J Pharm Pharmacol. 2009 Jul

Oesch S, Gertsch J.

University Children's Hospital Divisions of Clinical Chemistry and Oncology, University of Zürich, Switzerland.

October 14, 2004 - NOW Magazine (CN ON)

U.S. War on Drugs Stalling Mind-Blowing Research into Pot's Cancer-Healing Properties

By Paul Armentano

Clinical research published in a journal of the American Association for Cancer Research showing that marijuana's components can inhibit the growth of cancerous brain tumours is the latest in a long line of studies demonstrating the drug's potential as an anti-cancer agent.

This latest study, performed by researchers at Madrid's Complutense University, found that cannabis restricts the blood supply to glioblastoma multiforme tumours, an aggressive brain tumour that kills some 7,000 people in the United States every year.

But despite the value of such findings both in terms of the treatment of life-threatening illnesses and as news, U.S. media coverage has been almost non-existent.

Why the blackout? Not one such study has been acknowledged by the U.S. government.

This wasn't always the case. In fact, the first experiment documenting pot's anti-tumour effects took place in 1974 at the Medical College of Virginia at the behest of the U.S. government.

It showed that marijuana's psychoactive component, THC, "slowed the growth of lung cancers, breast cancers and a virus-induced leukemia in laboratory mice and prolonged their lives by as much as 36 per cent."

Despite these favourable preliminary findings, U.S. government officials refused to fund any follow-up research for two decades, until it conducted a similar - though secret - clinical trial in the mid-1990s.

That study, carried out by the U.S. National Toxicology Program, concluded that mice and rats administered high doses of THC over long periods had greater protection against malignant tumours than untreated controls.

Rather than publicize these findings, government researchers shelved the results, which only became public after a draft copy of the findings were leaked in 1997 to a medical journal that in turn forwarded the story to the national media.

However, in the eight years since then, the U.S. government has yet to fund a single additional study examining the drug's potential anti-cancer properties.

Is this a case of federal bureaucrats valuing politics more than the health and safety of patients? You be the judge.

Fortunately, scientists overseas have generously picked up where U.S. researchers so abruptly left off.

This month, researchers at the University of Milan in Italy, reported that marijuana's constituents inhibit the spread of brain cancer in human tumour biopsies from patients failed by standard cancer therapies.

Last year, the same researchers reported in the Journal of Pharmacology and Experimental Therapeutics that non-psychoactive compounds in marijuana inhibited the growth of glioma cells in a dose-dependent manner and selectively targeted and killed malignant cells, stimulating them to "commit suicide" in a natural process called apoptosis.

In 2000, a research team at Complutense's department of biochemistry and molecular biology reported in the journal Nature Medicine that injections of synthetic THC eradicated malignant gliomas (brain tumours) in one-third of treated rats.

The study was undertaken after the discovery in 1998 that THC can selectively induce apoptosis in brain tumour cells without negatively affecting the surrounding healthy cells.

Nevertheless, federal officials in the U.S. continue to refuse to express any interest in funding - or even acknowledging - this clinical research.

1. Mauro Maccarrone
2. Tatiana Lorenzon
3. Monica Bari
4. Gerry Melino
5. Alessandro Finazzi-Agrò

6. Abstract

   The endocannabinoid anandamide (AEA) is shown to induce apoptotic bodies formation and DNA fragmentation, hallmarks of programmed cell death, in human neuroblastoma CHP100 and lymphoma U937 cells. RNA and protein synthesis inhibitors like actinomycin D and cycloheximide reduced to one-fifth the number of apoptotic bodies induced by AEA, whereas the AEA transporter inhibitor AM404 or the AEA hydrolase inhibitor ATFMK significantly increased the number of dying cells. Furthermore, specific antagonists of cannabinoid or vanilloid receptors potentiated or inhibited cell death induced by AEA, respectively. Other endocannabinoids such as 2-arachidonoylglycerol, linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide did not promote cell death under the same experimental conditions. The formation of apoptotic bodies induced by AEA was paralleled by increases in intracellular calcium (3-fold over the controls), mitochondrial uncoupling (6-fold), and cytochrome c release (3-fold). The intracellular calcium chelator EGTA-AM reduced the number of apoptotic bodies to 40% of the controls, and electrotransferred anti-cytochrome c monoclonal antibodies fully prevented apoptosis induced by AEA. Moreover, 5-lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid and MK886, cyclooxygenase inhibitor indomethacin, caspase-3 and caspase-9 inhibitors Z-DEVD-FMK and Z-LEHD-FMK, but not nitric oxide synthase inhibitorNω-nitro-l-arginine methyl ester, significantly reduced the cell death-inducing effect of AEA. The data presented indicate a protective role of cannabinoid receptors against apoptosis induced by AEA via vanilloid receptors.

   Footnotes

7. *This work was supported in part by Istituto Superiore di Sanità (III AIDS Program), by Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Rome (to A.F.A.), and by Telethon Grant E872 (to G. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

8. To whom correspondence should be addressed. Tel./Fax: 39-06-72596468; E-mail: Finazzi@uniroma2.it.

9. Published, JBC Papers in Press, July 25, 2000, DOI 10.1074/jbc.M005722200

Abbreviations:

 

AEA

anandamide (arachidonoylethanolamide)

2-AG

2-arachidonoylglycerol

AM404

N-(4-hydroxyphenyl)arachidonoylamide

ATFMK

arachidonoyl-trifluoromethyl ketone

Caps

capsazepine

CBD

cannabidiol

CB1/2R

type 1/2 cannabinoid receptor

AM

acetoxymethyl ester

ELISA

enzyme-linked immunosorbent assay

ETYA

5,8,11,14-eicosatetraynoic acid

FAAH

fatty acid amide hydrolase

LEA

linoleoylethanolamide

l-NAME

Nω-nitro-l-arginine methyl ester

OEA

oleoylethanolamide

PBS

phosphate-buffered saline

PEA

palmitoylethanolamide

VR

vanilloid receptor

Z-DEVD-FMK

Z-Asp(OCH₃)-Glu(OCH₃)-Val-Asp(OCH₃)-fluoromethyl ketone

Z-LEHD-FMK

Z-Leu-Glu(OCH₃)-His-Asp (OCH₃)-fluoromethyl ketone

GAM-AP

goat anti-mouse alkaline phosphatase

PCD

programmed cell death

Title	The synthetic cannabinoid nabilone improves pain and symptom management in cancer patients
Author(s)	Maida V.
Journal, Volume, Issue	Abstract presented at the San Antonio Breast Cancer Symposium on 15 December 2006
Major outcome(s)	Nabilone treatment improved pain, nausea, appetite and several other symptoms
Indication	Nausea/vomiting;Appetite loss/weight loss;Cancer;Pain;Depression;Anxiety	Abstract
Medication	Nabilone	Background: Cancer patients experience numerous disease-related symptoms and side effects of treatment, such as pain, nausea, anorexia, anxiety, among others. Despite the use of the current drugs of first choice, many patients continue to suffer intractably from a number of symptoms. This impacts negatively on their quality of life, functional status, and their desire to continue with disease altering therapies. The synthetic cannabinoid, nabilone (Cesamet), is officially indicated for the treatment of refractory chemotherapy-induced nausea and vomiting. Pre-clinical studies and preliminary findings from clinical trials suggest cannabinoids may be useful for the management of multiple symptoms and side effects in cancer patients. Nabilone offers the opportunity to optimize pain and symptom management while reducing overall polypharmacy. Material and Methods: Data were retrospectively collected from the charts of patients referred to a specialist consultative palliative medicine program in a large urban centre between May 1, 2005 and June 30, 2006. The decision to prescribe nabilone was based on the presence of severe pain and symptom distress. The sample was selected on the basis that they had completed an Edmonton Symptom Assessment System (ESAS) questionnaire on the initial consultation, and then, at least one thereafter. Data from a total of 139 patients were reviewed, of which nabilone was prescribed to 82. All patients were followed by a specialist team consisting of a palliative medicine physician and nurse practictioner. ESAS questionnaires were completed on their initial consultation and serially thereafter. Although 17 patients discontinued nabilone owing to side effects or based on the recommendation of other treating physicians, their follow-up continued. In addition, serial performance status, measured by the Palliative Performance Scale, version 2 (PPSv2), and a recording of all other medications employed was documented. Data analysis was carried out by an academic biostatistical consultant using MS Windows based S-Plus 6.2 software. The change in ESAS score on all 10 items was compared between the cannabinoid and non-cannabinoid subjects. Results. The mean baseline PPSv2 was 56.7 ( 15.4) in the cannabinoid subjects and 53.9 ( 14.8) in the non-cannabinoid subjects; duration of follow-up (mean) was similar between the two groups (nabilone, 52.8 [ 80.3] days; non-nabilone, 51.6 [ 72.5] days). Compared with non-cannabinoid subjects, the nabilone subjects experienced significant (P<.0001) reductions in pain, markedly so in subjects with a PPS.v2 score of 60 or higher. For drowsiness, tiredness, appetite, and well-being, ESAS scores remained stable in the nabilone group but deteriorated in the non-nabilone group. While subjects in the nabilone group had significantly (P<.0001) greater nausea at baseline, they experienced a significant reduction (P<.0001), in contrast to non-cannabinoid subjects. Depression and anxiety were significantly (P<.0001) more prevalent in the nabilone group; however, reductions in both symptoms were significant (P<.0001) with use of the cannabinoid. Conversely, anxiety and depression increased in the non-cannabinoid group. Item No. 10 on the ESAS, Other, allows patients to rate a particularly bothersome symptom. Two symptoms emerged as important in nabilone subjects: insomnia and fever/night sweats. For both these symptoms, nabilone appeared to be efficacious. Distress, which is derived from scores on the first nine items of ESAS, improved significantly (P<.0001) in subjects receiving nabilone in contrast to non-cannabinoid subjects. Discussion: The study findings are limited by potential biases. Imbalances between the two groups in baseline scores were not adjusted, and the time to the last measurement, from which change in scores was calculated, was variable. The standard of care in the two groups also was not documented. Nonetheless, nabilone, when added to standard of care and taken longer-term, appears to offer significant alleviation of several symptoms in cancer patients, including pain, nausea, depression and anxiety, insomnia, fever/night sweats, and overall distress.
Route(s)	Oral
Dose(s)
Duration (days)	53
Participants	139 cancer patients
Design	Open study
Type of publication	Meeting abstract
Address of author(s)	University of Toronto; William Osler Health Center, Toronto, Canada
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Title	The effects of smoked cannabis in painful peripheral neuropathy and cancer pain refractory to opiods.
Author(s)	Abrams DI, Jay Ch, Petersen K, Shade S, Vizoso H, Reda H, Benowitz N, Rowbotham M.
Journal, Volume, Issue	IACM 2nd Conference on Cannabinoids in Medicine, Cologne, 12-13 September 2003, International Association for Cannabis as Medicine.
Major outcome(s)	10 of the 16 participants experienced a greater than 30% reduction in their pain
Indication	HIV/AIDS;Pain	Abstract
Medication	Cannabis	INTRODUCTION: There is significant evidence that cannabinoids may be involved in the modulation of pain, especially of neuropathic origin. There is also theoretical rationale to suggest that cannabinoids may provide synergistic analgesia with opioids while possibly reducing opioid-related side effects. No information is available on potential pharmacokinetic interactions between cannabinoids and opioids. METHODS: We are currently conducting two clinical trials of smoked marijuana in two populations of patients with pain: HIV patients with painful peripheral neuropathy and cancer patients with persistent pain despite an opioid analgesic. Both studies are designed to begin with a 16 patient open-label pilot proof-of-concept phase. If effectiveness is demonstrated in the pilot, the magnitude of the effect allows us to calculate a follow-on randomized, double-blind controlled trial of smoked marijuana vs smoked placebo. In addition to the effect of smoked marijuana on the subjects’ chronic clinical pain, we are also evaluating the impact on an experimental heat/capsaicin pain model. Here we report experience with the open label phase of the neuropathy study. RESULTS: Sixteen subjects (14 men, 2 women, mean age 43 years) completed the HIV neuropathy pilot trial. Patients had an average of 6 years of neuropathic pain. In 3 cases the pain was felt to be secondary to HIV alone, in 8 secondary to dideoxynucleoside antiretrovirals and to both in 5. Excellent correlation was seen between the response to smoking in the effect on both the chronic neuropathic and the acute experimental pain model over a six-hour period. Overall 10 of the 16 participants experienced a greater than 30% reduction in their neuropathic pain after seven days. This allowed us to proceed with our currently enrolling randomized placebo-controlled trial with a target sample size of 50 subjects. Additional controlled trials of smoked marijuana for HIV peripheral neuropathy are being conducted by other University of California Center for Medicinal Cannabis Research investigators. CONCLUSION: Preliminary results from a small, uncontrolled trial of smoked marijuana in HIV peripheral neuropathy are encouraging. The ongoing randomized trials will better elucidate the role of cannabinoids in this condition. A heat/capsaicin experimental pain model appears to be a good predictor of response to chronic pain. The potential of a beneficial clinical interaction between cannabinoids and opioids requires further study. All Conditions Benefited by Medical Marijuana   Top      Home
Route(s)	Inhalation
Dose(s)
Duration (days)
Participants	16 HIV patients with neuropathic pain
Design	Open study
Type of publication	Meeting abstract
Address of author(s)	The University of California San Francisco, San Francisco, California 94110, USA
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Title	A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia.
Author(s)	Nelson K, Walsh D, Deeter P, Sheehan F
Journal, Volume, Issue	Journal of Palliative Care 1994;10(1):14-18
Major outcome(s)	increase of appetite in 13 patients
Indication	Appetite loss/weight loss;Cancer	Abstract
Medication	Delta-9-THC	Purpose: To evaluate the appetite-stimulating properties of delta-9- tetrahydrocannabinol (THC) in patients with anorexia due to advanced cancer. Patients and methods: Nineteen patients with various malignancies were entered. All had cancer-associated anorexia and a life expectancy greater than four weeks. Patients were started on THC 2.5 mg p.o. t.i.d. one hour after meals for four weeks. Evaluations for side effects, efficacy, acceptability and satisfaction were conducted at two and four weeks. Results: 18 patients were evaluable. Ten patients completed the entire 28-day study. Four patients experienced grade I toxicity and three withdrew at their request. Thirteen patients reported an improved appetite. Conclusion: THC is an effective appetite stimulant in patients with advanced cancer. It is well tolerated at low doses. Further studies are needed to determine the most appropriate dose and the specific population most likely to respond. All Conditions Benefited by Medical Marijuana   Top      Home
Route(s)	Oral
Dose(s)	2.5 mg three times daily
Duration (days)	28
Participants	18 patients with cancer evaluable
Design	Open study
Type of publication
Address of author(s)	Palliative Care Program, Cleveland Clinic Foundation Ohio, USA
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Title	Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting.
Author(s)	Lane M, Vogel CL, Ferguson J, Krasnow S, Saiers JL, Hamm J
Journal, Volume, Issue	Journal of Pain and Symptom Management 1991;6:352-359
Major outcome(s)	prochlorperazine better than THC, both drugs combined better than both alone
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Delta-9-THC	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. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Oral
Dose(s)
Duration (days)	10 mg every 6 hr
Participants	67 patients on various cancer chemotherapie
Design	Controlled study
Type of publication
Address of author(s)
Full text

Title	Dronabinol enhancement of appetite in cancer patients.
Author(s)	Wadleigh R, Spaulding GM, Lumbersky B, Zimmer M, Shepard K, Plasse T.
Journal, Volume, Issue	Proc Am Soc Oncology 1990; 9: 331.
Major outcome(s)	Dronabinol stimulated mood and appetite
Indication	Appetite loss/weight loss;Cancer	Abstract
Medication	Delta-9-THC	Delta-9-tetrahydrocannabinol has previously been noted to enhance appetite in healthy individuals and in cancer patients. To further study this phenomenon, an open, dose- ranging study was carried out in patients with unresectable cancer. After a baseline observation period, patients were treated with dronabinol (delta-9-THC in sesame oil, Marinol, Roxane Labs, Columbus, OH) for up to six weeks at doses of 2.5 mg qd (N=8), 2.5 mg bid (N=9) or 5 mg qd (N=13); patient accrual and dose escalation are still continuing. Patients were weighed weekly; they recorded appetite before each meal and their overall mood once daily 0n 10cm visual analog scales (VAS). Five patients discontinued dronabinol because of adverse effects, although some may have been related to other medications; three discontinued because of progressive desease. Patients in all groups continued to lose weight, although the rate of weight loss decreased with therapy at all doses. Symptomatic improvement was noted in both mood and appetite, with 2.5 mg qd being a no- effect dose. For patients on study at least three weeks, the following was seen: Group 2.5 mg qd: N=6; Mean VAS Mode=-1.5; change, Appetite: -5.4; Mean decrease in weight loss, ib/wk=1.3. Group 2.5 mg bid: N=7; Mean VAS Mode=10.8; change, Appetite: 18; Mean decrease in weight loss, ib/wk=0.6. Group 5 mg qd: N=9; Mean VAS Mode=1.2; change, Appetite: 8.9; Mean decrease in weight loss, ib/wk=1.7 In this open, dose-ranging study, dronabinol appeared to stimulate both mood and appetite at well tolerated doses. All Conditions Benefited by Medical Marijuana   Top      Home
Route(s)	Oral
Dose(s)	2.5 mg twice - 5 mg four times daily
Duration (days)	42
Participants	30 cancer patients.
Design	Open study
Type of publication	Meeting abstract
Address of author(s)
Full text

Title	Efficacy of tetrahydrocannabinol in patients refractory to standard anti-emetic therapy
Author(s)	McCabe M, Smith FP, Goldberg D, Macdonald J, Woolley PV, Warren R
Journal, Volume, Issue	Investigational New Drugs 1988;6:243-246
Major outcome(s)	THC decreased nausea and vomiting in 23 of 36 (64%) patients
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Delta-9-THC	Oral delta-9-tetrahydrocannabinol (THC), 15 mg/m2, was compared to prochlorperazine (PCZ), 10 mg. for the control of cancer chemotherapy-related emesis. Thirty-six patients whose vomiting was refractory to standard antiemetic therapy were entered in this randomized comparative cross-over study. THC decreased nausea and vomiting in 23 of 36 (64%) patients compared to 1 of 36 receiving PCZ. THC efficacy was not dependent on the class of antineoplastic-agent inducing the emetic symptoms, age of patients or type of sensorial change experienced. Using the 15 mg/m2 dose, all patients experienced transient sensorial changes, characterized as a pleasant "high" in 19 or a variable state of dysphoria in 17 cases. This study confirms the usefulness of THC in patients whose chemotherapy-induced nausea and vomiting is refractory to other standard antiemetics. While excellent antiemetic control was achieved at the dosage 15 mg/m2, dysphoria was encountered at this dose level and we recommend that an initial dose of 5 mg/m2 which, if necessary, can be carefully increased to achieve maximum antiemetic benefit. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Oral
Dose(s)	dronabinol 15 mg/m2 1 h before chemotherapy and every 4 h thereafter for 24 h
Duration (days)
Participants	36 patients whose vomiting was refractory to standard antiem
Design	Controlled study
Type of publication
Address of author(s)	Division of Medical Oncology, Vincent T. Lombardi Cancer Research Center, Georgetown University, Washington, D.C. 20007
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Title	Inhalation marijuana as an antiemetic for cancer chemotherapy.
Author(s)	Vinciguerra V, Moore T, Brennan E.
Journal, Volume, Issue	New York State Journal of Medicine 1988;88:525-527.
Major outcome(s)	Marijuana effective as antiemetic agent
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Cannabis	A prospective pilot study of the use of inhalation marijuana as an 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 chemotherapy-induced nausea and vomiting. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Inhalation
Dose(s)
Duration (days)
Participants	56 patients
Design	Open study
Type of publication	Medical journal
Address of author(s)
Full text

Title	Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis.
Author(s)	Pomeroy M, Fennelly JJ, Towers M.
Journal, Volume, Issue	Cancer Chemother Pharmacol 1986;17(3):285-8.
Major outcome(s)	Nabilone superior to domperidone
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Nabilone	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 or subjectively adverse effects. Four of 19 patients completed only one cycle of D because of lack of efficacy or chemotherapy toxicity. 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 less than 0.02). The corresponding values for cycle 2 were 4.27 and 7.69 (P greater than 0.10), and for cycles 1 and 2 combined, 4.53 for N and 10.81 for D (P less than 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. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Oral
Dose(s)
Duration (days)
Participants	38 cancer patients
Design	Controlled study
Type of publication	Medical journal
Address of author(s)
Full text

Title	A multi-institutional Phase III study of nabilone vs. placebo in chemotherapy-induced nausea and vomiting.
Author(s)	Jones SE, Durant JR, Greco FA, Robertone A.
Journal, Volume, Issue	Cancer Treat Rev. 1982 Dec;9 Suppl B:45-8.
Major outcome(s)	Nabilone is an effective antiemetic agent for chemotherapy-induced nausea and vomiting.
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Nabilone	A prospective, randomized, double-blind, crossover study of nabilone versus placebo was undertaken in three university cancer centers to determine the antiemetic efficacy and toxicity of nabilone in patients experiencing nausea and vomiting due to cancer chemotherapy. Identical study drug (2 mg of nabilone or placebo) was given the evening before and the morning of chemotherapy and for at least 24h afterwards on a b.i.d. schedule. Careful assessment of nausea, vomiting and finally patient preference for study drug was carried out on each of two identical courses of combination chemotherapy. Fifty-four patients were entered. Of the 24 patients fully evaluable for efficacy, nabilone significantly reduced the mean number of vomiting episodes (7 vs. 18, P<0.001) and nausea (P<0.001) compared to placebo. In addition, 79% of patients experienced less vomiting and 63% less nausea while receiving nabilone compared to 13 and 4% of patients reporting less with placebo. Sixty-seven percent of patients preferred nabilone at the completion of this trial compared to 8” for placebo (P<0.001). Side effects were common with nabilone but acceptable and in 49 patients who were evaluable for toxicity consisted primarily of dizziness (65%), drowsiness (51%), dry mouth (31%), sleep disturbance (14%), ataxia (8%), nausea (8%) and euphoria (6%). Nabilone is an effective antiemetic agent for chemotherapy-induced nausea and vomiting. All Conditions Benefited by Medical Marijuana   Top      Home
Route(s)	Oral
Dose(s)	2 mg
Duration (days)
Participants	54 patients experiencing nausea and vomiting due to cancer c
Design	Controlled study
Type of publication	Medical journal
Address of author(s)
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Title	The antiemetic activity of tetrahydrocanabinol versus metoclopramide and thiethylperazine in patients undergoing cancer chemotherapy.
Author(s)	Colls BM, Ferry DG, Gray AJ, Harvey VJ, McQueen EG.
Journal, Volume, Issue	New Zealand Medical Journal 1980;91:449-451
Major outcome(s)	tetrahydrocannabinol given by mouth has an antiemetic effect of approximately the same order as thiethylperazine and metoclopramide
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Delta-9-THC	A double blind-cross-over randomised clinical trial has been conducted to compare the antiemetic effects of tetrahydrocannabinol, thiethylperazine and metoclopramide. There were no significant differences in the antiemetic effects of these drugs. The incidence of adverse reactions as recorded by both the staff and the patients was significantly higher in the tetrahydrocannabinol group than in either the metoclopramide or thiethylperazine groups. This trial has established that in the dosages used tetrahydrocannabinol given by mouth has an antiemetic effect of approximately the same order as thiethylperazine and metoclopramide. However, its adverse effects are sufficiently greater than those of the other agents to prevent is widespread usage for this purpose. Tetrahydrocannabinol taken by mouth is not recommended as a routine antiemetic agent in cancer chemotherapy. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Oral
Dose(s)
Duration (days)
Participants
Design	Controlled study
Type of publication
Address of author(s)
Full text

Title	Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A comparison with prochlorperazine and a placebo.
Author(s)	Frytak S, Moertel CG, O'Fallon JR, Rubin J, Creagan ET, O'Connell MJ, Schutt AJ, Schwartau NW
Journal, Volume, Issue	Annals of Internal Medicine 1979;91(6):825-830
Major outcome(s)	THC and PCP equally effective; both better than placebo; THC produced psychic effects in 82%
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Delta-9-THC	The antiemetic activity and side-effects of delta-9- tetrahydrocannabinol (THC) were evaluated in 116 patients (median age 61 years) receiving combined 5-fluorouracil and semustine (methyl CCNU) therapy for gastrointestinal carcinoma. In a double-blind study, patients were randomized to receive THC, 15 mg orally three times a day, prochlorperazine, 10 mg orally three times a day, or placebo. The THC had superior antiemetic activity in comparison to placebo, but it showed no advantage over prochlorperazine. Central nervous system side-effects, however, were significantly more frequent and more severe with THC. With the dosage and schedule we used, and in our patient population of largely elderly adults, THC therapy resulted in an overall more unpleasant treatment experience than that noted with prochlorperazine or placebo. Although THC may have a role in preventing nausea and vomiting associated with cancer chemotherapy, this role must be more clearly defined before THC can be recommended for general use. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Oral
Dose(s)	3 x 15 mg every 4 hours
Duration (days)	several days
Participants	116 cancer patients
Design	Controlled study
Type of publication
Address of author(s)	Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
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Title	Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomized evaluation.
Author(s)	Chang AE, Shiling DJ, Stillman RC, Goldberg NH, Seipp CA, Barofsky I, Simon RM, Rosenberg SA.
Journal, Volume, Issue	Annals of Internal Medicine 1979;91:819-824.
Major outcome(s)	14 of 15 patients had decreased vomiting and nausea
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Delta-9-THC	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. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Inhalation;Oral
Dose(s)	10mg/m2 oral, 17mg smoking every 3 hours
Duration (days)
Participants	15 patients receiving high-dose methotrexate
Design	Controlled study
Type of publication
Address of author(s)
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Title	Delta-9-tetrahydrocannabinol (THC) as an antiemetic in patients treated with cancer chemotherapy; a double-blind cross-over trial against placebo
Author(s)	Kluin-Nelemans JC, Nelemans FA, Meuwissen OJATh, Maes RAA
Journal, Volume, Issue	Veterinary and Human Toxicology 1979;21:338-340
Major outcome(s)	dronabinol superior to placebo (P<.01 for difference between groups at days 1 and 8 independently)
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Delta-9-THC	Summary A double-blind cross-over trial with delta-9-tetrahydrocannabinol (THC) and placebo was employed to test the antiemetic effect on nausea and vomiting after MOPP-therapy. Although THC had remarkable antiemetic effects, there side effects were severe. Most patients preferred the nausea and the vomiting after MOPP-therapy to the use of THC. A relation between the antiemetic action or the side-effects and the blood-level of THC could not be demonstrated. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Oral
Dose(s)	10 mg/m2 every 4 h, 3 doses a day
Duration (days)	on day 1 and day 8 of chemotherapy
Participants	patients receiving MOPP chemotherapy
Design	Controlled study
Type of publication
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Title	Amelioration of cancer chemotherapy-induced nausea and vomiting by delta-9-tetrahydrocannabinol.
Author(s)	Ekert H, Waters KD, Jurk IH, Mobilia J, Loughnan P
Journal, Volume, Issue	Med J Aust. 1979 Dec 15;2(12):657-9.
Major outcome(s)	THC was effective in reducing nausea and vomiting but not in all patients
Indication	Nausea/vomiting	Abstract
Medication	Delta-9-THC	The antinausea and antivomiting effects of delta-9-tetrahydrocannabinol (THC) in children receiving cancer chemotherapy were compared with those of metoclopramide syrup and prochlorperazine tablets in two double-blind studies. THC was found to be a significantly better antinausea and antivomiting agent, but not all patients obtained relief of nausea and vomiting with THC. In some patients, THC enhanced appetite during a course of chemotherapy. In two patients, a "high" associated with THC administrationwas reported. Drowsiness was reported significantly more frequently with THC. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Oral
Dose(s)	10 mg/m2 2 hr prior to chemo and 4, 8, 16 and 24 h after the first dose;
Duration (days)
Participants	Children receiving cancer chemotherapy
Design	Controlled study
Type of publication	Medical journal
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Title	Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy.
Author(s)	Herman TS, Einhorn LH, Jones SE, Nagy C, Chester AB, Dean JC, Furnas B, Williams SD, Leigh SA, Dorr RT, Moon TE.
Journal, Volume, Issue	N Engl J Med. 1979 Jun 7;300(23):1295-7.
Major outcome(s)	When both drugs were compared, both nausea and vomiting episodes were significantly lower in patients given nabilone.
Indication	Nausea/vomiting;Cancer;Cancer chemotherapy	Abstract
Medication	Nabilone	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. All Conditions Benefited by Medical Marijuana Top      Home

Title	Analgesic effect of delta-9-tetrahydrocannabinol.
Author(s)	Noyes R Jr, Brunk SF, Baram DA, Canter A
Journal, Volume, Issue	Journal of Clinical Pharmacology 1975;15(2-3):139-143
Major outcome(s)	pain relief with 15-20 mg THC
Indication	Cancer; Pain	Abstract
Medication	Delta-9-THC	A preliminary trial of oral delta-9-tetrahydrocannabinol (THC) demonstrated an analgesic effect of the drug in patients experiencing cancer pain. Placebo and 5, 10, 15, and 20 mg THC were administered double blind to ten patients. Pain relief significantly superior to placebo was demonstrated at high dose levels (15 and 20 mg). At these levels, substantial sedation and mental clouding were reported. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Oral
Dose(s)	5-20 mg
Duration (days)
Participants	10 cancer patients
Design	Controlled study
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Title	The analgesic properties of delta-9-tetrahydrocannabinol and codeine.
Author(s)	Noyes R Jr, Brunk SF, Avery DAH, Canter AC
Journal, Volume, Issue	Clinical Pharmacology and Therapeutics 1975;18(1):84-89
Major outcome(s)	milde analgesic effect; with 20 mg THC strong adverse effects
Indication	Cancer; Pain	Abstract
Medication	Delta-9-THC	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. All Conditions Benefited by Medical Marijuana Top      Home
Route(s)	Oral
Dose(s)	10-20 mg
Duration (days)
Participants	36 cancer patients
Design	Controlled study
Type of publication
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Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny T 
Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. [Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't]
J Clin Oncol 2006 Jul 20; 24(21):3394-400.

 

 PURPOSE: To compare the effects of cannabis extract (CE), delta-9-tetrahydrocannabinol (THC), and placebo (PL) on appetite and quality of life (QOL) in patients with cancer-related anorexia-cachexia syndrome (CACS).
PATIENTS AND METHODS: Adult patients with advanced cancer, CACS, weight loss (> or = 5% over 6 months), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2 were randomly assigned (2:2:1) to receive CE (standardized for 2.5 mg THC and 1 mg cannabidiol) or THC (2.5 mg) or PL orally, twice daily for 6 weeks. Appetite, mood, and nausea were monitored daily with a visual analog scale (VAS); QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (composite score: questions 29 and 30). Cannabinoid-related toxicity was assessed every 2 weeks.
RESULTS: Of 289 patients screened, 243 were randomly assigned and 164 (CE, 66 of 95 patients; THC, 65 of 100 patients; and PL, 33 of 48 patients) completed treatment. At baseline, groups were comparable for age (mean, 61 years), sex (54% men), weight loss (32% > or = 10%), PS (13% ECOG = 2), antineoplastic treatment (50%), appetite (mean VAS score, 31/100 mm), and QOL (mean score, 30/100). Intent-to-treat analysis showed no significant differences between the three arms for appetite, QOL, or cannabinoid-related toxicity. Increased appetite was reported by 73%, 58%, and 69% of patients receiving CE, THC, or PL, respectively. An independent data review board recommended termination of recruitment because of insufficient differences between study arms.
CONCLUSION: CE at the oral dose administered was well tolerated by these patients with CACS. No differences in patients' appetite or QOL were found either between CE, THC, and PL or between CE and THC at the dosages investigated.

 

ScienceDaily (Sep. 24, 2004) — Tampa, FL (Sept. 22, 2004)

The compound in marijuana that produces a high, delta-9 tetrahydrocannbinol or THC, may block the spread of several forms of cancer causing herpes viruses, University of South Florida College of Medicine scientists report.

 

The findings, published Sept. 15 in the online journal BMC Medicine, could lead to the creation of antiviral drugs based on nonpsychoactive derivatives of THC.

The gamma herpes viruses include Kaposi's Sarcoma Associated Herpes virus, which is associated with an increased risk of cancer that is particularly prevalent in AIDS sufferers. Another is Epstein-Barr virus, which predisposes infected individuals to cancers such as Burkitt's lymphoma and Hodgkin's disease.

Once a person is infected, these viruses can remain dormant for long periods within white blood cells before they burst out and begin replicating. This reactivation of the virus boosts the number of cells infected thereby increasing the chances that the cells will become cancerous.

The USF team, led by virologist Peter Medveczky, MD, found that this sudden reactivation was prevented if infected cells were grown in the presence of THC. While cells infected with a mouse gamma herpes virus normally died when the virus was reactivated, these same cells survived when cultured in the laboratory along with the cannabinoid compound – further evidence that THC prevents viral reactivation.

Furthermore, the researchers showed that THC acts specifically on gamma herpes viruses. The chemical had no effect on another related virus, herpes simplex-1, which causes cold sores and genital herpes.

Small concentrations of THC were more potent and selective against gamma herpes viruses than the commonly used antiviral drugs acyclovir, gancicyclovir and foscamet, said Dr. Medveczky, a professor in the Department of Medical Microbiology and Immunology.

The USF researchers suggest that THC selectively inhibits the spread of gamma herpes viruses by targeting a gene these viruses all share called ORF50.

Dr. Medveczky emphasized that more studies are needed. "We have not evaluated the effect of THC in an animal model yet so we do not recommend people start using pot to prevent or treat cancers."

In fact, Dr. Meveczky said, THC has also been shown to suppress the immune system so smoking marijuana could "do more harm than good" to patients whose immune systems are often already weakened.

 Story Source:

 The above story is reprinted (with editorial adaptations by CMMC) from materials provided by University Of South Florida Health Sciences Center.

 

 

By Neil Osterweil, Senior Associate Editor, MedPage Today
Published: May 24, 2006
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco .

 SAN DIEGO, May 24 — Smoking marijuana does not appear to increase the risk of lung cancer or head-and-neck malignancies, even among heavy users, researchers reported here.

"We expected that we would find that a history of heavy marijuana use, more than 500 to 1,000 uses, would increase the risk of cancer from several years to decades after exposure to marijuana, said Donald Tashkin, M.D., of the University of California in Los Angeles.

But in fact, they reported at the American Thoracic Society meeting here, marijuana use was associated with cancer risk ratios below 1.0, indicating that a history of pot smoking had no effect on the risk for respiratory cancers.

Dr. Tashkin was quick to point out, however, that marijuana does not appear to have a protective effect against cancer. "If it did, there would be a dose-dependent effect, with people who smoked more having a lower risk," he said. "We didn't see that."

Studies have shown that marijuana contains many compounds that when burned, produce about 50% higher concentrations of some carcinogenic chemicals than tobacco cigarettes.

In addition, heavy, habitual marijuana use can produce accelerated malignant change in lung explants, and evidence on bronchial biopsies of pre-malignant histopathologic and molecular changes, Dr. Tashkin said.

The investigators had also previously shown that smoking one marijuana cigarette leads to the deposition in the lungs of four times as much tar as smoking a tobacco cigarette containing the same amount of plant material. Marijuana cigarettes are not filtered and are more loosely packed than tobacco, so there's less filtration of the tar. In addition, pot smokers hold the smoke in their lungs about four times longer than tobacco smokers do, Dr. Tashkin pointed out.

He and his colleagues, led by epidemiologist Hal Morgenstern, Ph.D., of the University of Michigan in Ann Arbor, conducted a study to look at possible associations between marijuana use and the risk of respiratory cancers among middle-age adults in the Los Angeles area.

For the population-based case-control study, they identified cancer cases among people from the ages of 18 to 59, using the Los Angeles County Cancer Surveillance Program registry.

They identified 611 people with lung cancer, 601 with cancers of the head and neck, and 1,040 controls matched by age, gender and neighborhood (as a surrogate for socioeconomic status).

They conducted extensive personal interviews to determine lifetime marijuana use, measured in joint-years, with one joint-year equivalent to 365 marijuana cigarettes. The interviewers also asked participants about tobacco use, alcohol consumption, use of other drugs, socioeconomic status, diet, occupation, and family history of cancer.

The investigators also used logistic regression to estimate the effect of marijuana use on lung cancer risk, adjusting for age, gender, race/ethnicity, education, and cumulative tobacco smoking and alcohol use.

They found that the heaviest users in the study had smoked more than 60 joint years worth of marijuana, or more than 22,000 joints in their lifetime. Moderately heavy users smoked between 11,000 and 22,000 joints.

"That's an enormous amount of marijuana," Dr. Tashkin said.

Despite the heavy use, "in no category was there any increased risk, nor was there any suggestion that smoking more led to a higher odds ratio," he continued. "There was no dose-response—not even a suggestion of a dose response—and in all types of cancer except one, oral cancer, the odds ratios were less than one."

The confidence intervals around the odds ratios were wide however, and the odds ratios did not show a dose response.

In contrast, tobacco smoking was associated with increased risk for all cancers, and there was a "powerful" dose-response relationship. People who smoked more than two packs of cigarettes per day had a 21-fold risk for cancer, as opposed to a less than onefold risk for marijuana, Dr. Tashkin said.

"When we restricted the analysis to those who didn't smoke any tobacco we found the same results, and when we looked for interaction between tobacco and smoking—would marijuana increase the risk, potentiate the carcinogenic effect of tobacco—we didn't find that, nor did we find a protective effect against the effect of tobacco, which is very important, because the majority of marijuana smokers also smoke tobacco," he commented.

It's possible that tetrahydrocannabinol (THC) in marijuana smoke may encourage apoptosis, or programmed cell death, causing cells to die off before they have a chance to undergo malignant transformation, he said.

Dr. Tashkin also noted that "it's never a good idea to take anything into your lungs, including marijuana smoke."

• The American Society for Pharmacology and Experimental Therapeutics

 

PHILIP ROBSON, FRCPsych, Consultant Psychiatrist and Senior Clinical Lecturer, Warneford Hospital, Oxford OX3 7JX

 Abstract

Background: Review commissioned in 1996 by the Department of Health (DOH).

Aims: Assess therapeutic profile of cannabis and cannabinoids.

Method: Medline search, references supplied by DOH and others, and personal communications.

Results and Conclusions: Cannabis and some cannabinoids are effective antiemetics and analgesics and reduce intraocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.

Declaration of interest: Funding from DOH. Between writing this paper and its acceptance for publication, P.R. was appointed Medical Director of GW Pharmaceuticals.

 

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In 1996 I was commissioned by the Department of Health (DOH) to review the scientific literature regarding the potential therapeutic utility of cannabis and its derivatives. The review was based upon primary sources (identified from a Medline literature search, reference lists supplied by the DOH and the Institute for the Study of Drug Dependence, and personal communications with relevant academics and clinicians). This paper is a greatly shortened version of the review. The 4 years which have elapsed have seen little in the way of new clinical results but considerable advances in cannabinoid basic science (Institute of Medicine, 1999). Government licences have recently been granted for several controlled trials of both synthetic and plant-derived cannabinoids in multiple sclerosis and chronic pain. In January 2000, I was appointed Medical Director of GW Pharmaceuticals, a company established to derive medicinal extracts from standardised cannabis plants.

HISTORY OF THERAPEUTIC USE
The first formal report of cannabis as a medicine appeared in China nearly 5000 years ago when it was recommended for malaria, constipation, rheumatic pains and childbirth and, mixed with wine, as a surgical analgesic (Mechoulam, 1986). There are subsequent records of its use throughout Asia, the Middle East, Southern Africa and South America. Accounts by Pliny, Dioscorides and Galen remained influential in European medicine for 16 centuries.

It was not until the 19th century that cannabis became a mainstream medicine in Britain. W. B. O'Shaughnessy, an Irish scientist and physician, observed its use in India as an analgesic, anticonvulsant, antispasmodic, anti-emetic and hypnotic. After toxicity experiments on goats and dogs, he gave it to patients and was impressed with its muscle-relaxant, anticonvulsant and analgesic properties, and recorded its usefulness as an anti-emetic.

After these observations were published in 1842, medicinal use of cannabis expanded rapidly. It soon became available 'over the counter' in pharmacies and by 1854 it had found its way into the United States Dispensatory. The American market became flooded with dozens of cannabis-containing home remedies.

Queen Victoria's personal physician wrote (Reynolds, 1890), on the basis of more than 30 years' experience, that "Indian hemp, when pure and administered carefully, is one of the most valuable medicines we possess". He found it incomparable for "senile insomnia", "night restlessness" and "temper disease" in both children and adults, but not helpful in melancholia, "very uncertain" in alcoholic delirium, and "worse than useless" in mania. It was very effective in neuralgia, period pains, migraine, "lightning pain of the ataxic patient" and gout, but useless in sciatica and "hysteric pains". He found it impressive in clonic spasms and certain epileptiform convulsions related to brain damage, but no good at all in petit mal or "chronic epilepsy", tetanus, chorea or paralysis agitans. It effectively relieved nocturnal cramps, asthma and dysmenorrhoea.

Reynolds was writing at a time when the zenith of cannabis as prescribed medicine and home remedy was already past. Although Sir William Osler was still recommending it for migraine sufferers in 1913, it was by then in steep decline because of variable potency of herbal preparations, poor storage stability, unpredictable response to oral administration, increasing enthusiasm for parenteral medicines and availability of potent synthetic alternatives, commercial pressures and American concern about recreational use. Cannabis was outlawed in 1928 by ratification of the 1925 Geneva Convention on the manufacture, sale and movement of dangerous drugs. Prescription remained possible until final prohibition under the 1971 Misuse of Drugs Act, against the advice of the Advisory Committee on Drug Dependence.

In the USA, medical use was effectively ruled out by the Marijuana Tax Act 1937. This ruling has been under almost constant legal challenge and many special dispensations were made between 1976 and 1992 for individuals to receive 'compassionate reefers'. Although this loophole has been closed, a 1996 California state law permits cultivation or consumption of cannabis for medical purposes, if a doctor provides a written endorsement. Similar arrangements apply in Italy and Canberra, Australia.

CANNABINOID PHARMACOLOGY RELEVANT TO THERAPEUTICS
Cannabinol was isolated in 1895 and cannabidiol in 1934, but the most significant discovery was that of [DELTA]⁹-tetrahydrocannabinol (THC) in 1964. Chromatographic and spectroscopic methods subsequently uncovered many closely related compounds.

Capsules of synthetic THC (dronabinol) have been available for restricted medical use in the USA since 1985. Nabilone, a synthetic THC analogue, was marketed in 1983 and is the only cannabinoid licensed for prescription in the UK, restricted to treatment of nausea and vomiting caused by cytotoxic chemotherapy unresponsive to conventional anti-emetics. Use in other indications is only possible on a 'named patient' basis if the drug is supplied by a hospital pharmacy.

In 1988, a specific protein receptor (known as CB₁) for THC was discovered in mouse nerve cells. This mediates most of the central nervous system (CNS) responses to cannabinoids, and is abundant in basal ganglia, hippocampus and cerebellum, globus pallidus, substantia nigra and cerebral cortex. An endogenous ligand was identified in 1992 and labelled anandamide (ananda: 'bliss' in Sanskrit). Anandamide has analgesic and tranquillising effects in animals, is involved in muscle coordination and affects the secretion and function of certain hormones. Other endogenous agonists almost certainly exist.

In 1993, a second receptor (CB₂) was identified in rat spleen macrophages, and this occurs only outside the CNS. There is scope for chemical manipulation of cannabinoids to maximise selectivity for CB₂ and so avoid psychoactive effects. It is thought this receptor has relevance for anti-inflammatory and immunosuppressive activity.

Pertwee (1995) has suggested that the anandamide system might be concerned with mood, memory and cognition, perception, movement, coordination, posture and skeletal muscle tone, sleep, thermoregulation, appetite and immune response.

CLINICAL APPLICATIONS
Nausea and vomiting
Many cytotoxic drugs are powerful emetics, and this is the major limiting factor in patients' acceptance of cancer chemotherapy (see Table 1 and Appendix).

Table 1 Human randomised controlled trials (RCTs): anti-emetic effects

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Many recreational smokers receiving cancer chemotherapy have told their doctors that cannabis relieved their nausea (Grinspoon & Bakalar, 1993). Sallan et al's (1975) randomised control trial (RCT) compared oral THC and placebo in 22 cancer patients who had proved resistant to conventional anti-emetics. Comparisons using patients' self-reports of nausea and vomiting demonstrated that THC was statistically superior to placebo. THC (10 mg/m²) produced euphoria in the majority of patients, and one-third experienced sedation.

Subsequent RCTs (listed in Table 1) confirmed that natural and synthetic THC is invariably superior to placebo. Comparisons with anti-emetics available in the 1970s and 1980s suggest that THC is either equivalent in effect or better. A combination of prochlorperazine and THC was superior to either drug alone, and nabilone combined with prochlorperazine was better than dexamethazone plus metoclopramide. Although THC and nabilone produced more unwanted effects than comparison drugs, patients generally preferred them.

Children seem to respond well to nabilone and are tolerant of side-effects, but larger studies are required. [DELTA]⁸-THC performed well in a pilot study (Abrahamov et al, 1995) involving eight children aged 3-13 years with various blood cancers receiving chemotherapy, 60% of whom had experienced distressing vomiting despite treatment with metoclopramide. [DELTA]⁸-THC was given orally 2 hours before cytotoxics and repeated 6-hourly. No vomiting was recorded during this treatment and over the following 2 days. Two children were "slightly irritable" and one also showed "slight euphoria".

In a review of 12 studies involving 600 patients (Penta et al, 1981), THC was "effective" in 8/9 and nabilone in 3/3. The most common side-effects were somnolence (33%), dry mouth (9%), ataxia (8%), dizziness (6%), dysphoria (6%), and orthostatic hypotension (4%). A further review (Levitt, 1986) incorporating 55 studies, of which 32 were RCTs, showed that low-dose preventive treatment gives better results than targeting established vomiting. Younger patients may respond better than older ones.

Meta-analysis (Plasse et al, 1991) suggested that an optimal balance of efficacy and unwanted effects was achieved with relatively modest doses (7 mg/m² or less). Sedation and psychotropic symptoms are commonly reported, but are usually mild to moderate in intensity and resolve rapidly on discontinuation. No "persistent or fatal" adverse effects have been reported. Many American oncologists encourage nauseous patients to try cannabis and would prescribe it if it were legal (Doblin & Kleiman, 1991). Mode of action remains uncertain.

Multiple sclerosis and other neurological conditions
Drug therapy of muscle spasticity is generally only moderately effective and is limited by adverse effects (see Appendix). Spasticity is a central feature of multiple sclerosis (MS), cerebral palsy and spinal cord injury. Tremor, ataxia and incontinence also contribute to the high incidence of anxiety and depression in these conditions. Cannabis was often used to treat pain, muscle spasm, cramps and ataxia in the 19th century, and many modern sufferers have reported benefits (Grinspoon & Bakalar, 1993).

Most respondents to a questionnaire sent to British and American MS patients reported problems with symptom control (Consroe et al, 1997). Those who smoked cannabis claimed improvements in night-time spasticity and muscle pain (91-98%); night leg pain, depression, tremor, anxiety, spasms on walking, paraesthesiae (80-89%); leg weakness, trunk numbness, facial pain (71-74%); impaired balance (57%); constipation (33%); memory loss (31%).

In a small single-blind comparison with placebo (Clifford, 1983), THC improved tremor and ataxia in most patients. All experienced a 'high' at the top dose (15 mg), and two reported dysphoria. Dose-related improvements in dystonia were noted in five patients given cannabidiol 100-600 mg daily for 6 weeks. Hypotension, dry mouth, sedation and light-headedness occurred but were described as mild. Parkinsonian symptoms were aggravated in two subjects.

An RCT by Petro & Ellenberger (1981) compared the effects of placebo and THC in doses of 5 or 10 mg on muscle tone, reflexes and muscle power in nine MS patients. Both doses of THC reduced spasticity (P < 0.005). One patient receiving THC 10 mg and one patient receiving placebo felt 'high' but no other side-effects were recorded. In a small RCT (Ungerleider et al, 1987) with 5-day treatment periods, THC 7.5 mg significantly improved spasticity in comparison with placebo. Nabilone 1 mg on alternate days was compared with placebo in a double-blind randomised crossover trial with 4-week treatment periods in a single MS patient. Nocturia, muscle spasm and general well-being showed striking improvement during each active treatment period. Mild sedation was noted on active medication.

Cannabidiol had no beneficial effects in 15 patients with Huntington's disease (Consroe et al, 1991). Posture and balance were impaired by a single dose of smoked THC in 10 MS patients and 10 non-MS volunteers (Greenberg et al, 1994), but there was no active control to determine the effects of standard anti-spastic medication in this model.

Possible sites of action of cannabinoids in dystonia include basal ganglia, cerebellum, spinal motor neurons, somatic nerves and neuromuscular junction.

Loss of appetite and weight in cancer and AIDS
Several studies have investigated effect on appetite and weight (Table 2). The appetite-stimulating effect of cannabis was confirmed in fasting and non-fasting volunteers in an RCT of oral THC with alcohol, amphetamine and placebo (Hollister, 1971). A standardised THC smoking regime over 25 days in a residential laboratory was associated with significant increases in calorie intake and frequency of eating occasions in comparison with placebo.

Table 2 Human randomised controlled trials (RCTs): appetite and weight

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Open studies in cancer patients also showed appetite improvements and slowing of weight loss. Regelson et al's (1976) RCT explored the effect on appetite (and mood) of oral THC in 54 cancer patients over a 2-week period. There were nine with-drawals due to side-effects (six in THC period - dizziness, disassociation, confused thinking, panic, "feelings of disturbance"; three in the placebo period - anxiety, fits, dizziness, lethargy, weakness). Patients receiving THC in the first period gained weight (P<0.05), and those receiving placebo first showed reduced weight loss on transfer to THC (P<0.05). Depression, tranquillity and "forthrightness" scores all improved on THC. In a quarter of the patients, somnolence, dizziness and disassociation were severe enough to negate these effects.

Many people with AIDS have claimed that smoking marijuana inhibits nausea, improves appetite, reduces anxiety, relieves aches and pains, improves sleep and inhibits oral candidiasis. A small pilot study supported the hypothesis that dronabinol might reduce weight loss or even promote weight gain (Plasse et al, 1991).

Beal et al (1995) conducted an RCT over 42 days of treatment with dronabinol 5 mg daily in 139 AIDS patients who had lost at least 2.3 kg. Six receiving dronabinol and three receiving placebo withdrew because of "perceived drug toxicity". Dronabinol boosted appetite in comparison to placebo (P<0.015) and nausea was reduced (P=0.05). Improvement in mood was a strong trend (P=0.06) and there was a tendency toward weight gain (P=0.1). Dronabinol produced more adverse effects than placebo (P<0.001), but 75% of these were mild or moderate. Most frequent were euphoria (9), dizziness (5), thinking abnormalities (5) and sedation (4).

Further investigation is amply justified. Careful monitoring of possible effects upon the immune system is needed, although a prospective multi-centre study (Kaslow et al, 1989), which followed nearly 5000 HIV-positive men for 18 months, showed no link between use of psychoactive substances and mean T-cell counts or progression to AIDS.

Pain
Cannabinoids are effective analgesics in animal models with non-opiate mechanisms predominating. There are many anecdotal reports (Grinspoon & Bakalar, 1993) of benefits in bone and joint pain, migraine, cancer pain, menstrual cramps and labour.

Five small RCTs (Table 3) show that THC is significantly superior to placebo and produces dose-related analgesia peaking at around 5 hours, comparable to but out-lasting that of codeine. Side-effects were also dose-related, and consisted of slurred speech, sedation and mental clouding, blurred vision, dizziness and ataxia. Levonantradol was also superior to placebo and notably long-acting, but almost half the patients reported sedation. Cannabinoids may have considerable potential in neuropathic pain (Institute of Medicine, 1999).

Table 3 Human randomised controlled trials (RCTs): pain

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Raised intra-ocular pressure
Glaucoma due to obstructed outflow of aqueous humour or anatomical eye defects is the most common cause of blindness in the Western world. Some RCTs investigating this area are given in Table 4.

Table 4 Human randomised controlled trials (RCTs): raised intra-ocular pressure (IOP)

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There have been many anecdotal reports that street marijuana can relieve glaucoma symptoms and individuals have successfully argued in the USA for legal access to the drug (Grinspoon & Bakalar, 1993). A pilot study of smoked marijuana and oral THC (15 mg) in 11 glaucoma patients found an average intra-ocular pressure (IOP) reduction of 30% in seven subjects and no response in four (Hepler et al, 1976).

Randomised controlled trials in volunteers confirmed that oral, injected or smoked cannabinoids produce dose-related reductions of IOP (Hepler et al, 1976; Perez-Reyes et al, 1976). Conjunctival engorgement and tear reduction were often noted. THC, [DELTA]⁸-THC and 11-hydroxy-THC are more effective than cannabinol, while cannabidiol was without effect. Tolerance may develop on multiple dosing.

An RCT in patients showed IOP reductions of similar magnitude following smoked THC along with "alterations in mental status" and tachycardia (Merritt et al, 1980). THC eyedrops produced dose-related IOP reduction with minimal side-effects though parallel reductions in the untreated eye (also seen in animal models) suggested a systemic rather than local mode of action.

Insomnia, anxiety and depression
Randomised controlled trials investigating insomnia, anxiety and depression are given in Table 5.

Table 5 Human randomised controled trials (RCTs): insomnia, anxiety, depression

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Nabilone (1 mg three times daily) produced "dramatic improvements" on the Hamilton Anxiety Scale in 20 anxious patients in comparison to placebo (P<0.001), which were mirrored by other measures (Fabre & McLendon, 1981). Seven days into the study, nabilone patients' anxiety scores were halved, and this persisted unchanged throughout treatment. Side-effects included dry mouth, dry eyes and drowsiness. The authors concluded that nabilone is a "very effective anxiolytic deserving of further study". In a cross-over comparison of nabilone (1-2.5 mg twice daily) and placebo in 11 anxious patients (Ilaria et al, 1981), significant improvements in anxiety scores (P<0.05) were again noted. The only clinically significant adverse effect was postural hypotension with related dizziness, light-headedness or weakness. This was dose-related, experienced by most patients, and tended to tolerate out over time.

Preliminary data suggest that cannabidiol (160 mg) may be an effective hypnotic, and that THC (0.1 mg/kg) may have antidepressant properties in cancer patients and others (Grinspoon & Bakalar, 1993).

Epilepsy
Epilepsy afflicts 1% of the world's population. Conventional anticonvulsants provide unsatisfactory control for up to 30% of patients, and all can produce disabling or even life-threatening adverse effects.

The effect of cannabinoids on seizure activity in laboratory animals is complicated. Cannabidiol is a powerful anti-convulsant free of tolerance, but its profile varies between species. THC can produce seizures in big doses or when genetically seizure-sensitive animals are used, yet it is also robustly anticonvulsant in certain seizure models. A lack of stereospecificity suggests that the mechanism may not be related to a single receptor interaction. Serotonin, [gamma]-aminobutyric acid, acetylcholine or prostaglandin systems may be involved.

There are many anecdotal reports of beneficial effects in humans with epilepsy (Grinspoon & Bakalar, 1993) but research data are virtually non-existent. Two single-case reports (Keeler & Reifler, 1967; Consroe et al, 1975) give confounding information. A young man suffered seizures on his regular medication and began smoking several cannabis cigarettes nightly alongside this. No further seizures occurred while this combination was maintained. In contrast, a man with grand mal epilepsy stopped taking anticonvulsants and suffered no fits for 6 months. He then smoked cannabis on seven occasions over a 3-week period and suffered three fits during this time, although not coincident with actual intoxication.

Only one RCT (Cunha et al, 1980) exists. Fifteen poorly controlled patients with secondary generalised epilepsy continued with their regular therapy but were also given either cannabidiol or placebo daily for up to 4.5 months while undergoing regular clinical and electroencephalogram evaluation. Half the patients on cannabidiol remained "almost free" of fits throughout the experiment, and all but one of the others showed "partial improvement". All but one of the placebo patients remained entirely unchanged. Somnolence occurred in four patients receiving cannabidiol.

Asthma
Small-scale controlled studies in volunteers with asthma show that oral, smoked and aerosolised THC has comparable bronchodilatory activity to salbutamol, although onset is quicker with the latter. Dose-related tachycardia occurred in some individuals, and subjective intoxication with higher doses. A THC aerosol was free of systemic unwanted effects, but was irritant to the lungs (Tashkin et al, 1977). Nabilone does not produce bronchodilation. Since THC-induced bronchodilation is not mediated through the sympathetic nervous system, synergistic combinations with [beta]₂-adrenoceptor stimulants might be possible.

Other possible therapeutic applications
Basic research indicates that THC and analogues inhibit opioid withdrawal (Chesher & Jackson, 1985). Anecdotal reports from patients also point to beneficial effects beyond those which could be accounted for by sedative or hypnotic activity. Cannabinoids inhibit primary tumour growth and increase survival in animal tumour models (Harris et al, 1976) by an unknown mechanism. They also show antipyretic and anti-inflammatory activity (Formukong et al, 1989). Mechoulam (1986) has drawn attention to the lack of modern research directed at possible antihelmintic, antimigraine and oxytocic applications.

DISCUSSION
Therapeutic profile on existing evidence
Tetrahydrocannabinol and nabilone are effective anti-emetics but there are no comparisons with 5-HT₃ antagonists, so a role in modern anti-emetic regimes remains to be determined. Currently, only nabilone is licensed in the UK and available for prescription and research. THC (as dronabinol) has recently been rescheduled to permit prescription but remains unlicensed and must be specially imported on a named-patient basis. Delta-8-THC looks worthy of further investigation, particularly in children, and is much simpler to synthesise than THC.

Many individuals with MS have claimed a benefit from cannabis and small controlled trials support this, although effect upon posture and balance requires clarification. THC is an effective analgesic at the expense of sedation with larger doses and may have special merit in neuropathic pain. No conclusions are possible as yet about anticonvulsant potential. Some cannabinoids reduce IOP, though side-effects of products currently available limit application and effects of tolerance are uncertain. The mechanism for bronchodilation probably differs from that of [beta]₂-stimulants, so synergistic combinations may be possible.

Cannabis and THC are effective appetitc stimulants. Alongside anti-emetic, analgesic, anxiolytic, hypnotic and antipyretic properties this suggests a unique role in alleviating symptoms in selected patients with cancer or AIDS. This is a compelling area for future research, although possible effects upon immune function require careful monitoring.

Optimal doses and routes of delivery have not been established. Absorption by the oral route is unreliable. Smoking the drug is generally not a viable option since advantages such as rapid onset, accurate titration of effects and reliability in patients who are vomiting have to be set against the likelihood of lung irritation or damage, and it would in any case be unacceptable to most patients. However, pending availability of more satisfactory preparations, I believe that the existing profile of efficacy and toxicity justifies the provision of a legal supply of standardised herbal material ('compassionate reefers') to patients with terminal conditions who currently obtain relief with street cannabis. Sublingual sprays or tablets, nebulisers and aerosols look promising for the future, and THC is effective by the rectal route. Many potentially active cannabinoids have yet to be investigated and the recent identification of a peripheral receptor may lead to new drugs devoid of central nervous system effects.

Cannabis arouses passion in those who support or condemn it, and few people approach the clinical literature with dispassionate objectivity. Poorly controlled research produces ambiguous results which are then interpreted according to the prejudices of the reader. Anecdotes seem to be more readily accepted when they point to adverse rather than positive effects (Hall et al, 1994). Yet the known adverse effects of oral cannabinoids are rarely intolerable or life-threatening, in contrast to those associated with some standard therapies. A British Medical Association survey indicated that many UK doctors believe that cannabis should once again be available on prescription (Meek, 1994).

The way forward
A Select Committee of the House of Lords recently examined the scientific information concerning medical cannabis and took verbal and written evidence from a wide range of witnesses. Their conclusion (House of Lords, 1998) published in November 1998, was that, although cannabis should remain a controlled drug, the law should be changed to allow doctors to prescribe "an appropriate preparation of cannabis if they saw fit". The government rejected this recommendation on the day of publication.

Under the auspices of the Royal Pharmaceutical Society, large-scale multi-centre trials are under way to explore further the efficacy of cannabinoids in relieving spasticity and postoperative pain. A pharmaceutical company has obtained a licence to cultivate medicinal cannabis on a large scale in the UK. By selecting a specific genotype then carefully controlling all other relevant variables such as soil conditions, temperature and humidity, it is possible to obtain levels of purity in plant extracts equal or superior to those of 'pure' synthetic cannabinoids. Most of the 60 or so naturally occurring cannabinoids are present in tiny amounts, and synthetic cannabinoids such as nabilone themselves contain up to 5% impurities, some of which are of unknown identity. Whether obtained by synthetic means or by plant extraction, it is essential that cannabinoids for prescription and research in the future should demonstrate excellent purity, stability and bioavailability.

The medicinal properties of cannabis are still mainly delineated by the anecdotal reports of those who believe their symptoms are relieved by its use, and these accounts are often dismissed as wishful thinking or even mischievous. Since the conventional treatments for many of these disorders are both toxic and relatively ineffectual, a more constructive response would be to expose such claims to careful scientific examination and, in the meantime, search for a way to avoid criminalising those who seek only to assuage their own suffering.

CLINICAL IMPLICATIONS
* Cannabis and its derivatives show promise of beneficial effects in a number of medical conditions for which standard treatment is less than satisfactory, and further controlled research is fully justified.
* Cannabis is very safe in overdose, but often produces unwanted effects which are better tolerated by patients with some conditions (e.g. multiple sclerosis, chronic pain, AIDS, cancer) than others (e.g. glaucoma).
* Optimal for mutations, doses and routes of delivery have not yet been established.

LIMITATIONS
* Because of imposed time constraints, the review is not fully comprehensive, although all accessed sources were incorporated.
* Much of the evidence is anecdotal, and many of the research studies cited have serious methodological shortcomings.
* Few researchers (or reviewers) approach the subject of cannabinoid therapeutics in a spirit of dispassionate objectivity.

ACKNOWLEDGEMENT
This review was originally commissioned and funded by the Department of Health. The author thanks Dr Anthony Thorley for his support and encouragement. The views expressed in the paper are those of the author and not necessarily of the Department of Health.

APPENDIX
Existing anti-emetics
Phenothiazzines and butyrophenones can cause sedation, movement disorders which may be irreversible, neuroleptic malignant syndrome, dry mouth, blurred vision, urinary retention, hypotension, allergic reactions, jaundice, hypothermia, hormonal disturbances, irreversible eye damage and, rarely, life-threatening anaemias. Domperidone has a more benign profile but is not recommended for long-term use. Metoclopramide produces movement disorders (1% of patients), dizziness and drowsiness. Selective 5-HT₃ antagonists (ondansetron, granisetron) are newer and more expensive. Side-effects include constipation, headache, flushing, liver enzyme changes, allergic reactions, visual disturbances, chest pain and dysrhythmias.

Existing neurological treatments
Baclofen alleviates spasticity, but may accentuate muscle weakness. It produces dose-related nausea and vomiting, drowsiness, vertigo, confusion, fatigue and hypotonia. Less commonly, fits, psychiatric disorder and hypotension occur. Sudden withdrawal can cause hallucinations. Diazepam is useful but can worsen weakness or incoordination and cause drowsiness; ataxia, depression, disinhibition and dependence. Dantrolene may cause weakness, hypotonia, drowsiness, dizziness, vertigo and anxiety. Rarely, it damages the liver, and is not recommended in those with co-existing heart or lung disease.

Existing glaucoma treatments
Eye-drops. Miotics can produce blurring of vision, headache, and parasympathetic effects including sweating, bradycardia, colic and bronchospasm. Adrenaline often causes local discomfort. Dipivefrine and guanethicline may cause conjunctival fibrosis on chronic use. Beta-blockers may cause bradycardia, heart block or bronchoconstriction.

Systemic drugs (acctazolamide, dichlorphenamide) can cause hypokalaemia, appetite suppression, paraesthesiae, drowsiness, depression, rashes and, rarely, bone marrow suppression. [Context Link]

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by GW Pharmaceuticals

Emerging research indicates that cannabinoids may help protect against the development of certain types of tumors. Most recently, a Spanish research team reported in Nature that injections of synthetic THC eradicated malignant brain tumors - so-called gliomas - in one-third of treated rats, and prolonged life in another third by as much as six weeks.Team leader Manuel Guzman called the results "remarkable" and speculated that they "may provide a new therapeutic approach for the treatment of malignant gliomas.  An accompanying commentary remarked that this was the first convincing study to demonstrate that cannabis-based treatment may combat cancer. Other journals have also recently reported on cannabinoids' antitumoral potential.

Earlier studies also indicate that cannabinoids may successfully stave certain types of tumors. One study examined the effects of delta-9-tetrahydrocannabinol (THC), delta-8-THC, and cannabinol (CBN) on cancer cells in mice lungs. Researchers reported that cannabinoids reduced the size of the tumors by 25 to 82 percent, depending on dose and duration of treatment, with a corresponding increase in survival time. A two-year federal study by the U.S. National Toxicology Program found that mice and rats given high doses of THC over long periods of time appeared to have greater protection against malignancies than untreated controls. Researchers concluded that in both mice and rats, "the incidence of benign and malignant neoplasms was decreased in a dose dependent manner."  Dr. Lester Grinspoon writes in Marihuana: The Forbidden Medicine (with James Bakalar) that other animal studies also suggest that some cannabinoids have tumor-reducing properties. 

An Italian research team reported in 1998 that the endocannabinoid anandamide, which binds to the same brain receptors as cannabis, "potently and selectively inhibits the proliferation of human breast cancer cells in vitro" by interfering with their DNA production cycle. Non-mammary tumor cells were not affected by anandamide. Clearly, further research is necessary and appropriate.

 

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1. Sami Sarfaraz
2. Vaqar M. Adhami
3. Deeba N. Syed
4. Farrukh Afaq
5. Hasan Mukhtar
6. 
   

Requests for reprints:
Hasan Mukhtar, Department of Dermatology, University of Wisconsin-Madison, 1300, University Avenue, Medical Sciences Center, B-25, Madison, WI 53706. Phone: 608-263-3927; Fax: 608-263-5223; E-mail: hmukhtar@wisc.edu. 

 

Abstract

Cannabinoids are a class of pharmacologic compounds that offer potential applications as antitumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival. In particular, emerging evidence suggests that agonists of cannabinoid receptors expressed by tumor cells may offer a novel strategy to treat cancer. Here, we review recent work that raises interest in the development and exploration of potent, nontoxic, and nonhabit forming cannabinoids for cancer therapy. [Cancer Res 2008;

 Figure 1.

Schematic representation of signaling pathways associated with cannabinoid receptor activation induced by its agonists. Upon receptor binding, cannabinoid receptor agonists inhibit cell proliferation through inhibition of cAMP-dependent protein kinase, which activates mitogen-activated protein kinases (MAPK). Stimulation of ceramide synthesis via activation of serine pamitoyltranferase (SPT) up-regulates p8, leading to the subsequent induction of apoptosis. Cannabinoid receptor agonists also activates MAPKs and PI3K/Akt pathways; sustained activation of ERK1/2 leads to the induction of cyclin kinase inhibitor p27/KIP1with modulation of cell cycle regulatory molecules, resulting in G₁ arrest and apoptosis. The proposed mechanisms are based on the available literature and are cell specific, and not all pathways are triggered simultaneously. Further studies are needed to unravel the detailed mechanism of action of cannabinoid receptor activation by their agonists. CHOP, CAAT/enhancer binding protein homologous protein; PARP, poly(ADP)ribose polymerase; cdk, cyclin-dependent kinase. PKA, cAMP-dependent kinase.

 

 

Maurizio Bifulco, Chiara Laezza, Simona Pisanti, and Patrizia Gazzerro

 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, Fisciano 84084, Salerno, Italy

 Abstract

In the last two decades, research has dramatically increased the knowledge of cannabinoids biology and pharmacology. In mammals, compounds with properties similar to active components of Cannabis sativa, the so called ‘endocannabinoids', have been shown to modulate key cell-signalling pathways involved in cancer cell growth, invasion and metastasis. To date, cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increased evidences showed direct antiproliferative actions of cannabinoid agonists on several tumour cells in vitro and in animal models. In this article, we will review the principal molecular pathways modulated by cannabinoids on cancer and summarize pros and cons evidence on the possible future use of endocannabinoid-based drugs in cancer therapy.

 Introduction

Alexander A, Smith PF, Rosengren RJ

Cannabinoids, the active components of the hemp plant Cannabis sativa, along with their endogenous counterparts and synthetic derivatives, have elicited anti-cancer effects in many different in vitro and in vivo models of cancer. While the various cannabinoids have been examined in a variety of cancer models, recent studies have focused on the role of cannabinoid receptor agonists (both CB(1) and CB(2)) in the treatment of estrogen receptor-negative breast cancer. This review will summarize the anti-cancer properties of the cannabinoids, discuss their potential mechanisms of action, as well as explore controversies surrounding the results.

 

 

 

Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):117-31.

Pisanti S, Malfitano AM, Grimaldi C, Santoro A, Gazzerro P, Laezza C, Bifulco M.

Department of Pharmaceutical Sciences, University of Salerno, Italy.

Maurizio Bifulco, Chiara Laezza, Simona Pisanti, Patrizia Gazzerro

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, Fisciano 84084, Salerno, Italy

 Received August 22, 2005; Revised October 27, 2005; Accepted November 22, 2005

Abstract

 In the last two decades, research has dramatically increased the knowledge of cannabinoids biology and pharmacology. In mammals, compounds with properties similar to active components of Cannabis sativa, the so called ‘endocannabinoids', have been shown to modulate key cell-signalling pathways involved in cancer cell growth, invasion and metastasis. To date, cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increased evidences showed direct antiproliferative actions of cannabinoid agonists on several tumour cells in vitro and in animal models. In this article, we will review the principal molecular pathways modulated by cannabinoids on cancer and summarize pros and cons evidence on the possible future use of endocannabinoid-based drugs in cancer therapy.

 

 

Unpublished Federal Study Found THC-Treated Rats Lived Longer, Had Less Cancer

"What other drug would increase life expectancy of rats when given in huge overdoses daily for two years?"

by John S. James

AIDS TREATMENT NEWS has obtained a 126-page draft report of a major toxicology study of THC, the main psychoactive ingredient of marijuana. The study was completed over two and a half years ago, and passed peer review for publication, but has been kept quiet until this month, when someone leaked copies of the draft report. As far as we know, the public has never been told about this research -- for example, the drug- reform movement seems not to have known about its existence. This work may have been hushed because its findings are not what the drug-war industry would want.

The study gave huge doses of THC to rats and mice by stomach tube, and looked for cancers and other evidence of toxicity. First there were small toxicity studies, which used enough THC to kill some of the animals; later, two-year studies were run in both rats and mice, using doses which were still much higher than those of marijuana smokers. The two-year studies tested THC in several hundred rats and several hundred mice. In rats, those given THC had a clear survival advantage over the untreated controls; this effect was statistically significant in all dose groups, and in both males and females. In mice (which were given much larger doses than the rats relative to body weight) there was no survival difference among the groups -- except that those given the highest dose (which was close to the lethal dose for mice) had worse survival.

In both mice and rats, in both males and females, "the incidence of benign and malignant neoplasms ... were decreased in a dose-dependent manner" -- meaning that the more THC the animals were given, the fewer tumors they developed.

The treated animals weighed less than the controls (even though both ate about the same amount of food); the researchers speculated that the lower body weight may have partly accounted for the increased survival and reduced tumors in the THC-treated animals.

The doses were large enough to cause seizures and convulsions in many of the animals, especially when they were dosed or handled. These did not start immediately, but after many weeks, depending on the dose. The researchers looked for brain lesions in animals which had seizures, but found none.

No evidence of carcinogenic activity in the rats, but there was "equivocal evidence" of one kind of thyroid tumor in the mice -- with no evidence of a dose-dependent response. Other tumors were less common in the treated animals than in the controls -- except in one case, which the toxicologists believed was due to the fact that the treated animals lived longer, and therefore had more opportunity to develop tumors. The report includes a professionally objective review of the biological effects, possible toxicities, and possible medical uses of THC and marijuana.

The title of the report is "NTP Technical Report on the Toxicology and Carcinogenesis Studies of 1-Trans-Delta(9)- Tetrahydrocannabinol (CAS No. 1972-08-3) in F344/N Rats and B6C3F(1) Mice (Gavage Studies)." Over 35 researchers contributed to this study, and 12 others reviewed their work; several institutions, including the National Toxicology Program and SRI International, were involved. The document we received is report NTP TR 446, NIH Publication No. 94-3362, of the U.S. Department of Health and Human Services. ("NTP" stands for National Toxicology Program, which is made up of four Federal agencies within Health and Human Services.) Each page of the draft is stamped "not for distribution or attribution." In addition to the 126-page document we have reviewed here, there are 11 appendices, which we have not seen.

According to the draft, the report will be available from NTP Central Data Management, 919/541-1371. AIDS TREATMENT NEWS requested a copy of the final report when it is ready, and also requested a copy of the draft. Now that the existence of the report has become publicly known, we have heard that draft copies are being sent if requested -- despite the notice on each page not to distribute them.

Comment

It would be wrong to interpret this study as showing a beneficial or protective effect of marijuana. The animals were given very large doses, resulting in substantially lower body weight, which may itself have caused much of the survival and tumor improvements. Also, this study used THC, not marijuana smoke -- which like any smoke contains many chemicals, some of which are likely to be harmful. But the study does provide strong evidence that there is no significant cancer risk (if any at all) from the main psychoactive ingredient of marijuana; any such risk would be from incidental substances in the smoke. And if there is such a risk, the modern high-potency marijuana would likely reduce it, by reducing the amount of smoke required to obtain the desired effect.

Also, there is no known case of any human death from overdose of marijuana or THC, or from any other acute toxicity of these substances -- a remarkable safety record, compared with alcohol, aspirin, or many other common drugs. (The toxicology report does not say there have been no deaths, but the authors listed none, after doing an exhaustive survey of the literature.)

The literature review on the effects of THC and marijuana shows how medical research has been politically skewed (although the paper itself does not state this point). There are almost no studies of possible medical uses of marijuana, but many studies looking for possible harm. Any positive findings, therefore, can be used to support the drug war -- while negative findings (those which fail to show any effect) are usually ignored. Although many doctors and patients have reported important medical benefits, scientific studies of medicinal use have seldom been allowed to happen, since positive findings could challenge the official public- relations tactic of demonization. The drug war itself has controlled the medical research agenda, since it controls legal access to marijuana. Like most permanent wars, it strives for self preservation.

The newly available Federal toxicology study provides the best evidence yet that the risks of THC are small. What other drug would increase life expectancy of rats when given in huge overdoses daily for two years? The recent Federal attacks on medical marijuana -- against doctors and desperately ill patients -- are needlessly cruel, and bizarrely inappropriate to scientific and medical understanding.

AIDS TREATMENT NEWS Published twice monthly

Editor and Publisher: John S. James

 

Derivatives of the cannabis plant (hashish) have been shown by a Hebrew University of Jerusalem Ph.D. student to be effective in arresting cancerous growths in laboratory and animal tests.

For her work, Natalya Kogan was one of the winners of a Kaye Innovation Award, presented today during the 68th meeting of the Hebrew University Board of governors.

Working under the supervision of Prof. Raphael Mechoulam at the Hebrew University School of Pharmacy (in collaboration with Prof. Michael Schlesinger at the Hebrew University-Hadassah Medical School and Prof. Ester Priel at Ben-Gurion University of the Negev), Kogan has developed new compounds – known as quinonoid cannabinoids – that parallel in their activity a group of anti-cancer drugs, the best known of which is daunomycin.

However, while daunomycin is toxic to the heart, Kogan, with Dr. Ronen Beeri and Dr. Gergana Marincheva of Hadassah University Hospital, Ein Kerem, found that the quinonoid cannabinoids are much less cardiotoxic. The development of quinonoid compounds that display anticancer activity, but are less toxic, is a major therapeutic goal. At present, Kogan is continuing to investigate the mechanism of action of these promising compounds.

All of the compounds synthesized by Kogan inhibited cancer cell growth in cell culture, and one of them was found to markedly reduce the volume of tumors in animal studies The cannabinoid quinones were found to act through a rather unique pathway of cancer cell destruction -- by specific inhibition of topoisomerase II, an enzyme that participates in cell replication. Most of the known anti-cancer drugs are less selective, acting by numerous mechanisms.

Additionally, the most active compound in the series developed by Kogan, as well as some other cannabinoids, were found by Kogan and Prof. Ruth Galilli of the Hebrew University to have anti-angiogenic properties. Angiogenesis, the process of new blood vessel formation, is crucial for tumor growth, and much effort has been invested by researchers in the development of compounds with anti-angiogenic activity.

Since the compounds developed by Kogan have anti-cancer properties and are more selective and potent than standard chemotherapy drugs, they have a high potential for use in new anti-cancer drugs

Kogan was born in 1980 in Cherkassy, Ukraine, and immigrated to Israel in 1995. She earned B.Pharm and M.Sc degrees at the Hebrew University School of Pharmacy and graduated with excellence.

She has received numerous prior awards: the Wolf Prize for junior investigators (2005); the Keren Kayemet prize (2005); and a Best Poster Award at the 2004 Symposium of the International Cannabinoids Research Society. Her Ph.D. work is supported by a personal award (for high grades and research achievements) from the Canadian Friends of the Hebrew University. The Kaye Innovation Awards at the Hebrew University have been awarded annuallysince 1994. Isaac Kaye of England, a prominent industrialist in the pharmaceutical industry, established the awards to encourage faculty, staff, and students of the University to develop innovative methods and inventions with good commercial potential which have benefited or will benefit the University and society.