Therapeutic uses of cannabis
... Nabilone is a synthetic cannabinoid, pharmacologically similar to THC, but with higher potency, a lesser likelihood to produce euphoria, and displaying a lower "abuse potential" (Association 1997). It is manufactured by Eli Lilly Company as Cesamet ® and is available in the UK, Australia, Canada, and some European nations (Grotenhermen 2001), where it is primarily utilized as an anti-nausea agent in chemotherapy. ...
... Analgesic benefits of up to 6 hours were noted in post-operative pain patients in a prior trial (Jain et al. 1981), but without clear dose-response effects. Adverse effects are prominent with this agent, including somnolence in 50-100% and dysphoria in 30-50% (Association 1997), termed "unacceptable" by that authority. ...
. This study reviews human clinical experience to date with several synthetic cannabinoids, including nabilone, levonantradol, ajulemic acid (CT3), dexanabinol (HU-211), HU-308, and SR141716 (Rimonabant ®). Additionally, the concept of "clinical endogenous cannabinoid defi-ciency" is explored as a possible factor in migraine, idiopathic bowel dis-ease, fibromyalgia and other clinical pain states. The concept of analgesic synergy of cannabinoids and opioids is addressed. A cannabinoid-medi-ated improvement in night vision at the retinal level is discussed, as well as its potential application to treatment of retinitis pigmentosa and other conditions. Additionally noted is the role of cannabinoid treatment in neuroprotection and its application to closed head injury, cerebrovas-cular accidents, and CNS degenerative diseases including Alzheimer, Huntington, Parkinson diseases and ALS. Excellent clinical results employing cannabis based medicine extracts (CBME) in spasticity and spasms of MS suggests extension of such treatment to other spasmodic and dystonic conditions. Finally, controversial areas of cannabinoid treatment in obstetrics, gynecology and pediatrics are addressed along with a rationale for such interventions.
... However, people who self-medicate with ∆ 9 -THC may raise the dose over time as they become tolerant to the symptom-relieving effects, increasing their level of intake well above that used by occasional recreational users, although this has not been shown to be relevant for licensed medicinal cannabinoids. 70,71 At the same time, tolerance also occurs to adverse effects, such as drowsiness and sedation, and therefore the subject will function whilst receiving amounts of ∆ 9 -THC that may be debilitating to someone who does not regularly use cannabis. Wade et al 52 and Zajicek et al 46 have both reported on the long-term effects of ∆ 9 -THC medication. ...
... A special issue is the use of cannabis for medical purposes. Two important reports considering the scientific evidence have appeared recently (British Medical Association 1997;Great Britain 1998). While there is evidence that there are therapeutic benefits (Robson 2001), it is debated whether people should have access to the plant, or whether the effective compound should be extracted in a licensed medicine (Morris 2001;Travis 2001;BBC News 2001). ...
... People who self-titrate, or self-medicate for THC may raise the dose that they seek over time, because they can become tolerant to the analgesic effects of THC (Association, 1997;Lichtman et al., 2005), and thus seek higher amounts to relieve their pain. At the same time, tolerance also occurs to adverse effects, such as drowsiness and sedation. ...
PLAIN LANGUAGE SUMMARY
Cannabis is being recognised for its therapeutic potential after decades of prohibition. The regulation of medicinal cannabis varies around the world. The Australian government, for example, has opted for a prescription model. Their policy was implemented after polling revealed the Australian public supported the idea of legal medicinal cannabis. However, the government has not yet sought public input on the substance of that policy.
Public input into government decisions is essential to the democratic process. This study investigates what features of medicinal cannabis policy are important to the Australian public.
We conducted several studies to achieve specific objectives. The first objective was to develop a large list of potential policy characteristics. A review of the literature and a document analysis of Australian consumer submissions to a government enquiry into medicinal cannabis access fulfilled that objective. Focus groups participants and medicinal cannabis experts reduced that list to policy characteristics that were important to the Australian public. Finally, interviews with 10 members of the Australian public reviewed the final list of characteristics for language clarity.
The final list of six characteristics included: (1) The situations under which access to medicinal cannabis is granted? (2) Whether evidence for medicinal cannabis use is available? (3) What form of medical supervision is required? (4) How much intoxicating ingredient the medicinal cannabis includes? (5) What form the medicinal cannabis therapy is administered? and (6) If subsidies for the costs of medicinal cannabis are available? Decisions about medicinal cannabis policy were impacted by patients' medical condition. Decisions about policy were relaxed when patients were terminally ill.
The final list is compatible with the characteristics of current Australian medicinal cannabis policy. Access, evidence, amount of intoxicating ingredient, and to a lesser degree therapy form of administration, are important to the provision of medicinal cannabis in Australia. Subsidies toward medicinal cannabis costs are also important but are currently unavailable to most patients.
Background
Medicinal cannabis registries typically report pain as the most common reason for use. It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis.
Methods
Via electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain, demographics and patterns of cannabis use including methods, frequency, quantity, preferred strains, cannabinoid and terpene profiles, and prescription substitutions were recorded. Cannabis use for migraine among headache patients was assessed via the ID Migraine™ questionnaire, a validated screen used to predict the probability of migraine.
Results
Of 2032 patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for 42.4% (n = 861) overall; chronic pain 29.4% (n = 598;), arthritis 9.3% (n = 188), and headache 3.7% (n = 75;). Across all 21 illnesses, headache was a symptom treated with cannabis in 24.9% (n = 505). These patients were given the ID Migraine™ questionnaire, with 68% (n = 343) giving 3 “Yes” responses, 20% (n = 102) giving 2 “Yes” responses (97% and 93% probability of migraine, respectively). Therefore, 88% (n = 445) of headache patients were treating probable migraine with cannabis. Hybrid strains were most preferred across all pain subtypes, with “OG Shark” the most preferred strain in the ID Migraine™ and headache groups. Many pain patients substituted prescription medications with cannabis (41.2–59.5%), most commonly opiates/opioids (40.5–72.8%). Prescription substitution in headache patients included opiates/opioids (43.4%), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anti-convulsants (7.7%), muscle relaxers (7%), ergots (0.4%).
Conclusions
Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine. Hybrid strains were preferred in ID Migraine™, headache, and most pain groups, with “OG Shark”, a high THC (Δ9-tetrahydrocannabinol)/THCA (tetrahydrocannabinolic acid), low CBD (cannabidiol)/CBDA (cannabidiolic acid), strain with predominant terpenes β-caryophyllene and β-myrcene, most preferred in the headache and ID Migraine™ groups. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Opiates/opioids were most commonly substituted with cannabis. Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes.
En este capitulo se expone el estado actual del conocimiento sobre las propiedades terapeuticas del Cannabis (marihuana y derivados sinteticos). En los ultimos anos se han presentado un gran numero de evidencias cientificas sobre las propiedades terapeuticas de los cannabinoides, en especial analgesia, disminucion de la presion intraocular, efecto antiemetico en vomitos inducidos por quimioterapia antineoplasica, propiedades relajantes musculares en esclerosis multiple, traumatismos medulares y alteraciones del movimiento. Ademas, algunas aportaciones recientes indican otros posibles usos de estas sustancias como neuroprotectores (en modelos animales de enfermedades neurodegenerativas e isquemia cerebral), antiasmaticos y anticonvulsivantes. Mas recientemente, algunos compuestos naturales y agentes sinteticos agonistas de receptores CB han demostrado efectos antineoplasicos in vivo e in vitro. En la actualidad se esta llevando a cabo un amplio debate internacional sobre las evidencias cientificas versus las restricciones de tipo legal sobre el posible uso de estos compuestos. Se necesitan mas estudios clinicos cpn el fin de establecer que dosis, vias de administracion son las mas adecuadas en cada caso, asi como el balance entre beneficio y riesgo comparando los cannabinoides con otras estrategias terapeuticas.
The synthesis of “designer drugs” intended to mimic the effects of chemically similar controlled substances while circumventing existing drug laws has grown exponentially since the turn of the century. These novel psychoactive substances (NPSs) have been introduced into the market with some regularity over the previous century in response to regulations which outlaw the use of existing agents, but more recently the Internet has allowed for worldwide distribution and encouraged NPS production on a global scale. These synthetic compounds contain modified molecular structures similar enough to controlled or illegal substances so as to produce a similar effect in the user but different enough so as to not fall under the same restrictions placed on the production, distribution, possession, and use of the parent compound. These drugs are often produced clandestinely with little or no quality control processes, and there is a wide variation in chemical content among commercial preparations purported to be the same product. Typically, the existence of a new NPS comes to the attention of law enforcement or the medical community only after users begin to die in large numbers or present to hospitals for treatment with heretofore unseen symptoms.
Inhalation of many substances has been part of civilization for thousands of years, for both pleasure and medicinal reasons.
Abuse of this practice has become indigenous to our society. While tobacco is probably the most abused inhalant, many other
agents have been sniffed and inhaled through the respiratory tract by all segments of our population. In addition to agents
produced specifically for the purpose of recreational inhalation, there exist a number of readily obtained and easily abused
volatile compounds with the potential to complicate an anesthetic procedure.
Cannabinoids such as Cannabis-based medicinal extracts (CBMEs) are increasingly being used in the treatment of spasticity associated with multiple sclerosis (MS). They have been shown to have a beneficial effect on spasticity; however, this evidence is largely based on subjective rating scales. Objective measurements using the Ashworth scale have tended to show no significant effect; however, the validity of this scale has been questioned. The available clinical trial data suggest that the adverse side effects associated with using CBMEs are generally mild, such as dry mouth, dizziness, somnolence, nausea and intoxication. However, most of these trials were run over a period of months and it is possible that other adverse side effects could develop with long-term use. There may be reason to be concerned about the use of therapeutic cannabinoids by adolescents, people predisposed to psychosis and pregnant women.
Comorbidity and dual diagnosis have a fashionable, and thus ephemeral, ring that belies their relevance to day-to-day practice. The topic has been increasingly addressed in North American literature where there is a recognition of the extent of substance misuse in the severely mentally ill, and the need to find ways of effectively managing its consequences. Substance misuse may colour the diagnosis, management and prognosis of major mental illness and can adversely affect the relationship between staff and patients. Despite its common occurrence, it frequently remains undetected (Ananth et al , 1989). With burgeoning research interest, there is some consensus as to how to manage the problem, but, as yet, little agreement on the precise nature of causal relationships.
Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands
for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry
and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a
radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent
inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids.
These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
Methodological issues involved in assessing the prevalence of substance abuse in schizophrenia are discussed, and previous research in this area is comprehensively reviewed. Many studies suffer from methodological shortcomings, including the lack of diagnostic rigor, adequate sample sizes, and simultaneous assessment of different types of substance abuse (e.g., stimulants, sedatives). In general, the evidence suggests that the prevalence of substance abuse in schizophrenia is comparable to that in the general population, with the possible exceptions of stimulant and hallucinogen abuse, which may be greater in patients with schizophrenia. Data are presented on the association of substance abuse with demographics, diagnosis, history of illness, and symptoms in 149 recently hospitalized DSM-III-R schizophrenic, schizophreniform, and schizoaffective disorder patients. Demographic characteristics were strong predictors of substance abuse, with gender, age, race, and socioeconomic status being most important. Stimulant abusers tended to have their first hospitalization at an earlier age and were more often diagnosed as having schizophrenia, but did not differ in their symptoms from nonabusers. A history of cannabis abuse was related to fewer symptoms and previous hospitalizations, suggesting that more socially competent patients were prone to cannabis use. The findings show that environmental factors may be important determinants of substance abuse among schizophrenic-spectrum patients and that clinical differences related to abuse vary with different types of drugs.
Synopsis
Data on the history of cannabis use and a spot urine test for cannabinoids were obtained for 137 schizophrenics in treatment. Subjects who were using cannabis during the 6-month observation period presented with a significantly higher degree of delusional and hallucinatory activity than those who did not. Moreover, the group using cannabis made a higher average number of visits to the hospital during the same period. The status of cannabis use appeared to contribute to such variance more than did other relevant factors (age, stage of the illness, amount of medication prescribed, occasional use of other psychoactive substances).
A recent, informal, confidential survey was taken on a Spinal Cord Injury ward concerning the effects of marijuana on pain and spasticity in spinal cord injured males. Ten patients who admitted that they had used marijuana after they had been injured were asked how the drug affected burning, phantom pain, muscle spasms, bladder spasms, urinary retention, headache pain and pleasant sensations. A table indicates the number of patients in each category with the column labelled 'Distract' indicating that the drug did not decrease the pain but helped the patient pay less attention to it and the column labelled 'Not applicable' indicating that the patient did not experience the sensation in the non drug state. The perceived decrease in pain and spasticity shown by this survey, even though replies may be biased, indicates that better controlled studies would be worth while.
The cannabinoids are compounds unique to Cannabis sativa L., the source of the drug marihuana. The major active principle of this drug, delta-9-tetrahydrocannabinol, was first characterized in 1964, and since then over 60 related compounds have been discovered. The cannabinoids are very lipophilic, are extensively metabolized, and accumulate in fat, where they pose problems for chronic users of the drug. The general illegality of cannabis use has necessitated the development, in recent years, of many methods for detection and quantification. Forensically, radioimmunoassay and related techniques are the most suitable, but positive results should be confirmed by more specific techniques such as mass spectrometry. The mechanism of action of this drug is not clear, but an interaction with the cell membrane, similar to that demonstrated by general anesthetics, has been demonstrated. This general site of action may explain the widespread adverse effects shown by this drug.
Eighty evaluable patients receiving chemotherapy were entered on a random prospective double-blind study to evaluate the effectiveness of nabilone, a synthetic cannabinoid, compared to prochlorperazine. Most of these patients received cisplatin, a drug that universally produces severe nausea and vomiting, as part of a combination chemotherapy regimen. The patients served as their own controls, receiving either nabilone or prochlorperazine during two consecutive treatment courses with the identical chemotherapy. Side effects consisting of hypotension and lethargy were more pronounced with nabilone. Toxicity, in general, did not preclude antiemetic treatment and in no way interfered with chemotherapy. Sixty patients (75 per cent) reported nabilone to be more effective than prochlorperazine for relief of nausea and vomiting. Of these 60 patients, 46 required further chemotherapy and continued taking nabilone as the antiemetic of choice.
We studied the incorporation of cocaine (COC), benzoylecgonine (BE) and ecgonine methyl ester (EME) into hair from blood. At first, the time courses of three drugs in rat plasma following i. p. administration of cocaine were investigated over 360 min. AUCs of COC, BE and EME in plasma were 14.2, 60.7 and 53.4 Μg/ml/min, respectively. In contrast, the concentrations of the three compounds in hair were 16.4, 1.7 and 0.8 ng/mg. In spite of that, the AUC of COC in plasma was much lower than that of the other two compounds in plasma, the concentration of COC in hair was much higher than that of the other two compounds. The incorporation of COC into hair was much greater than that of BE and EME. If the incorporation of drugs from blood into hair is compared by [concentration in hair]/[AUC in plasma], that of COC, BE and EME is represented by 77∶1.9∶1. Our results suggest that the incorporation of drugs into hair from blood unexpectedly depends upon the physical properties of each drug.
The author first describes the history of medical use of cannabis and its revival in the 1990s. He then provides an overview of the legal situation and how this affects doctors and patients if cannabis is prescribed or recommended as treatment. Subsequently, the state of the art of cannabis medication research is described and analyzed. Finally, the public and political discourse that arose in reaction to legal and political efforts to legalize cannabis for medical purposes is described.
Recent work contributing towards an understanding of the mechanism of action of cannabis and its constituents is described and the known therapeutic and pharmacological activities of these substances reviewed, together with synthetic drugs derived from tetrahydrocannabinol (Δ1-THC). The medical uses discussed include the actions of cannabinoids in the treatment of glaucoma, asthma, emesis, hyperthermia, convulsion, muscle spasticity, anxiety, hypertension, pain and inflammation.
1. Chemical content, assay procedures, and pharmacokinetics of cannabis sativa are discussed briefly.2. Cannabinoid cellular effects relating to chromosomes and immunity including cellular metabolism and allergic reactions are presented.3. Gross and microscopic brain pathology due to cannabis use is reviewed involving EEG alterations, psychopathology including aggressive behaviour as well as properties of psychomotor impairment, tolerance and dependence.4. Cardiopulmonary effects of marihuana are recorded under pulmonary pharmacological effects including the macrophage defense system and effects of smoke constituents; under cardiovascular effects cardiac toxicity and possible mechanism of action are discussed.5. Alterations of reproductive hormonal production and maturation of reproductive cells by marihuana in males and females with attendant impairment of reproductive function or fertility including reproductive outcome are reported.6. Field studies with healthy chronic cannabis users in Jamaica, Greece and Costa Rica are related as to observed medical alterations.7. Potential clinical effects are summarized in point form.
The administration of single oral doses of delta-9-tetrahydrocannabinol (THC) to patients with cancer pain demonstrated a mild analgesic effect. At a dose of 20 mg, however, THC induced side effects that would prohibit its therapeutic use including somnolence, dizziness, ataxia, and blurred vision. Alarming adverse reactions were also observed at this dose. THC, 10 mg, was well tolerated and, despite its sedative effect, may analgesic potential.
Fifteen patients with osteogenic sarcoma receiving high-dose methotrexate chemotherapy were studied in a randomized, double-blind, placebo-controlled trial of oral and smoked delta-9-tetrahydrocannabinol (THC) as an antiemetic. Each patient served as his or her own control. Fourteen of 15 patients had a reduction in nausea and vomiting on THC as compared to placebo. Delta-9-tetrahydrocannabinol was significantly more effective than placebo in reducing the number of vomiting and retching episodes, degree of nausea, duration of nausea, and volume of emesis (P less than 0.001). There was a 72% incidence of nausea and vomiting on placebo. When plasma THC concentrations measured less than 5.0 ng/mL, 5.0 to 10.0 ng/mL, and greater than 10.0 ng/mL, the incidences of nausea and vomiting were 44%, 21%, and 6%, respectively. Delta-9-tetrahydrocannabinol appears to have significant antiemetic properties when compared with placebo in patients receiving high-dose methotrexate.
Effects on airway dynamics, heart rate, and the central nervous system of various doses of delta9-tetrahydrocannabinol administered in a random, double blind fashion using a Freon-propelled, metered-dose nebulizer were evaluated in 11 healthy men and 5 asthmatic subjects. Effects of aerosolized delta9-tetrahydrocannabinol were compared with aerosolized placebo and isoproterenol and with 20 mg of oral and smoked delta9-tetrahydrocannabinol. In the normal subjects, after 5 to 20 mg of aerosolized delta9-tetrahydrocannabinol, specific airway conductance increased immediately, reached a maximum (33 to 41 per cent increase) after 1 to 2 hours, and remained significantly greater than placebo values for 2 to 3 hours. The bronchodilator effect of aerosolized delta9-tetrahydrocannabinol was less than that of isoproterenol after 5 min, but significantly greater than that of isoproterenol after 1 to 3 hours. The magnitude of bronchodilatation after all doses of aerosolized delta9-tetrahydrocannabinol was comparable, but 5 mg of delta9-tetrahydrocannabinol caused a significantly smaller increase in heart rate and level of intoxication than the 20-mg dose. Smoked delta9-tetrahydrocannabinol produced greater cardiac and intoxicating effects than either aerosolized or oral delta9-tetrahydrocannabinol. Side effects of aerosolized delta9-tetrahydrocannabinol included slight cough and/or chest discomfort in 3 of the 11 normal subjects. Aerosolized delta9-tetrahydrocannabinol caused significant bronchodilatation in 3 of 5 asthmatic subjects, but caused moderate to severe bronchoconstriction associated with cough and chest discomfort in the other 2. These findings indicate that aerosolized delat9-tetrahydrocannabinol, although capable of causing significant bronchodilatation with minimal systemic side effects, has a local irritating effect on the airways, which may make it unsuitable for therapeutic use.
As early as 1971, it was noted that smoking marijuana lowered intraocular pressure. In this study one of the active components of marijuana, delta-9-tetrahydrocannabinol, was given intravenously to ten subjects with normal intraocular pressures. Two strengths were used--0.022 mg/kg of body weight and 0.044 mg/kg of body weight. Intraocular pressure was found to decrease as much as 51% of baseline normal with an average decrease of 37%. Heart rate increased in a range of 22% and 65% of the resting pulse. Respiratory rate was not affected. No analgesic properties were demonstrated by either cutaneous or periosteal stimulation. Anxiety levels were increased by delta-9-tetrahydrocannabinol over placebo and diazepam (Valium). The mechanism of action is still uncertain but it is believed by some workers to be similar to that of a beta-adrenergic stimulator.
Two double-blind, crossover trials comparing the antiemetic effectiveness of nabilone, a new synthetic cannabinoid, with that of prochlorperazine were conducted in patients with severe nausea and vomiting associated with anticancer chemotherapy. Of 113 patients evaluated, 90 (80 per cent) responded to nabilone therapy, whereas only 36 (32 per cent) responded to prochlorperazine (P less than 0.001). Complete relief of symptoms was infrequent, occurring only in nine patients (8 per cent) given nabilone. When both drugs were compared, both nausea (P less than 0.01) and vomiting episodes (P less than 0.001) were significantly lower in patients given nabilone. Moreover, patients clearly favored nabilone for continued use (P less than 0.001). Predominant side effects noted by patients were similar for both agents and included somnolence, dry mouth and dizziness but were about twice as frequent and more often severe in patients receiving nabilone. In addition, four patients (3 per cent) taking nabilone had side effects (hallucinations in three, hypotension in one) that required medical attention. Euphoria associated with nabilone was infrequent (16 per cent) and mild.
Ten volunteer inpatient asthmatics in a steady state were given a single inhalation of an aerosol (63 mul) delivered in random order, on each of three consecutive days, in the laboratory of a respiratory unit. Before, and for one hour after treatment the pulse, blood pressure (lying and standing), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), peak flow rate (PFR), and self-rating mood scales (SRMS) were recorded. Treatments were placebo-ethanol only; delta1-tetrahydrocannabinol (THC) 200 mug in ethanol; or salbutamol 100 mug (Ventolin inhaler), administered double blind. Salbutamol and THC significantly improved ventilatory function. Maximal bronchodilatation was achieved more rapidly with salbutamol, but at 1 hour both drugs were equally effective. No cardiovascular or mood disturbance was detected, and plasma total cannabinoids at 15 minutes were undectable by radioimmunoassay. The mode of action of THC differs from that of sympathomimetic drugs, and it or a derivative may make a suitable adjuvant in the treatment of selected asthmatics.
Marihuana smoking, in conjunction with therapeutic doses of phenobarbital and diphenylhydantoin, was apparently necessary for controlling seizures in one 24-year-old epileptic patient.
Two intravenous doses of tetrahydrocannabinol (THC) (0.022 mg/kg and 0.044 mg/kg) were compared to intravenous diazepam (0.157 mg/kg) and to placebo (Ringer's lactate) as premedication for dental extraction in 10 healthy volunteers. Pain detection and tolerance thresholds were measured and psychiatric interviews were supplemented by Minnesota Multiphasic Personality Inventories (MMPI), the Zung Depression Scale (ZDS), Beck Depression Inventories (BDI), and the State-Trait Anxiety Inventory (STAI). Pain detection thresholds were altered unpredictably with high THC doses, but analgesia as indicated by pain tolerance was less than that after diazepam and placebo. In three subjects low-dose THC (0.022 mg/kg) was a better analgesic than placebo but not diazepam. Six subjects preferred placebo to low-dose THC as an analgesic; this group experienced increases in subjective surgical pain and were submissive, rigid, and less introspective with high State Anxiety and MMPI profiles that differed from subjects whose pain was not increased. STAI following THC presaged a poor analgesic response in this group.
In this paper, the mutagenicity and carcinogenicity of alternariol monomethyl ether (AME), alternariol (AOH), and their relevance to the etiology of human esophageal cancer were studied. These mycotoxins were produced by Alternaria alternata which was the main contaminating fungi isolated from the grain in Linxian County, an area with high incidence of esophageal cancer. This study demonstrated that: 1. AME and AOH might cause cell mutagenicity and transformation; 2. AME and AOH could combine with the DNA isolated from human fetal esophageal epithelium, activate the oncogens, c-H-ras and c-mys in it, and promote proliferation of human fetal esophageal epithelium in vitro; 3. squamous cell carcinoma of the fetal esophagus could be induced by AOH. According to the results of the studies of AME and AOH mentioned above, we consider that Alternaria alternata plays an important role in the etiology of human esophageal cancer.
Dronabinol (Marinol, Roxane Laboratories, Columbus, OH) and prochlorperazine were tested alone and in combination in a randomized, double-blind, parallel group, multicenter study. Patients were randomized to receive either 1) dronabinol 10 mg every 6 hr plus placebo; 2) placebo plus prochlorperazine 10 mg every 6 hr; or 3) dronabinol and prochlorperazine, each 10 mg every 6 hr. Antiemetic treatment was begun 24 hr prior to and continued for 24 hr after the last dose of chemotherapy; all was given orally. Only 29% of patients in group 3 versus 47% in group 1 and 60% in group 2 experienced nausea after chemotherapy. In addition, the median duration per episode and severity of nausea were significantly less with combination therapy. Vomiting occurred after chemotherapy in 41%, 55%, and 35% of patients in groups 1, 2, and 3, respectively. The median duration per episode of vomiting was 1 min in group 3 versus two in group 1 and four in group 2. Side effects, primarily CNS, were more common in group 1 than in group 2; addition of prochlorperazine to dronabinol appeared to decrease the frequency of dysphoric effects seen with the latter agent. The combination was significantly more effective than was either single agent in controlling chemotherapy-induced nausea and vomiting.
Dronabinol, delta-9-tetrahydrocannabinol in sesame oil, has been used for several years as an antiemetic for patients receiving cancer chemotherapy. In combination studies with prochlorperazine, enhancement of efficacy, as measured by duration of episodes of nausea and vomiting and by severity of nausea, has been found. The incidence of psychotropic effects from dronabinol appears to be decreased by concomitant administration of prochlorperazine. In open pilot studies, dronabinol caused weight gain in seven of ten patients with symptomatic HIV infection. In both HIV and cancer patients, dronabinol improved appetite at a dose which was well tolerated for chronic administration.
Nineteen patients receiving cancer chemotherapy were randomized in a double-blind fashion to receive either (a) dronabinol, 10 mg plus placebo q.i.d.; (b) prochlorperazine, 10 mg plus placebo q.i.d.; or (c) dronabinol plus prochlorperazine, each 10 mg q.i.d. There were six evaluable patients in each of the two single-agent groups and five in the combination group. The median duration and severity per episode of nausea was significantly greater in the group receiving prochlorperazine alone versus the other two groups. The median duration per episode of vomiting was also significantly greater in the prochlorperazine group than in the other two groups. The proportion of patients vomiting was the same in all groups; however, only one patient in the combination group versus three each in the single-agent groups experienced nausea (p = NS). The majority of side effects were associated with the CNS, including somnolence, dizziness, and confusion. Side effects were somewhat more common in both groups receiving dronabinol, though they were not statistically different from the side effects in the group receiving prochlorperazine as a single agent. Efficacy, as measured by duration of nausea and vomiting and by severity of nausea, was significantly greater in both groups receiving dronabinol.
A double-blind study was performed comparing 5 mg delta-9-tetrahydrocannabinol (THC) p.o., 50 mg codeine p.o., and placebo in a patient with spasticity and pain due to spinal cord injury. The three conditions were applied 18 times each in a randomized and balanced order. Delta-9-THC and codeine both had an analgesic effect in comparison with placebo. Only delta-9-THC showed a significant beneficial effect on spasticity. In the dosage of THC used no altered consciousness occurred.
The chronic motor handicaps of a 30-year-old multiple sclerosis patient acutely improved while he smoked a marihuana cigarette. This effect was quantitatively assessed by means of clinical rating, electromyographic investigation of the leg flexor reflexes and electromagnetic recording of the hand action tremor. It is concluded that cannabinoids may have powerful beneficial effects on both spasticity and ataxia that warrant further evaluation.
The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.
Delta-9-tetrahydrocannabinol (THC), the main psychoactive principle of cannabis, has been shown to attenuate the exhibition of signs of the quasi-morphine withdrawal syndrome in rats. Cannabinol (CBN) showed the same activity but required a dosage of approximately eight times that of THC to produce an equivalent effect. Cannabidiol was without effect at the dosage levels used. The efficacy of these cannabinoids and the potency differences recorded in this study are in accord with their effects on other behaviours, both in experimental animals and in man. The activity of THC and CBN was not affected by the narcotic antagonist, naloxone.
An anti-emetic drug, nabilone, a synthetic cannabinoid, has been compared with prochlorperazine in 24 lung cancer patients receiving cancer chemotherapy. Each of the drugs studied was given orally every 12 hours, starting the night before chemotherapy, during one of two consecutive identical chemotherapy cycles in accordance with a double-blind cross-over random order assignment. Single doses were 2 mg of nabilone, or 15 mg of prochlorperazine. The chemotherapeutic regimens given included the following drugs in various combinations: cis-platinum, vincristine, cyclophosphamide, adriamycin, vindesine, and etoposide (VP16). Nabilone was significantly superior to prochlorperazine in the reduction of vomiting episodes. Side effects, mainly vertigo, were evident in nearly half of the patients after nabilone, and three patients were withdrawn from the study due to decreased coordination and hallucinations after nabilone. Side effects from prochlorperazine were limited to mild drowsiness in one patient. Two-thirds of the patients preferred nabilone to prochlorperazine. We conclude that nabilone is a moderately effective anti-emetic drug, but that the unpredictability of its side effects call for careful patient information, especially with elderly outpatients. We recommend that at least after the first dose of nabilone, the patient should be kept under close observation during 4 hours.
Twenty nonseminomatous testicular cancer patients not pretreated with emetogenic chemotherapy were included in a crossover study of antiemetic therapy. Patients were randomly assigned to receive either nabilone (2 X 2 mg/day) or alizapride (3 X 150 mg/day) prior to beginning low-dose cisplatin chemotherapy. Patients on nabilone had significantly fewer episodes of emesis than those on alizapride (medians, 1.1 vs 2.9; p less than 0.01). Nabilone was superior to alizapride in giving complete relief from nausea (medians, 65% vs 30%; p less than 0.01), and was more effective in shortening the duration of nausea (medians, 1.3 h vs 5.1 h; p less than 0.01); however, it caused more adverse effects. It is concluded that nabilone has greater antiemetic activity than alizapride in young patients receiving low-dose cisplatin chemotherapy. Nabilone dosage should be reduced to decrease the incidence and degree of adverse reactions while leaving the definite antiemetic activity unchanged.
A prospective randomised double blind crossover trial was conducted comparing the new synthetic cannabinoid nabilone with oral domperidone in a group of children receiving repeated identical courses of emetogenic chemotherapy for a variety of malignant diseases. Eighteen of 23 consecutive eligible children, aged 10 months to 17 years, completed the trial. When taking nabilone they experienced significantly fewer vomiting episodes and less nausea, and two thirds expressed a preference for the drug. The most common side effects of treatment with nabilone were somnolence and dizziness, with one patient being disturbed by hallucinations. The results indicate that nabilone is an effective antiemetic for children having chemotherapy, even for young children. It seems to be superior in this respect to domperidone, and although it has a higher incidence of side effects, these are mostly acceptable to patients. It can be recommended as an alternative to conventional antiemetic treatment throughout childhood.
A prospective randomized double-blind trial comparing the butyrophenone analogue domperidone (D) and the synthetic cannabinoid nabilone (N) in the treatment of cytotoxic-induced emesis was conducted in 38 patients receiving highly emetogenic chemotherapy regimens (70% containing cisplatin). Patients received 20 mg D or 1 mg N the night before chemotherapy and 8-hourly on each chemotherapy day for two consecutive cycles of treatment.
Three of 19 patients randomized to N completed only one cycle because of disease progression (2) or subjectively adverse effects (1). Four of 19 patients completed only one cycle of D because of lack of efficacy (3) or chemotherapy toxicity (1). In all, 32 cycles of N and 33 cycles of D were evaluable for efficacy. The mean number of vomiting episodes in cycle 1 was 4.76 for N and 12.95 for D (P<0.02). The corresponding values for cycle 2 were 4.27 and 7.69 (P>0.10), and for cycles 1 and 2 combined, 4.53 for N and 10.81 for D (P<0.01). Nausea and food intake scores did not differ significantly, although there was a trend towards less nausea and an increased food intake with N. Subjectively adverse effects were more frequent with N and included drowsiness, dizziness, dry mouth, and postural hypotension. N is superior to D for the control of cytotoxic-induced emesis.
In a randomized, double-blind, crossover trial, nabilone was compared to prochlorperazine for control of cancer chemotherapy-induced emesis in 30 children 3.5 to 17.8 years of age. All subjects received two consecutive identical cycles of chemotherapy with the trial antiemetics given in accordance to a body weight-based dosage schedule beginning eight to 12 hours before treatment. The overall rate of improvement of retching and emesis was 70% during the nabilone and 30% during the prochlorperazine treatment cycles (P = .003, chi 2 test). On completion of the trial, 66% of the children stated that they preferred nabilone, 17% preferred prochlorperazine, and 17% had no preference (P = .015, chi 2 test). Major side effects (dizziness, drowsiness, and mood alteration) were more common (11% v 3%) during the nabilone treatment cycles. CNS side effects appeared to be dose related and were most likely to occur when the nabilone dosage exceeded 60 micrograms/kg/d, but individual tolerance to nabilone varied considerably. Lower dosages of nabilone were associated with equivalent efficacy and no major side effects. Nabilone appears to be a safe, effective, and well-tolerated antiemetic drug for children receiving cancer chemotherapy. Although major side effects may occur at higher dosages, nabilone is preferable to prochlorperazine because of improved efficacy.
A prospective pilot study of the use of inhalation marijuana as a antiemetic for cancer chemotherapy was conducted. Fifty-six patients who had no improvement with standard antiemetic agents were treated and 78% demonstrated a positive response to marijuana. Younger age and prior marijuana exposure were factors that predicted response to treatment. Toxicity was mild and consisted primarily of sedation and xerostomia. This preliminary trial suggests the usefulness of inhalation marijuana as an antiemetic agent. Because of the lack of a randomized placebo control group, the precise role of this agent is unclear. Further studies should include derivatives of this substance in combination with standard effective drugs to control to chemotherapy-induced nausea and vomiting.
To compare the pulmonary hazards of smoking marijuana and tobacco, we quantified the relative burden to the lung of insoluble particulates (tar) and carbon monoxide from the smoke of similar quantities of marijuana and tobacco. The 15 subjects, all men, had smoked both marijuana and tobacco habitually for at least five years. We measured each subject's blood carboxyhemoglobin level before and after smoking and the amount of tar inhaled and deposited in the respiratory tract from the smoke of single filter-tipped tobacco cigarettes (900 to 1200 mg) and marijuana cigarettes (741 to 985 mg) containing 0.004 percent or 1.24 percent delta 9-tetrahydrocanabinol. As compared with smoking tobacco, smoking marijuana was associated with a nearly fivefold greater increment in the blood carboxyhemoglobin level, an approximately threefold increase in the amount of tar inhaled, and retention in the respiratory tract of one third more inhaled tar (P less than 0.001). Significant differences were also noted in the dynamics of smoking marijuana and tobacco, among them an approximately two-thirds larger puff volume, a one-third greater depth of inhalation, and a fourfold longer breath-holding time with marijuana than with tobacco (P less than 0.01). Smoking dynamics and the delivery of tar during marijuana smoking were only slightly influenced by the percentage of tetrahydrocanabinol. We conclude that smoking marijuana, regardless of tetrahydrocannabinol content, results in a substantially greater respiratory burden of carbon monoxide and tar than smoking a similar quantity of tobacco.