Specific Medicinal Uses of Cannabis: Use as an Antiemetic

2015

Many agents used in cancer chemotherapy produce severe nausea and vomiting in most patients. Symptoms can last for hours or days and have a major impact on patient nutrition and electrolyte status, body weight and physical and mental resilience to both the disease and its treatment. The current choice of available anti-emetics is limited and most are only partially effective, which may lead patients to refuse therapy all together, or for clinicians to use chemotherapeutic regimens which are less than optimum. For these reasons, the search for more effective antiemetics continues.

Cannabis

In the late 1960s and early 1970s, patients receiving various cancer chemotherapy regimes (including mustine, vincristine, prednisone and procarbazine) noted that smoking cannabis from illicit sources, before and during chemotherapy, reduced the incidence of nausea and vomiting to a variable degree. Only since the isolation of THC have formal clinical trials on the safety and efficacy of cannabis derivatives been conducted. As far as crude cannabis is concerned, we have only anecdotal evidence that inhaling its smoke is effective in a variable percentage of patients who vomit, despite supposedly adequate doses of standard antiemetics.

There is a growing population who, with or without the approval of their doctors, smoke cannabis to combat the emetogenic effects of cancer chemotherapy. The results of questionnaire surveys of oncologists’ attitudes to this use have been ambiguous. In a survey of US oncologists (Doblin and Kleiman, 1991), 44% said that they had recommended cannabis to at least one of their patients and 48% said that they would prescribe cannabis if it were legal to do so. Many of the respondents believed that smoking cannabis was more effective than using orally administered ‘synthetic’ cannabinoids. However, these findings were subject to response bias and were certainly not supported by a later and more credible US study where, in a survey of clinical oncologists’ prescribing habits, although 65% reported having prescribed marijuana or oral THC, prescribing rates were extremely low, relative to other antiemetics.

Cannabis ranked ninth behind established antiemetics for treating mild/moderate chemotherapy induced nausea and vomiting and sixth, behind metoclopramide, lorazepam, corticosteroids, prochlorperazine and promazine, for the treatment of severe vomiting; 3.5% had prescribed marijuana more than 100 times. Those who had prescribed cannabis thought that it had been effective in 50% of patients but that 25% of patients had experienced unpleasant side effects. Just 6% of respondents said that they would prescribe cannabis much more frequently if there were no legal barriers to its medicinal use; 76% said that they would not prescribe cannabis more frequently if legal restrictions were eased.

THC

Clinical trials with cannabinoids were encouraged by anecdotal reports of decreased emesis in younger patients who smoked marijuana when receiving their chemotherapy and North American states had by 1985, enacted legislation to allow the creation of medical research programs on cannabis and its constituents.

On September 10, 1980, the US Surgeon General announced that ‘synthetic’ THC capsules were approved by the FDA, permitting use by up to 4000 cancer specialists to treat cancer chemotherapy-induced nausea and vomiting.

Most studies investigating the antiemetic efficacy of cannabinoids have involved THC or nabilone. Detailed reviews of these studies appear elsewhere. A summary of the salient features of trials with THC, involving a total of 1001 evaluable patients appears in Table Summary of clinical trials investigating THC as an antiemetic for cancer chemotherapyinduced nausea and vomiting.

The earliest study involving THC was that reported by Sallan et al. (). Oral THC was compared to placebo in 22 patients. No antiemetic effect was noted for the placebo, but several complete and partial responses were noted in those given THC, which was found to be statistically superior. The most frequent side effect was somnolence in two thirds of patients; ten suffered brief periods of dysphoria. The characteristic cannabis ‘high’ was seen in patients taking THC, but was positively associated with its antiemetic effect.

Chang et al. () compared THC with placebo in 15 patients receiving high dose methotrexate for osteogenic sarcoma. The problem of subjects vomiting their orally administered treatment was circumvented by supplementing it with cigarettes containing THC or placebo. THC was found to be superior to placebo, providing “substantial therapeutic benefit and minimal toxicity”. Efficacy could be related to THC blood levels — at THC levels of 10 ng/ml, the incidence of nausea and vomiting was 6%. THC was not so effective in five patients who received adriamycin plus cylophosphamide. Somnolence, tachycardia and orthostatic hypotension were observed, together with a low incidence (2% of all THC doses) of dysphoric reactions.

It is of significance that the authors were able to demonstrate superiority of THC over placebo in patients receiving methotrexate; however they could not demonstrate a difference in a later study where more emotogenic agents (cyclophosphamide, doxorubicin) were used. A reduction in antiemetic response was observed in several patients who continued to receive THC after the trial had ended; but it was not possible to determine if this was due to tolerance, normal variation in response to chemotherapy or the development of anticipatory nausea and vomiting.

Sallan et al. () compared THC with prochlorperazine in 84 cancer patients, 82 of which were refractory to standard antiemetic drugs. THC was described as completely effective in 36 of 79 courses; in comparison, prochlorperazine was only as effective in 16 of 78 courses. Younger patients appeared to respond better than older patients. Of 25 patients who were treated with both drugs and who expressed a preference, 20 preferred THC. Increased food intake occurred more frequently with THC. The only reactions to THC were somnolence and a high associated with the beneficiai effects of THC; four patients developed highs described as “excessive”.

Lucas and Laszlo tested oral THC in 53 patients, refractory to standard antiemetics. A response rate of 72% was obtained (19% complete and 53% partial). A dose of 15 mg/m2 produced dysphoric reactions in 3 of 9 patients. It was found that this effect could be avoided, whilst maintaining antiemetic efficacy at a dose of 5 mg/m2; somnolence and dry mouth were observed at this dose.

It is clear from these studies that the effect of THC was reproducible in individual patients upon repeat courses of the same chemotherapy and that there was no tachyphylaxis. The dependency of the degree of response to THC on the nature of the chemotherapy used was illustrated by the fact that of 21 patients who failed to derive relief from THC, 11 were receiving the highly emetogenic cisplatin in combination with other agents. In contrast, THC was effective in patients given high-dose intravenous infusions of carmustine or cyclophosphamide — both experimental regimes, characteristically associated with a high incidence of nausea and vomiting.

Orr et al. () compared the antiemetic efficacy of THC to prochlorperazine and placebo in 55 patients, described as refractory to conventional antiemetic therapy. Of the 55 patients, only 3 actually vomited whilst taking THC and 12 felt nauseous. With prochlorperazine, the corresponding figures were 18 and 29 respectively. Both treatments were considered to be superior to placebo. In the THC group, reported ‘highs’ were described as being favourably related to the antiemetic effect. Loss of physical control, possibly ataxia, was reported in an unspecified number of patients and dysphoric reactions were observed in two patients; these responded to tranquilliser therapy.

Ungerleider et al. () found THC to be as effective as prochlorperazine in the reduction of nausea and vomiting associated with cancer chemotherapy in a randomised, double-blind, crossover study in 214 patients. The same group gathered data on patient preferences in 139 of these patients in order to determine the relative influence of perceived efficacy and side effect profile. Nausea reduction was the main determinant of preference. Suprisingly, preference for THC was associated with an increased level of side effects, notably sedation; the latter may reflect the patients’ desire for sedation during chemotherapy. Subjects who reported being anxious or depressed prior to therapy did not experience accentuation as a result of either regime and there was no difference in the numbers of patients preferring THC in age groups above or below 50 years. The common assumptions that THC was contraindicated in older, cannabis-naive patients or indeed, those who are anxious and depressed, were not supported by this study.

Ekert et al. () compared the efficacy of THC versus metoclopramide in a double-blind, parallel group, trial in 19 children, 5–19 years old, receiving a wide range of chemotherapies, including high-dose methotrexate. The incidence of both nausea and vomiting was significantly reduced with THC compared with metoclopramide. Similar results were obtained in a subgroup of eight children where crossover of antiemetic drugs was possible. THC was also shown to be superior to prochlorperazine in a paediatric population, both when the drugs were given double-blind to parallel groups (18 episodes each) or in crossover fashion in seven children. By no means all children obtained relief with THC in these trials. Somnolence was observed after THC; one patient had a dysphoric reaction and another reported agitation, anxiety and bad dreams. This is interesting; although it has been argued that the brain receptor(s) responsible for these effects are less well-developed in children and therefore that THC may be used in higher doses to prevent vomiting, it appears that the central side effects cannot be avoided completely.

Combinations of standard antiemetics are commonly used in refractory patients and it seems logical that THC should also be investigated in this respect. Garb et al. () combined THC with prochlorperazine or thiethylperazine. Eight of 10 patients responded better to the combination of actives compared with a placebo-phenothiazine combination. In a second study, the dose of THC was escalated to a maximum ‘of 120mg/day, in combination with phenothiazine according to the following schedule: THC up to 40 mg/day combined with equal doses of phenothiazine; 7–9 mg increases of phenothiazine were given for each step increase of 5 mg THC. A mean protection rate of 83% was achieved among 24 evaluable patients. At lower doses of THC, the degree of protection was dependent on the nature of the cancer chemotherapy; THC was effective against cyclophosphamide and adriamycin but higher doses were needed against nitrogen mustard, dacarbazine, actinomycin D and cisplatin. It was suggested that the phenothiazine component protected against the development of a THC ‘high’. Two patients did develop dysphoria, managed with additional phenothiazine. Drowsiness was a major side effect; other reactions were confusion, orthostatic hypotension, decreased concentration, anxiety and hallucinations.

Lane et al. () studied 55 patients with a variety of tumors who were randomised in a placebo-controlled, parallel-group trial, to receive THC 10mg, prochlorperazine 10mg, or a combination of the two, four times a day when receiving a range of cancer chemotherapies, with the exception of high-dose cisplatin. Side effects, primarily related to the CNS, were more common in the THC-only group. The antipsychotic effect of prochlorperazine may have decreased the incidence and severity of the psychrotropic effects of THC. The THC — prochlorperazine combination was superior to each agent alone in terms of reducing the median duration and severity of nausea and in comparison with prochlorperazine, the mean duration of vomiting.

Not every trial has demonstrated a favourable profile for THC as an antiemetic. Frytak et al. () conducted a placebo controlled comparison of THC and prochlorperazine in 116 patients with gastrointestinal carcinoma, treated with either 5-fluorouracil plus methyl-lomustine or vincristine, adriamycin and an investigational compound, ICRF-159. Nausea and vomiting were suppressed in 42% of patients in both the THC and prochlorperazine groups; the corresponding figure for the placebo group was 19%. Thirty-two percent of patients in the THC group had dose-limiting toxicity, which included ataxia, hypotension, visual hallucinations, blurred vision, muddled thinking, paresthesias, faecal incontinence and dysphoria. In this study of generally older patients, fewer subjective side effects were seen with the phenothiazine and it was the preferred treatment over THC. Elderly patients may be less willing to accept the adverse effects associated with THC or may metabolise the drug differently.

In other trials, THC was found to be as effective as metoclopramide or thiethylperazine, but with a significantly greater incidence of side effects (); to the extent that the authors could not recommend the drug for routine use as an adjunct to cancer chemotherapy. Neidhart et al. () reported similar antiemetic efficacy for THC and haloperidol; but again, more side effects were noted with THC.

Gralla et al. () conducted a randomised clinical trial of THC versus high-dose metoclopramide in patients receiving their first dose of cisplatin (120mg/ m2 over 20 minutes). The first cisplatin dose was chosen to avoid the possibility of conditioned emesis. Metoclopramide was significandy superior to THC in reducing the number of emetic episodes and the percentage of patients receiving major emesis support over the 24-hour observation period. Also the volume of vomit and duration of nausea and vomiting were less with metoclopramide. However, over one quarter of the patients taking THC showed a major antiemetic effect for the drug. Interestingly, THC appeared to be effective in combating cisplatin-induced diarrhoea — a traditional indication for cannabis!

Kluin-Neleman et al. () compared the use of THC with placebo in a small group of patients receiving a combination of nitrogen mustard, vincristine, procarbazine and prednisone. THC had appreciable antiemetic efficacy, but there was a high incidence of serious side effects, including somnolence, dizziness, depersonalisation and derealisation; mania was triggered in one patient. Although a direct relationship between either antiemetic effect or side effects and THC blood level was not established, the increased incidence of side effects was explained by the high blood levels of THC measured in this trial — several hundred ng/ml, compared with an accepted therapeutic level of 10ng/ml. These may have been produced by allowing patients a second dose of THC if they vomited after the first.

Data from an uncontrolled, open-label trial by Stanton suggest that 5.0 and 7.5mg/m2 doses of THC given every 4 hours, during a variety of cancer chemotherapy regimens, were equipotent in terms of antiemetic efficacy but that side effects (mainly sedation) were less with the lower dose.

In an interesting footnote study, Ungerleider et al. () reported a randomised, double-blind, crossover comparison of THC (7.5–12.5 mg, every 4 hours, three times a day) with prochlorperazine, 10mg, on the same schedule, in 11 patients with various cancers requiring radiotherapy of the abdomen. Drug administration coincided with the five day per-week radiotherapy schedule. Four patients withdrew from the trial, including two who had dizziness and depersonalisation after THC and one who experienced excessive nausea and vomiting. Five of the remaining 7 patients had previous experience with marijuana. Patients were asked to rate the severity of their illness, as well as the extent of their subsequent moods, their level of concentration, their amount of physical activity and their desire for social interaction. They chose the drug they preferred and recorded its side effects. Improved alleviation of nausea and vomiting was noted in 4 patients taking THC and 3 taking prochlorperazine; but the difference between drugs was not significant. Significant differences in favour of THC were a reduction in appetite suppression and ability to concentrate. Side effects noted with THC included somnolence, dizziness, dry mouth, increased heart rate and dysphoria. The authors concluded that based on all the psychological and physiological parameters assessed, THC was slightly more advantageous than prochlorperazine.

Plasse et al. () conducted a meta-analysis of 454 patients from published clinical trials reporting the efficacy and side effects of THC as a function of dose. Drowsiness and other, non-psychotropic symptoms were as common in patients receiving oral doses of less than or equal to 7 mg/m2 as in those receiving a greater dose. The incidence of dysphoric effects was only 12% in the low dose group compared to 28% in the high dose group; a corresponding reduction of efficacy with dose was not observed. The authors concluded that a relatively low dose of THC could minimise side effects while preserving efficacy.

In all of the studies, patients were receiving chemotherapy for a variety of solid tumours and haematological dyscrasias. Usual doses of THC ranged from 5–15 mg/ m2, given at fixed time intervals, prior to, during and after chemotherapy. When given with a phenothiazine, it was possible to give higher doses without severe toxicity, including the characteristic high. Of the comparative studies carried out, there was only one study in which THC did not have an effect which was superior to prochlorperazine. Regelson et al. () have pointed out that the drug not only reduces nausea and vomiting, but can improve appetite and mood in nutritionally depleted cancer patients.

All of the studies in Table Summary of clinical trials investigating THC as an antiemetic for cancer chemotherapyinduced nausea and vomiting reported some degree of efficacy for oral THC as an antiemetic, even where the level of toxicity was considered to be unacceptable. The incidence and severity of dysphoria observed in some cases is worrying although in those patients with refractory nausea and vomiting, attempts to manage dysphoria, either by psycho — or pharmacotherapy may reduce this reaction to an acceptable risk level. Hypotension, ataxia and tachycardia may be manageable by THC dose reduction.

Penta et al. () have reviewed the side effect profile of THC in a collection of the clinical trials summarised in Table Summary of clinical trials investigating THC as an antiemetic for cancer chemotherapyinduced nausea and vomiting; the effects they describe as frequent, include somnolence (31%), dry mouth (9.1%), ataxia (8.2%), dizziness (6.1%), dysphorias (5.8%) and orthostatic hypotension (3.6%). Infrequent toxicities associated with the use of THC were: visual distortions/hallucinations (1.8%), confusion (0.9%), muddled thinking (0.6%), paresthesias (0.6%), amnesia (0.3%), syncope (0.3%), slurred speech (0.3%) and faecal incontinence (0.3%). The nature of this side effect profile is not dissimilar to that of other cannabinoids when used under the same conditions.

It has been suggested that younger patients are less susceptible to developing side effects compared with older subjects (); this may be because older subjects are not first-time users and have developed some tolerance to the side effects. Another reason may be that brain cannabinoid receptors associated with CNS side effects are not so well-developed in children and therefore the effects are less pronounced.

So although the side effect profile of THC is notable, it is manageable, and it may still be an attractive alternative to intractable nausea and vomiting; however there are additional problems with its use.

Firstly, response does appear to be related to the emetogenicity of the chemotherapeutic agents used, with high dose methotrexate, doxorubicin and cyclophosphamide/fluorouracil combinations responding better than nitrosourea, mustine or cisplatin.

Secondly, THC is usually given, formulated in sesame seed oil, in gelatin capsules. Oral bioavailability is known to be low (5–10% only) and unpredictable. This may have led to the wide range of efficacies observed in clinical trials. Indeed, this may be the reason why patients have been reported to derive faster and more predictable relief from smoking cannabis. Thirdly, because of the abuse potential of this agent, secure storage, prescription and dispensing procedures are required. Finally, it is clear that there are certain groups of patients in whom THC is contraindicated. Those patients with epilepsy; cardiovascular disorders; mental disorders (); and children — where THC can cause neurohormonal regulatory disorders.

In conclusion, THC appears to be a useful drug in sub-sets of patients where the only alternative is the misery of intractable chemotherapy-induced nausea and vomiting and where the stakes of non-compliance with chemotherapy are high indeed. Many antiemetics are available but none is entirely satisfactory in all patients. Even the serotonin antagonists such as ondansetron, can have failure rates as high as 40%, depending on dose and the nature of the chemotherapy — once again, cisplatin appears to be the most difficult agent in this respect. Insufficient research has been conducted on the combination with established antiemetics and on producing a stable, oral formulation which has a satisfactory and reproducible bioavailability.

In an outstanding review of the use of THC as an antiemetic in clinical trials, Carey et al. () noted that the often conflicting and confusing results obtained owe much to the inadequacy of the study designs and methods. While acknowledging that a study of antiemetic activity in cancer patients on a wide variety of cancer chemotherapies holds unavoidable difficulties, there are many variables, such as chemotherapy regimen, age, drug dose regimen, drug tolerance, route of administration, toxicity and drug interactions which have been analysed inadequately. More research is needed into the management of nausea and vomiting which is conditioned rather than organic. Environment variables, such as in — or out-patient setting, and the attitudes of carers to the use of THC also need closer scrutiny. The authors argue that only through carefully designed and controlled trials, can the efficacy of THC be identified, its limits defined and its effectiveness relative to other treatments established.

From September 1995, THC was made available in the UK, to be prescribed on a named patient basis, as an antiemetic in patients receiving cancer chemotherapy. This change followed advice from the World health Organisation, accepted by the UN Commission on Narcotic Drugs, that THC has a recognised therapeutic use in cancer patients. This situation now mirrors that in the US where THC formulated as an oral capsule in sesame seed oil, and called dronabinol, is already marketed as a second-line antiemetic and to treat anorexia in AIDS patients.

Nabilone

This synthetic derivative of THC is licenced in a number of countries, solely for the prevention of chemotherapy-induced nausea and vomiting. It is the result of research on a range of THC analogues, driven by the desire to produce a drug which is effective, but lacking the often severe, central side effects of THC.

It appears that with nabilone, some separation between euphoric and antiemetic effects has been achieved. Key investigations featuring nabilone, involving 579 evaluable patients, are shown in Table Summary of clinical trials investigating nabilone as an antiemetic for cancer chemotherapy-induced nausea and vomiting.

Like THC, nabilone appears to have significant antiemetic activity and has been shown to be superior to prochlorperazine in both animals and man and in one small study, equivalent to intramuscular chlorpromazine. It appears to be useful in cases of nausea and vomiting refractory to other antiemetics. It is also interesting to note that in the studies reported by Einhorn et al. () and Vincent et al. () nabilone was judged to be effective from the first day of treatment when nausea and vomiting were most severe.

Archer et al. () have reviewed phase 2 and phase 3 clinical trials of nabilone in the control of nausea and vomiting associated with cancer chemotherapy. As with THC, nabilone is more effective against lower doses of cisplatin compared with higher doses, and against regimes which do not contain this drug. Nabilone is by no means free of side effects however: drowsiness, dry mouth, divided co-ordination, blurred vision, postural hypotension, and dizziness occur in significant proportions of patients (); rare cases of depersonalisation and hallucinations have been reported and psychotic reactions have also been noted. Reports of other CNS side effects persist, including descriptions of ‘highs’, which can be euphoric or dysphoric, (); these have prompted patients to withdraw from clinical trials, but are likely to be dose-related. There is no agreement on whether the ‘high’ is an essential component of the antiemetic activity. These reports are of concern, especially as nabilone has been shown to be effective in children, where the side effect profile was considered acceptable).

Ahmedzai et al. () could find no statistical association between age, sex and nabilone toxicity and recommended that if the dose of nabilone was restricted to 2 mg, 12-hourly, for anti-emetic control in regimens which did not contain platinum-based drugs, its use would generally be associated with a moderate but overall, acceptable incidence of side effects.

Other (unlicenced) areas where nabilone has been shown to be effective are in combating nausea and vomiting in patients undergoing radiotherapy (); total abdominal hysterectomy and in a patient experiencing nausea and vomiting due to an AIDS related cryptosporydial infection.

Levonantradol

Cronin and Sallan described the intramuscular use of this synthetic analogue in patients receiving a wide range of cancer chemotherapies, who were refractory to treatment with prochloperazine or thiethylperazine. Of the 18 chemotherapy regimes used, 11 contained cisplatin. After initial dose titration, 15 of 16 patients showed improvement in the extent of nausea and in the number of vomiting episodes. Two patients experienced dysphoria. Other side effects were somnolence, drowsiness and dizziness; these were described as mild and acceptable.

Tyson et al. () described a phase 1 trial of intramuscular levonantradol in 34 patients who received a total of 52 courses of cancer chemotherapy. Chemotherapy included high dose cisplatin alone or in combination with other drugs. Major (0–2 emetic episodes) or minor (3–5 episodes) antiemetic effects were observed in 23% of patients receiving cisplatin and in 53% receiving non-cisplatin regimens, at levonantradol doses ranging from 0.5 to 4mg, every four hours. Centrally-mediated side effects (sedation: 44%; dysphoria: 29%) were observed, together with dizziness (65%), postural hypotension (37%) pain at the injection site (48%) dry mouth (67%) and urinary retention (10%). Levonantradol was acceptable to most patients at doses of 3mg or less, although side effects were common. Marked toxicity, including urinary retention, occurred at higher doses. While antiemetic efficacy is undoubtedly dose — related, Laszlo et al. () have recommended a maximum dose of 1 mg to minimise the development of euphoria and that both oral and intramuscular routes might be combined to good effect to combat persistent nausea and vomiting.

Further randomised, double blind studies have confirmed that levonantradol has antiemetic activity equal to or superior to placebo or other antiemetic agents including prochlorperazine (); but that its use is frequently associated with a greater incidence of side effects than these comparators. Levonantradol has also been shown to be as effective as THC, with the advantage that it may be given intramuscularly.

Other Derivatives

In further attempts to dissociate dysphoric reactions from antiemetic activity and to develop agents which are more potent at combating nausea and vomiting caused by cisplatin, additional chemical modifications of cannabinoids have been made and at least partial efficacy has been demonstrated for some of these agents in man. In the study by Bron et al. (), the analogue, BRL-4664 was more effective at combating cisplatin-induced nausea and vomiting in patients who had not received cisplatin before. In cisplatin-experienced individuals, the reduction in vomiting episodes was not nearly so marked. This emphasises the role of conditioned reflexes in trials of this nature. The authors make the point that a stratified, parallel-group design might be better than a crossover study in future trials.

In summary, the effectiveness of at least two derivatives of cannabis (THC and nabilone) in treating chemotherapy-induced nausea and vomiting is now firmly established. Acceptance has come only after gathering clear clinical evidence of efficacy. The side effect profiles of the synthetic derivatives of cannabis appear to be qualitatively similar and in the absence of head to head clinical trial data, it is difficult to favour one compound over another. Suffice it to say that the level and nature of side effects with any of them is far from ideal. If the development of additional agents from the cannabinoids is to succeed, then trials must avoid the pitfalls of earlier work which have hampered direct comparison of trial data; these include the use of:

(i) Several different dosing schedules, doses and routes of administration;

(ii) differing chemotherapy regimens;

(iii) differing antiemetic combinations;

(iv) differing patient populations, in terms of pre-treatment history, age, sex, psychological status and premorbid personality structure;

(v) different assessment techniques;

(vi) different response criteria;

(vii) differing environmental factors associated with the administration setting.

By the same token, there is no denying that cannabinoids are extremely effective antiemetics, given particular combinations of the above conditions. To date, the combinations, have not been clearly defined.

One observation, supported by observations when cannabis has been used in other conditions, is that patients derive equal, if not greater relief after smoking cannabis compared with the oral ingestion of a single cannabinoid; this may be due to a number of reasons:

(i) THC is more readily absorbed via the lung than through the gut;

(ii) enteral absorption is slowed in patients with gastrointestinal hypermotility;

(iii) the impressive cocktail of actives in crude cannabis may modify the antiemetic cactivity of certain cannabinoids in a synergistic or additive way;

(iv) smoking allows self-titration which is not possible with a fixed oral dose of a cannabinoid.

To-date, there have been no trials comparing cannabis or its derivatives with newer antiemetics such as ondansetron. One can speculate from accumulated wisdom that the latter would prove to be more effective; however, because of their unique pharmacological profile, rather than in spite of it, the cannabinoids still retain a place in the antiemetic armamentarium, particularly for intractable nausea and vomiting, perhaps in combination with more established agents.

Mode of Action

How cannabis and its isolated cannabinoids achieve their antiemetic effects is far from clear. Bhargava has suggested that, as THC is known to decrease brain dopamine levels, the drug may be inactivating central dopaminergic activity associated with the vomiting reflex. Studies with nabilone in the cat suggest that it may act in the forebrain, inhibiting the vomiting control mechanism in the medulla oblongata through descending pathways as well as the chemoreceptor trigger zone. The intravenous administration of naloxone blocks the antiemetic effect of nabilone in the cat indicating an action on central opiate receptors. The mode of action of cannabinoids is likely to be different from that of the phenothiazines, which are known to block dopaminergic receptors responsible for apomorphine-induced nausea and vomiting, as they do not significantly inhibit apomorphine-induced vomiting in dogs and cats.