ranging from 0.5 to 5 mg/kg (i.p.).⁴⁷ Furthermore, when administered repeatedly (daily for 7 days) or over four weekly treatments, CBD (5 mg/kg, s.c.) maintained its anti-nausea properties.³⁸ This is clinically important as patients undergoing chemotherapy experience multiple sessions and need CBD's effects to be maintained, without the development of tolerance. Of importance, higher doses of CBD (20 and 40 mg/kg, i.p.) do not promote conditioned gaping.⁴⁷ Finally, the combination of an ineffective dose of CBD (0.5 mg/kg, s.c. or 0.1 mg/kg, i.p.) with an ineffective dose of the 5-HT_1A agonist 8-OH-DPAT,²⁴ or an ineffective dose of THC (0.1 mg/kg, i.p.)⁴⁷ resulted in a synergistic suppression of conditioned gaping. These findings indicate that rather low doses of CBD can be coadministered with low doses of other anti-nausea compounds to achieve acute anti-nausea efficacy.

CBD's acute anti-nausea effects likely occur through its action at 5-HT_1A receptors, as CBD's effect is blocked by administration of a 5-HT_1A receptor antagonist.²⁴ Furthermore, injection of CBD (0.21 ng) into the dorsal raphe nucleus (a brain region responsible for the production of forebrain 5-HT and the location of somatodendritic 5-HT_1A autoreceptors) suppressed conditioned gaping, an effect also mediated by the 5-HT_1A receptor.²⁴ The dorsal raphe nucleus projects to the interoceptive insular cortex (IIC), a critical forebrain region implicated in nausea. Administration of illness-inducing LiCl selectively elevates 5-HT in the IIC, with CBD (5 mg/kg, i.p.) reducing this 5-HT elevation.⁴⁸ This suggests that CBD's anti-nausea effect is mediated by its action at 5-HT_1A autoreceptors in the dorsal raphe nucleus to reduce the firing of 5-HT neurons projecting to the IIC. This action prevents the LiCl-induced elevation of 5-HT in the IIC, a trigger for nausea. These results suggest that IIC 5-HT produces the experience of nausea, and CBD may act to reduce it.

In addition, in the acute nausea model, CBDA (0.5, 1, 5, 10, and 100 μg/kg, i.p.) potently reduced conditioned gaping,^30,49 and like CBD, this effect was 5-HT_1A receptor mediated,^14,30 but not CB₁ receptor mediated.³⁰ Oral CBDA (2.5, 10, and 20 μg/kg, i.g.) also reduced conditioned gaping.⁵⁰ When administered daily (for 7 days) or weekly (for four treatments), CBDA (1 μg/kg, s.c.) maintained its anti-nausea efficacy.³⁸ Enhanced anti-nausea effects have been demonstrated with coadministration of an ineffective dose of CBDA (0.1 μg/kg, i.p.) with an ineffective dose of typical anti-emetic drugs such as metoclopramide (an anti-emetic pre-dating the 5-HT₃ receptor antagonists)⁵¹ or a low dose of OND (1.0 μg/kg, i.p.).⁴⁹ Similar synergistic anti-nausea effects with combined ineffective doses of CBDA have also been shown with THC^14,50 and THC's acidic precursor tetrahydrocannabinolic acid (THCA).⁴⁷ As well, CBDA-ME (0.1, 1 μg/kg, i.p.) is more effective than CBDA in reducing acute nausea, also acting through a 5-HT_1A receptor mechanism,³¹ with repeated daily dosing and weekly dosing (1 μg/kg, s.c.), maintaining its anti-nausea efficacy.³⁸ Together, these findings suggest that CBD, and more potently CBDA and CBDA-ME, reduce acute nausea, likely by preventing the elevation of nausea-inducing 5-HT in the IIC. Of importance, this acute anti-nausea effect is maintained over repeated dosing, without the development of tolerance.

In a rodent model of anticipatory nausea, CBD (1, 5 mg/kg, i.p.) reduced,⁵² and CBDA (1, 10, 100 μg/kg, i.p.; 10 μg/kg i.g.) more potently reduced contextually elicited conditioned gaping.^14,30,50,53 Even at the extremely low dose of 0.01 μg/kg (i.p.), CBDA-ME effectively reduced anticipatory nausea³¹ demonstrating its potency. The anti-nausea effects of CBDA and CBDA-ME were blocked by a 5-HT_1A receptor antagonist.^30,31 Combined ineffective doses of CBDA with THC or THCA enhanced the suppression of anticipatory nausea.^14,50,53

Together, the anti-nausea effects of CBD, with increased efficacy for CBDA (and even more so for CBDA-ME) suggest that these compounds may be effective therapeutics for oncology patients experiencing acute or anticipatory nausea. Of particular importance is their ability to reduce anticipatory nausea, as there are currently no specific treatments for this condition. Extremely low doses of CBD (and CBDA) can be combined with other anti-emetic compounds for synergistic suppression of nausea. These positive in vivo findings demonstrate the need for human clinical trials assessing the anti-nausea/anti-emetic effects of CBD, CBDA, and CBDA-ME.

Effects of CBD in Human Chemotherapy-Induced Nausea and Vomiting

Anecdotal reports from oncology patients about the benefits of smoking cannabis to manage their nausea and vomiting compelled oncologists to examine its efficacy. Cannabis use before a chemotherapy appointment has been reported to be useful in managing anticipatory nausea.⁵⁴ Numerous recent meta-analyses and systematic reviews^55–57 concluded that in comparison with placebo, dronabinol and nabilone were superior, and in comparison with the early anti-emetics, they are just as effective or superior in managing chemotherapy-induced nausea and vomiting.

To date, no published studies have evaluated the anti-nausea/anti-emetic effects of CBD in oncology patients, although two promising clinical trials are currently underway (www.clinicaltrials.gov). A randomized, double-blind, placebo-controlled study (NCT03948074) by Pippa Hawley at the British Columbia Cancer Agency will investigate the use of cannabis oil extracts (high THC/low CBD, low THC/high CBD, equal amounts THC/CBD) for symptom management (nausea, pain, anxiety, and sleep disturbance) in cancer patients. As well, a study by Jens Rikardt Andersen at the University of Copenhagen is currently recruiting cancer patients (NCT04585841) to monitor the effects of CBD on lean body mass during chemotherapy. Among the outcome measures are self-reported changes in nausea and emesis. These studies will be critical in gaining more knowledge about CBD's effects in oncology patients.

A single case report has examined the effect of adjunct CBD treatment (100–450 mg/day, oral capsule, for 2 years) in two male patients with gliomas who underwent chemotherapy and radiation.⁵⁸ During their treatment period, the patients reported few symptoms of nausea and showed no evidence of disease progression for at least 2 years, nor did they develop any significant alterations in blood counts/plasma biochemistry. Although these results seem promising, future randomized placebo-controlled trials with a larger number of patients are needed to confirm the beneficial effects of CBD in cancer patients.

Does CBD Produce Vomiting?

Paradoxically, vomiting is an adverse effect that can be associated with CBD treatment in animals and humans, although it often cannot be verified that the product does not contain some THC or other contaminants. The few canine and cat studies that have reported adverse effects of CBD treatment do indicate vomiting in 0.45–20% of healthy animals, although it is unclear whether this was a single episode or multiple occasions of vomiting.^59,60 In an open-label study of 607 patients with treatment-resistant epilepsies, no vomiting was reported in those treated with the lowest dose of purified CBD (100 mg/mL) in oral solution (Epidiolex; 2–10 mg/kg/day) as an adjunct, whereas increased incidences of vomiting were reported at higher doses (>40 mg/kg/day),⁶¹ suggesting a dose-dependent effect, although it is difficult to determine that the vomiting exhibited in these patients was not simply a consequence of the oral solution vehicle. Because patients also continue taking other anti-epileptic medications during these trials, it is difficult to determine if high doses of CBD are producing vomiting or whether this is an effect of an interaction with an adjunct treatment. A recent meta-analysis of the adverse events associated with CBD treatment in randomized clinical trials (12 trials contributed data from 803 participants) determined there was no significant increased odds of experiencing nausea or vomiting in those treated with CBD, relative to placebo.⁶² Properly randomized placebo-controlled trials are needed to evaluate whether CBD or its analogs specifically suppresses nausea and vomiting in people.

Cannabinoid Hyperemesis Syndrome and Potential Relief by CBD

In some individuals, prolonged use of cannabis may induce cannabinoid hyperemesis syndrome.⁶³ Cannabinoid hyperemesis syndrome patients present with cyclical episodes of nausea, vomiting, and severe abdominal pain. For a recent review see DeVuono and Parker.⁶⁴ Although the incidence is unknown, and may very well be underreported, Habboushe et al.⁶⁵ reported that 33% of chronic cannabis smokers from a New York City hospital reported experiencing some symptoms of cannabinoid hyperemesis syndrome.

Typical anti-emetic drugs are ineffective,⁶⁶ but topical capsaicin cream (made of the chemical in chili peppers) applied to the abdomen⁶⁷ and hot showers are treatments that provide some relief for patients.⁶⁸ The dysregulation of TRPV1 receptors may be one contributing factor, given that hot showers and capsaicin activate these receptors^66,69 and help to manage symptoms. Of interest, CBD activates and desensitizes TRPV1.⁷⁰ This suggests that CBD may be a potential treatment for cannabinoid hyperemesis syndrome. Indeed, in a preclinical study with rats, CBD reduced the nausea-induced conditioned gaping reactions and increase in plasma levels of the stress hormone corticosterone produced by a high dose (10 mg/kg, i.p.) of THC.⁷¹ Thus, smoking cannabis strains with higher CBD content (and therefore lower THC content) may prevent this syndrome from occurring or help to manage its symptoms. Further research is needed to understand the consequences of high-dose cannabis use and the therapeutic role that CBD may play.

Concluding Remarks

Vomiting and especially nausea are symptoms that are not effectively managed, and oncology patients deserve better treatments. In vitro and in vivo evidence suggests that like classic anti-emetic compounds, CBD, CBDA, and CBDA-ME act to reduce illness-inducing 5-HT through action at the 5-HT_1A receptor. Furthermore, CBD and CBDA may themselves have beneficial effects on cancer cell migration and survival and synergize with chemotherapeutic agents.

Although CBD seems to have a narrow therapeutic window for its toxin-induced anti-emetic effects in shrews, with higher doses promoting toxin-induced vomiting, the more potent CBDA does not. In fact, CBDA is effective in reducing motion-induced vomiting, whereas CBD is not. Furthermore, coadministration of low doses of CBD or CBDA with other anti-emetic agents may be an effective anti-emetic strategy, although no such studies have been conducted with motion-induced vomiting. In addition, repeated daily dosing of CBD seems to maintain its anti-emetic efficacy, but this has not been extended to CBDA or CBDA-ME. Future studies should examine CBDA-ME's anti-emetic properties.

CBD reduces acute nausea (at a wide range of doses and does not promote nausea at higher doses) and anticipatory nausea in rats. CBDA and CBDA-ME potently reduce acute and anticipatory nausea in rats. Preclinical evidence also suggests that low doses of CBD and CBDA can be combined with other anti-emetic compounds and synergistically reduce acute and anticipatory nausea, but this has not been explored with CBDA-ME. This coadministration of low doses is an important therapeutic advantage, as lower doses of these drugs are less likely to result in adverse side-effects.

Only one case report has assessed the effect of CBD on two patients who were undergoing chemotherapy and radiation, with favorable anti-nausea effects. These promising results should be cautiously interpreted, as randomized placebo-controlled trials are still needed. Ongoing clinical trials with CBD treatment will help to further inform these preliminary findings. Finally, CBD may be a potential treatment for cannabinoid hyperemesis syndrome, characterized by cyclical episodes of nausea and vomiting in high THC content chronic cannabis users. These promising anti-nausea and anti-emetic effects of CBD need to be further explored in properly controlled clinical trials with oncology patients.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

L.A.P. is supported by research grants from the Natural Sciences and Engineering Research Council of Canada (NSERC-03629) and the Canadian Institutes of Health Research (CIHR-388239).

Abbreviations Used

References

Navari

, Aapro

. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016; 374:1356–1367.

Fernández-Ortega

, Caloto

, Chirveches

, et al. Chemotherapy-induced nausea and vomiting in clinical practice: impact on patients' quality of life. Support Care Cancer. 2012; 20:3141–3148.

Hesketh

PJ.

Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008; 358:2482–2494.

Morrow

, Roscoe

, Kirshner

, et al. Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer. 1998; 6:244–247.

Hornby

PJ.

Central neurocircuitry associated with emesis. Am J Med. 2001; 111(Suppl 8A):106S–112S.

Tavorath

, Hesketh

. Drug treatment of chemotherapy-induced delayed emesis. Drugs. 1996; 52:639–648.

Hesketh

, Bohlke

, Kris

. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update Summary. J Oncol Pract. 2017; 13:825–830.

Hickok

, Roscoe

, Morrow

, et al. Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics: a University of Rochester James P. Wilmot Cancer Center Community Clinical Oncology Program Study of 360 cancer patients treated in the community. Cancer. 2003; 97:2880–2886.

Poli-Bigelli

, Rodrigues-Pereira

, Carides

, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003; 97:3090–3098.

10.

Navari

RM.

5-HT3 receptors as important mediators of nausea and vomiting due to chemotherapy. Biochim Biophys Acta. 2015; 1848:2738–2746.

11.

Sepúlveda-Vildósola

, Betanzos-Cabrera

, Lastiri

, et al. Palonosetron hydrochloride is an effective and safe option to prevent chemotherapy-induced nausea and vomiting in children. Arch Med Res. 2008; 39:601–606.

12.

Maida

, Daeninck

. A user's guide to cannabinoid therapies in oncology. Curr Oncol. 2016; 23:398–406.

13.

Fogel

, Kelly

, Westgate

, et al. Sex differences in the subjective effects of oral Δ(9)-THC in cannabis users. Pharmacol Biochem Behav. 2017; 152:44–51.

14.

Rock

, Limebeer

, Parker

. Effect of combined doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea using rat (Sprague-Dawley) models of conditioned gaping. Psychopharmacology (Berl). 2015; 232:4445–4454.

15.

DeVuono

, Hrelja

, Sabaziotis

, et al. Conditioned gaping produced by high dose Δ(9)-tetrahydracannabinol: dysregulation of the hypothalamic endocannabinoid system. Neuropharmacology. 2018; 141:272–282.

16.

Adams

, Hunt

, Clark

. Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. I. J Am Chem Soc. 1940; 62:196–200.

17.

Mechoulam

, Shvo

, Hashish

. The structure of cannabidiol. Tetrahedron. 1963; 19:2073–2078.

18.

Crippa

, Guimarães

, Campos

, et al. Translational investigation of the therapeutic potential of cannabidiol (CBD): toward a new age. Front Immunol. 2018; 9:2009.

19.

Thomas

, Baillie

, Phillips

, et al. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007; 150:613–623.

20.

Laprairie

, Bagher

, Kelly

, et al. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015; 172:4790–4805.

21.

Pertwee

RG.

The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008; 153:199–215.

22.

Bisogno

, Hanus

, De Petrocellis

, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001; 134:845–852.

23.

Russo

, Burnett

, Hall

, et al. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005; 30:1037–1043.

24.

Rock

, Bolognini

, Limebeer

, et al. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-T(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br J Pharmacol. 2012; 165:2620–2634.

25.

Potter

, Clark

, Brown

. Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci. 2008; 53:90–94.

26.

Mechoulam

, Gaoni

. Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron. 1965; 21:1223–1229.

27.

Crombie

, Crombie

WML

. Cannabinoid acids and esters: miniaturized synthesis and chromatographic study. Phytochemistry. 1977; 16:1413–1420.

28.

Yang

, Galadari

, Isaev

, et al. The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. J Pharmacol Exp Ther. 2010; 333:547–554.

29.

Blier

, Pineyro

, el Mansari

, et al. Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission. Ann N Y Acad Sci.1998;861:204–216.

30.

Bolognini

, Rock

, Cluny

, et al. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol. 2013; 168:1456–1470.

31.

Pertwee

, Rock

, Guenther

, et al. Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5-HT1A receptor-mediated suppression of nausea and anxiety in rats. Br J Pharmacol. 2018; 175:100–112.

32.

, Kim

, et al. Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020; 10:20622.

33.

Henry

, Shoemaker

, Prieto

, et al. The effect of cannabidiol on canine neoplastic cell proliferation and mitogen-activated protein kinase activation during autophagy and apoptosis. Vet Comp Oncol. 2020:e12669.

34.

Takeda

, Okajima

, Miyoshi

, et al. Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration. Toxicol Lett. 2012; 214:314–319.

35.

Kwiatkowska

, Parker

, Burton

, Mechoulam

. A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the Suncus murinus (house musk shrew). Psychopharmacology (Berl). 2004; 174:254–259.

36.

Parker

, Kwiatkowska

, Burton

, et al. Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew). Psychopharmacology (Berl). 2004; 171:156–161.

37.

Rock

, Goodwin

, Limebeer

, et al. Interaction between non-psychotropic cannabinoids in marihuana: effect of cannabigerol (CBG) on the anti-nausea or anti-emetic effects of cannabidiol (CBD) in rats and shrews. Psychopharmacology (Berl). 2011; 215:505–512.

38.

Rock

, Sullivan

, Collins

, et al. Evaluation of repeated or acute treatment with cannabidiol (CBD), cannabidiolic acid (CBDA) or CBDA methyl ester (HU-580) on nausea and/or vomiting in rats and shrews. Psychopharmacology (Berl). 2020; 237:2621–2631.

39.

Rock

, Parker

. Synergy between cannabidiol, cannabidiolic acid, and Delta(9)-tetrahydrocannabinol in the regulation of emesis in the Suncus murinus (house musk shrew). Behav Neurosci. 2015; 129:368–370.

40.

Cluny

, Naylor

, Whittle

, et al. The effects of cannabidiol and tetrahydrocannabinol on motion-induced emesis in Suncus murinus. Basic Clin Pharmacol Toxicol. 2008; 103:150–156.

41.

Billig

, Yates

, Rinaman

. Plasma hormone levels and central c-Fos expression in ferrets after systemic administration of cholecystokinin. Am J Physiol Regul Integr Comp Physiol. 2001; 281:R1243–R1255.

42.

Grill

, Norgren

The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. Brain Res.1978;143:263–279.

43.

Parker

LA.

Conditioned flavor avoidance and conditioned gaping: rat models of conditioned nausea. Eur J Pharmacol. 2014; 722:122–133.

44.

Limebeer

, Krohn

, Cross-Mellor

, et al. Exposure to a context previously associated with nausea elicits conditioned gaping in rats: a model of anticipatory nausea. Behav Brain Res. 2008; 187:33–40.

45.

Parker

, Mechoulam

, Schlievert

. Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport. 2002; 13:567–570.

46.

Parker

, Mechoulam

. Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats. Integr Physiol Behav Sci. 2003; 38:133–145.

47.

Rock

, Sullivan

, Pravato

, et al. Effect of combined doses of Δ(9)-tetrahydrocannabinol and cannabidiol or tetrahydrocannabinolic acid and cannabidiolic acid on acute nausea in male Sprague-Dawley rats. Psychopharmacology (Berl). 2020; 237:901–914.

48.

Limebeer

, Rock

, Sharkey

, et al. Nausea-induced 5-HT release in the interoceptive insular cortex and regulation by monoacylglycerol lipase (MAGL) inhibition and cannabidiol. eNeuro. 2018; 5:ENEURO.0256-18.2018.

49.

Rock

, Parker

. Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats. Br J Pharmacol. 2013; 169:685–692.

50.

Rock

, Connolly

, Limebeer

, et al. Effect of combined oral doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea in rat models. Psychopharmacology (Berl). 2016; 233:3353–3360.

51.

Rock

, Parker

. Suppression of lithium chloride-induced conditioned gaping (a model of nausea-induced behaviour) in rats (using the taste reactivity test) with metoclopramide is enhanced by cannabidiolic acid. Pharmacol Biochem Behav. 2013; 111:84–89.

52.

Rock

, Limebeer

, Mechoulam

, et al. The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat. Psychopharmacology (Berl). 2008; 196:389–395.

53.

Rock

, Limebeer

, Navaratnam

, et al. A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping. Psychopharmacology (Berl). 2014; 231:3207–3215.

54.

Wilkie

, Sakr

, Rizack

. Medical marijuana use in oncology: a review. JAMA Oncol. 2016; 2:670–675.

55.

Whiting

, Wolff

, Deshpande

, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015; 313:2456–2473.

56.

Tramér

, Carroll

, Campbell

, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ. 2001; 323:16–21.

57.

Machado Rocha

, Stefano

, De Cassia Haiek

, et al. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care. 2008; 17:431–443.

58.

Dall'Stella

, Docema

MFL

, Maldaun

MVC

, et al. Case report: clinical outcome and image response of two patients with secondary high-grade glioma treated with chemoradiation, PCV, and cannabidiol. Front Oncol. 2019; 8:643.

59.

Deabold

, Schwark

, Wolf

, et al. Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp nutraceutical in healthy dogs and cats. Animals (Basel). 2019; 9:832.

60.

McGrath

, Bartner

, Rao

, et al. A report of adverse effects associated with the administration of Cannabidiol in healthy dogs. J Am Holistic Vet Med Assoc. 2018; 52:34–38.

61.

Szaflarski

, Bebin

, Comi

, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018; 59:1540–1548.

62.

Chesney

, Oliver

, Green

, et al. Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology. 2020; 45:1799–1806.

63.

Allen

, de Moore

, Heddle

, et al. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut. 2004; 53:1566–1570.

64.

DeVuono

, Parker

. Cannabinoid hyperemesis syndrome: a review of potential mechanisms. Cannabis Cannabinoid Res. 2020; 5:132–144.

65.

Habboushe

, Rubin

, Liu

, et al. The prevalence of cannabinoid hyperemesis syndrome among regular marijuana smokers in an urban public hospital. Basic Clin Pharmacol Toxicol. 2018; 122:660–662.

66.

Richards

, Gordon

, Danielson

, et al. Pharmacologic treatment of cannabinoid hyperemesis syndrome: a systematic review. Pharmacotherapy. 2017; 37:725–734.

67.

Dezieck

, Hafez

, Conicella

, et al. Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series. Clin Toxicol. 2017; 55:908–913.

68.

Wallace

, Martin

A-L

, Park

. Cannabinoid hyperemesis: marijuana puts patients in hot water. Australas Psychiatry. 2007; 15:156–158.

69.

Rudd

, Nalivaiko

, Matsuki

, et al. The involvement of TRPV1 in emesis and anti-emesis. Temperature. 2015; 2:258–276.

70.

De Petrocellis

, Ligresti

, Moriello

, et al. Effects of cannabinoids and cannabinoid-enriched cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011; 163:1479–1494.

71.

DeVuono

, La Caprara

, Petrie

, et al. Cannabidiol interferes with establishment of Δ9-tetrahydrocannabinol-induced nausea through a 5-HT 1A mechanism. Cannabis Cannabinoid Res. 2020. [Epub ahead of print]; DOI: 10.1089/can.2020.0083.