Friday, January 6, 2012

Cannabis and Cannabinoids, Cancer Antitumor Effects, Prion prevention, Pain management, Muscle relaxer, and Palliative Medicine

National Cancer Institute at the National Institutes of Health

Cannabis and Cannabinoids (PDQ®), Cancer Antitumor Effects, Prion prevention, Pain management, muscle relaxer, and Palliative Medicine

Cannabis and Cannabinoids (PDQ®)

Laboratory/Animal/Preclinical Studies

Antitumor Effects Appetite Stimulation Analgesia

Cannabinoids are a group of 21-carbon–containing terpenophenolic compounds produced uniquely by Cannabis sativa and Cannabis indica species.[1,2] These plant-derived compounds may be referred to as phytocannabinoids. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biologic activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thought to have significant analgesic and anti-inflammatory activity without the psychoactive effect (high) of delta-9-THC.

Antitumor Effects

One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors.[3] During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, delta-9-THC, delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo .[4] In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5-8]

Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis and metastasis.[9-11] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. These compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats. Cannabinoids protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.[12]

The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in hepatocellular carcinoma (HCC).[13] Both agents reduced the viability of hepatocellular carcinoma cells in vitro and demonstrated antitumor effects in hepatocellular carcinoma subcutaneous xenografts in nude mice. The investigations documented that the anti-HCC effects are mediated by way of the CB2 receptor. Similar to findings in glioma cells, the cannabinoids were shown to trigger cell death through stimulation of an endoplasmic reticulum stress pathway that activates autophagy and promotes apoptosis. Other investigations have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma[14] and breast cancer.[15]

In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[16] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[17,18]

In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[19] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[20-23]

Appetite Stimulation
Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[24] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[25]

Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[26] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[27,28]

Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described.[29-31]


1.Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PUBMED Abstract]

2.Grotenhermen F, Russo E, eds.: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Binghamton, NY: The Haworth Press, 2002.

3. National Toxicology Program .: NTP toxicology and carcinogenesis studies of 1-trans-delta(9)-tetrahydrocannabinol (CAS No. 1972-08-3) in F344 rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser 446 (): 1-317, 1996. [PUBMED Abstract]

4.Bifulco M, Laezza C, Pisanti S, et al.: Cannabinoids and cancer: pros and cons of an antitumour strategy. Br J Pharmacol 148 (2): 123-35, 2006. [PUBMED Abstract]

5.Sánchez C, de Ceballos ML, Gomez del Pulgar T, et al.: Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61 (15): 5784-9, 2001. [PUBMED Abstract]

6.McKallip RJ, Lombard C, Fisher M, et al.: Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100 (2): 627-34, 2002. [PUBMED Abstract]

7.Casanova ML, Blázquez C, Martínez-Palacio J, et al.: Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111 (1): 43-50, 2003. [PUBMED Abstract]

8.Blázquez C, González-Feria L, Alvarez L, et al.: Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64 (16): 5617-23, 2004. [PUBMED Abstract]

9.Guzmán M: Cannabinoids: potential anticancer agents. Nat Rev Cancer 3 (10): 745-55, 2003. [PUBMED Abstract]

10.Blázquez C, Casanova ML, Planas A, et al.: Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17 (3): 529-31, 2003. [PUBMED Abstract]

11.Vaccani A, Massi P, Colombo A, et al.: Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 144 (8): 1032-6, 2005. [PUBMED Abstract]

12.Torres S, Lorente M, Rodríguez-Fornés F, et al.: A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 10 (1): 90-103, 2011. [PUBMED Abstract]

13.Vara D, Salazar M, Olea-Herrero N, et al.: Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 18 (7): 1099-111, 2011. [PUBMED Abstract]

14.Preet A, Qamri Z, Nasser MW, et al.: Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res (Phila) 4 (1): 65-75, 2011. [PUBMED Abstract]

15.Nasser MW, Qamri Z, Deol YS, et al.: Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion. PLoS One 6 (9): e23901, 2011. [PUBMED Abstract]

16.Preet A, Ganju RK, Groopman JE: Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 27 (3): 339-46, 2008. [PUBMED Abstract]

17.Zhu LX, Sharma S, Stolina M, et al.: Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol 165 (1): 373-80, 2000. [PUBMED Abstract]

18.McKallip RJ, Nagarkatti M, Nagarkatti PS: Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol 174 (6): 3281-9, 2005. [PUBMED Abstract]

19.Massa F, Marsicano G, Hermann H, et al.: The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 113 (8): 1202-9, 2004. [PUBMED Abstract]

20.Patsos HA, Hicks DJ, Greenhough A, et al.: Cannabinoids and cancer: potential for colorectal cancer therapy. Biochem Soc Trans 33 (Pt 4): 712-4, 2005. [PUBMED Abstract]

21.Liu WM, Fowler DW, Dalgleish AG: Cannabis-derived substances in cancer therapy--an emerging anti-inflammatory role for the cannabinoids. Curr Clin Pharmacol 5 (4): 281-7, 2010. [PUBMED Abstract]

22.Malfitano AM, Ciaglia E, Gangemi G, et al.: Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets 15 (3): 297-308, 2011. [PUBMED Abstract]

23.Sarfaraz S, Adhami VM, Syed DN, et al.: Cannabinoids for cancer treatment: progress and promise. Cancer Res 68 (2): 339-42, 2008. [PUBMED Abstract]

24.Mechoulam R, Berry EM, Avraham Y, et al.: Endocannabinoids, feeding and suckling--from our perspective. Int J Obes (Lond) 30 (Suppl 1): S24-8, 2006. [PUBMED Abstract]

25.Fride E, Bregman T, Kirkham TC: Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) 230 (4): 225-34, 2005. [PUBMED Abstract]

26.Walker JM, Hohmann AG, Martin WJ, et al.: The neurobiology of cannabinoid analgesia. Life Sci 65 (6-7): 665-73, 1999. [PUBMED Abstract]

27.Meng ID, Manning BH, Martin WJ, et al.: An analgesia circuit activated by cannabinoids. Nature 395 (6700): 381-3, 1998. [PUBMED Abstract]

28.Walker JM, Huang SM, Strangman NM, et al.: Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U S A 96 (21): 12198-203, 1999. [PUBMED Abstract]
29.Facci L, Dal Toso R, Romanello S, et al.: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 92 (8): 3376-80, 1995. [PUBMED Abstract]

30.Ibrahim MM, Porreca F, Lai J, et al.: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A 102 (8): 3093-8, 2005. [PUBMED Abstract]

31.Richardson JD, Kilo S, Hargreaves KM: Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75 (1): 111-9, 1998. [PUBMED Abstract]

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1
Robert Ramer*, Katharina Bublitz*, Nadine Freimuth*, Jutta Merkord*, Helga Rohde*, Maria Haustein*, Philipp Borchert*, Ellen Schmuhl*, Michael Linnebacher† and Burkhard Hinz*,1

+ Author Affiliations

*Institute of Toxicology and Pharmacology and

†Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany

↵1Correspondence: Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany. E-mail:


Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001–3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ9-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.

—Ramer, R., Bublitz, K., Freimuth, N., Merkord, J., Rohde, H., Haustein, M., Borchert, P., Schmuhl, E., Linnebacher, M., Hinz, B. Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. cannabinoids tissue inhibitor of metalloproteinases-1 experimental metastasis ICAM-1 Received October 17, 2011. Accepted December 5, 2011.

Cannabis in Palliative Medicine: Improving Care and Reducing Opioid-Rel­ated Morbidity

Published online before print March 28, 2011, J HOSP PALLIAT CARE August 2011 vol. 28 no. 5 297-303

Cannabis in Palliative Medicine: Improving Care and Reducing Opioid-Related Morbidity

Gregory T. Carter, MD, MS Hospice Services, Providence Medical Group, Olympia, WA, USA, Aaron M. Flanagan, MD Providence Medical Group, Olympia, WA, USA Mitchell Earleywine, PhD Department of Psychology, University at Albany State University of New York, Albany, NY, USA Donald I. Abrams, MD University of California, San Francisco, CA, USA Sunil K. Aggarwal, MD, PhD Physical Medicine and Rehabilitation, The Rusk Institute of Rehabilitation Medicine, New York University, USA Lester Grinspoon, MD Department of Psychiatry, Harvard Medical School, USA, Massachusetts Mental Health Center, Boston, MA, USA


Unlike hospice, long-term drug safety is an important issue in palliative medicine. Opioids may produce significant morbidity. Cannabis is a safer alternative with broad applicability for palliative care. Yet the Drug Enforcement Agency (DEA) classifies cannabis as Schedule I (dangerous, without medical uses). Dronabinol, a Schedule III prescription drug, is 100% tetrahydrocannabinol (THC), the most psychoactive ingredient in cannabis. Cannabis contains 20% THC or less but has other therapeutic cannabinoids, all working together to produce therapeutic effects. As palliative medicine grows, so does the need to reclassify cannabis. This article provides an evidence-based overview and comparison of cannabis and opioids. Using this foundation, an argument is made for reclassifying cannabis in the context of improving palliative care and reducing opioid-related morbidity.
cannabis medical marijuana opioids hospice chronic pain palliative medicine

Published online ahead of print August 30, 2010 CMAJ 10.1503/cm­aj.091414

Smoked cannabis for chronic neuropathi­c pain: a randomized controlled trial


Background: Chronic neuropathic pain affects 1%–2% of the adult population and is often refractory to standard pharmacologic treatment. Patients with chronic pain have reported using smoked cannabis to relieve pain, improve sleep and improve mood.

Methods: Adults with post-traumatic or postsurgical neuropathic pain were randomly assigned to receive cannabis at four potencies (0%, 2.5%, 6% and 9.4% tetrahydrocannabinol) over four 14-day periods in a crossover trial. Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle, followed by a nine-day washout period. Daily average pain intensity was measured using an 11-point numeric rating scale. We recorded effects on mood, sleep and quality of life, as well as adverse events.

Results: We recruited 23 participants (mean age 45.4 [standard deviation 12.3] years, 12 women [52%]), of whom 21 completed the trial. The average daily pain intensity, measured on the 11-point numeric rating scale, was lower on the prespecified primary contrast of 9.4% v. 0% tetrahydrocannabinol (5.4 v. 6.1, respectively; difference = 0.7, 95% confidence interval [CI] 0.02–1.4). Preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief. Participants receiving 9.4% tetrahydrocannabinol reported improved ability to fall asleep (easier, p = 0.001; faster, p < 0.001; more drowsy, p = 0.003) and improved quality of sleep (less wakefulness, p = 0.01) relative to 0% tetrahydrocannabinol. We found no differences in mood or quality of life. The most common drug-related adverse events during the period when participants received 9.4% tetrahydrocannabinol were headache, dry eyes, burning sensation in areas of neuropathic pain, dizziness, numbness and cough.

Conclusion­:: A single inhalation of 25 mg of 9.4% tetrahydro­cannabinol herbal cannabis three times daily for five days reduced the intensity of pain, improved sleep and was well tolerated. Further long-term safety and efficacy studies are indicated. (Internati­onal Standard Randomised Controlled Trial Register no. ISRCTN6831­4063)

Our results support the claim that smoked cannabis reduces pain, improves mood and helps sleep. We believe that our trial provides a methodological approach that may be considered for further research. Clinical studies using inhaled delivery systems, such as vaporizers,32,33 are needed.

Cases J. 2009; 2: 7487.
Published online 2009 May 18

Standardiz­ed natural product cannabis in pain management and observatio­ns at a Canadian compassion society: a case report

Cases J. 2009; 2: 7487. Published online 2009 May 18. doi: 10.1186/1757-1626-2-7487 PMCID: PMC2740265

Copyright © 2009 Hornby et al.; licensee Cases Network Ltd.

Standardized natural product cannabis in pain management and observations at a Canadian compassion society: a case report

A Paul Hornby,1 Manju Sharma,2 and Bree Stegman3 1Department of Medial Cannabis Research, The Green Cross Society of BC, 2127 Kingsway, Vancouver, B.C., V5N 2T4, Canada 2Department of Pathology and Laboratory Medicine, Heather Pavilion, Vancouver General Hospital, Vancouver, B.C., Canada 3Canadian Registered Nurses Association of B.C., Vancouver Coastal Health Authority, 2755 Arbutus Street, Vancouver, B.C., Canada Corresponding author. A Paul Hornby: ; Manju Sharma: ; Bree Stegman:

Received November 5, 2008; Accepted February 13, 2009.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC.


An adult Caucasian male with excruciating pains following multiple traumas was monitored, daily, over one year while managing chronic pain by self-administering quantifiable amounts of natural cannabis. Tetrahydrocannabinol, Cannabidiol, and Cannabinol were all measured in tinctures, capsules, smoke-able product plus some baked goods, prior to their administration. By allowing standardization, the subject was able to develop a daily regimen of pain management that was resistant to a battery of most patent analgesics.



The case reported here represents one of many observed at the Green Cross Society. With 70% of the members treating chronic pain the same phenomenon is observed over and over that people achieve a significant degree of pain management using standardized natural product cannabis. Often a better quality of life is attained with cannabis use only, or in conjunction with reduced opiate consumption. The subject in this study is nearly one year using only natural product cannabis plus supplements for his severe pain. He recently went through yet another two surgeries to back and hand using only cannabis for post-operative pain.

The roughly 4000 members of the Green Cross Society find similar benefit from standardized natural product cannabis medicine. To follow, will be publication of the Society's demographic data regarding use for various conditions such as arthritis, fybromyalgia, HIV/AIDS, and chronic pain, to name a few. A breakdown of the illnesses, what strains (cannabinoid profiles) is most effective, and at what dosages will be published at a later time.

Effect of D9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans
H Beaumont1, J Jensen2, A Carlsson2, M Ruth3, A Lehmann2 and GE Boeckxstaens1,4 1Academic Medical Centre, Department of Gastroenterology and Hepatology, Amsterdam, the Netherlands, 2AstraZeneca R&D, Integrative Pharmacology, Mölndal, Sweden 3Discovery Medicine, Mölndal, Sweden, and 4University Hospital Leuven, Catholic University of Leuven, Department of Gastroenterology, Leuven, Belgium

Background and purpose: Transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-oesophageal reflux and are a potential pharmacological treatment target. We evaluated the effect of the CB1/CB2 receptor agonist D9-tetrahydrocannabinol (D9-THC) on TLESRs in dogs. Based on these findings, the effect of D9-THC was studied in healthy volunteers.

Experimental approach: In dogs, manometry was used to evaluate the effect of D9-THC in the presence and absence of the CB1 receptor antagonist SR141716A on TLESRs induced by gastric distension. Secondly, the effect of 10 and 20 mg D9-THC was studied in 18 healthy volunteers in a placebo-controlled study. Manometry was performed before and for 3 h after meal ingestion on three occasions.
Key results: In dogs, D9-THC dose-dependently inhibited TLESRs and reduced acid reflux rate. SR141716A significantly reversed the effects of D9-THC on TLESRs. Similarly, in healthy volunteers, D9-THC significantly reduced the number of TLESRs and caused a non-significant reduction of acid reflux episodes in the first postprandial hour. In addition, lower oesophageal sphincter pressure and swallowing were significantly reduced by D9-THC. After intake of 20 mg, half of the subjects experienced nausea and vomiting leading to premature termination of the study. Other side-effects were hypotension, tachycardia and central effects. Conclusions and implications: D9-THC significantly inhibited the increase in meal-induced TLESRs and reduced spontaneous swallowing in both dogs and humans. In humans, D9-THC significantly reduced basal lower oesophageal sphincter pressure. These findings confirm previous observations in dogs and indicate that cannabinoid receptors are also involved in the triggering of TLESRs in humans.

In conclusion, the present study demonstrates that D9-THC significantly inhibits the increase in TLESRs evoked by meal ingestion and reduces spontaneous swallowing in both dogs and humans. Furthermore, D9-THC reduces basal LES pressure in humans. These findings confirm previous findings in dogs and indicate that CB receptors are also involved in the triggering of TLESRs in humans.

British Journal of Pharmacology (2009) 156, 153–162; doi:10.1111/j.1476-5381.2008.00010.x; published online 5 December 2008

Keywords: gastro-oesophageal reflux disease; cannabinoid; transient lower oesophageal sphincter relaxation; D9-tetrahydrocannabinol

Abbreviations: GERD, gastro-oesophageal reflux disease; LES, lower oesophageal sphincter; TLESRs, transient lower oesophageal sphincter relaxations; CB, cannabinoid; D9-THC, D9-tetrahydrocannabinol; DMN, dorsal motor nucleus of the vagus; NTS, nucleus tractus solitarius; PPIs, proton pump inhibitors

J Neurosci. 2007 Sep 5;27(36):9­537-44.

Nonpsychoa­ctive cannabidio­l prevents prion accumulati­on and protects neurons against prion toxicity.
Dirikoc S, Priola SA, Marella M, Zsürger N, Chabry J.

Institut de Pharmacolo­gie Moléculair­e et Cellulaire­, Unité Mixte de Recherche 6097, Centre National de la Recherche Scientifiq­ue, 06560 Valbonne, France.


Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the CNS of the protease-resistant prion protein (PrPres), a structurally misfolded isoform of its physiological counterpart PrPsen. Both neuropathogenesis and prion infectivity are related to PrPres formation. Here, we report that the nonpsychoactive cannabis constituent cannabidiol (CBD) inhibited PrPres accumulation in both mouse and sheep scrapie-infected cells, whereas other structurally related cannabinoid analogs were either weak inhibitors or noninhibitory. Moreover, after intraperitoneal infection with murine scrapie, peripheral injection of CBD limited cerebral accumulation of PrPres and significantly increased the survival time of infected mice. Mechanistically, CBD did not appear to inhibit PrPres accumulation via direct interactions with PrP, destabilization of PrPres aggregates, or alteration of the expression level or subcellular localization of PrPsen. However, CBD did inhibit the neurotoxic effects of PrPres and affected PrPres-induced microglial cell migration in a concentration-dependent manner. Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug.

Drugs: 9 July 2010 - Volume 70 - Issue 10 - pp 1245-1254 doi: 10.2165/11537930-000000000-00000 Review Articles Pharmacological Management of Pain in Patients with Multiple Sclerosis
Solaro, Claudio1; Messmer Uccelli, Michele2
Multiple sclerosis (MS) is an inflammatory, demyelinating, autoimmune disease of the CNS. There are currently a number of disease-modifying medications for MS that modulate or suppress the immune system; however, these medications do not directly relieve MS symptoms, which include visual deficits, gait problems, sensory deficits, weakness, tremor, spasticity and pain, among others.
Pain is a common symptom in MS which has recently been estimated to be experienced by more than 40% of patients. Nociceptive pain occurs as an appropriate physiological response transmitted to a conscious level when nociceptors in bone, muscle or any body tissue are activated, warning the organism of tissue damage. Neuropathic pain is initiated as a direct consequence of a lesion or disease affecting the somatosensory system, with no physiological advantage. Nociceptive and neuropathic pain in MS may be present concurrently and at different stages of the disease, and may be associated with other symptoms. Central neuropathic pain has been reported to be among the most common pain syndromes in MS. It is described as constant, often spontaneous, burning occurring more frequently in the lower limbs. Treatment typically includes tricyclic antidepressants and antiepileptic medications, although studies have been conducted in relatively small samples and optimal dosing has not been confirmed. Cannabinoids have been among the few treatments studied in well designed, randomized, placebo-controlled trials for central neuropathic pain. In the largest of these trials, which included 630 subjects, a 15-week comparison between Δ9-tetrahydrocannabinol and placebo was performed. More patients receiving active treatment perceived an improvement in pain than those receiving placebo, although approximately 20% of subjects reported worsening of pain while on active treatment.
Trigeminal neuralgia, while affecting less than 5% of patients with MS, is the most studied pain syndrome. The pain can be extreme and is typically treated with carbamazepine, although adverse effects can mimic an MS exacerbation. Painful topic spasms occur in approximately 11% of the MS population and are treated with antispasticity medications such as baclofen and benzodiazepines. Gabapentin has also demonstrated efficacy, but all studies have included small sample sizes.
In general, evidence for treating pain in MS is limited. Many clinical features of pain are often unrecognized by clinicians and are difficult for patients to describe. Treatment is often based on anecdotal reports and clinical experience. We present a review of treatment options for pain in MS, which should serve to update current knowledge, highlight shortcomings in clinical research and provide indications towards achieving evidence-based treatment of pain in MS.
Cannabinoids control spasticity and tremor in a multiple sclerosis model

David Baker1, Gareth Pryce1, J. Ludovic Croxford1, Peter Brown2, Roger G. Pertwee3, John W. Huffman4 & Lorna Layward
Neuroinflammation Group, Department of Neurochemistry, Institute of Neurology, University College London, 1 Wakefield Street, London WC1N 1PJ and the Institute of Ophthalmology, UCL, London EC1V 9EL, UK

The Medical Research Council Human Movement and Balance Unit, National Hospital for Neurology and Neurosurgery , Queen Square, London, WC1N 3BG, UK

Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill , Aberdeen AB25 2ZD, UK

Department of Chemistry, Clemson University, Clemson, South Carolina 29634-1905 , USA
Multiple Sclerosis Society of Great Britain and Northern Ireland , 25 Effie Road, London SW6 1EE, UK Correspondence to: Correspondence and requests for materials should be addressed to D.B. (e-mail: Email:
Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis1. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens1 Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use2. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes3, 4, 5, 6, 7, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, 9-tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis2, and provides a means of evaluating more selective cannabinoids in the future.
Association Between Marijuana Exposure and Pulmonary Function Over 20 Years
Mark J. Pletcher, MD, MPH; Eric Vittinghoff, PhD; Ravi Kalhan, MD, MS; Joshua Richman, MD, PhD; Monika Safford, MD; Stephen Sidney, MD, MPH; Feng Lin, MS; Stefan Kertesz, MD
[+] Author Affiliations
Author Affiliations: Department of Epidemiology and Biostatistics (Drs Pletcher and Vittinghoff and Mr Lin) and Division of General Internal Medicine, Department of Medicine (Dr Pletcher), University of California, San Francisco; Asthma-COPD Program, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Dr Kalhan); Department of Surgery (Dr Richman) and Division of Preventive Medicine (Drs Safford and Kertesz), University of Alabama at Birmingham; Center for Surgical, Medical and Acute Care Research and Transitions, Veterans Affairs Medical Center, Birmingham (Drs Richman and Kertesz); and Division of Research, Kaiser Permanente of Northern California, Oakland (Dr Sidney). Abstract Context Marijuana smoke contains many of the same constituents as tobacco smoke, but whether it has similar adverse effects on pulmonary function is unclear.
Objective To analyze associations between marijuana (both current and lifetime exposure) and pulmonary function.
Design, Setting, and Participants The Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal study collecting repeated measurements of pulmonary function and smoking over 20 years (March 26, 1985-August 19, 2006) in a cohort of 5115 men and women in 4 US cities. Mixed linear modeling was used to account for individual age-based trajectories of pulmonary function and other covariates including tobacco use, which was analyzed in parallel as a positive control. Lifetime exposure to marijuana joints was expressed in joint-years, with 1 joint-year of exposure equivalent to smoking 365 joints or filled pipe bowls.
Main Outcome Measures Forced expiratory volume in the first second of expiration (FEV1) and forced vital capacity (FVC).
Results Marijuana exposure was nearly as common as tobacco exposure but was mostly light (median, 2-3 episodes per month). Tobacco exposure, both current and lifetime, was linearly associated with lower FEV1 and FVC. In contrast, the association between marijuana exposure and pulmonary function was nonlinear (P < .001): at low levels of exposure, FEV1 increased by 13 mL/joint-year (95% CI, 6.4 to 20; P < .001) and FVC by 20 mL/joint-year (95% CI, 12 to 27; P < .001), but at higher levels of exposure, these associations leveled or even reversed. The slope for FEV1 was −2.2 mL/joint-year (95% CI, −4.6 to 0.3; P = .08) at more than 10 joint-years and −3.2 mL per marijuana smoking episode/mo (95% CI, −5.8 to −0.6; P = .02) at more than 20 episodes/mo. With very heavy marijuana use, the net association with FEV1 was not significantly different from baseline, and the net association with FVC remained significantly greater than baseline (eg, at 20 joint-years, 76 mL [95% CI, 34 to 117]; P < .001).
Conclusion Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function.
bottom line, big brother and pharmaceutical companies i.e. $$$ i.e. Washington. ...

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