The analgesic potential of cannabinoids.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Marijuana use is followed by disruption of short-term memory, cognitive impairment, a sense of slowing of time, mood alterations, enhanced body awareness, reduced ability to focus, incoordination, and sleepiness.

“Marijuana use is followed by a disruption of short-term memory, cognitive impairment, a sense of slowing of time, mood alterations, enhanced body awareness, reduced ability to focus, incoordination, and sleepiness [9].”

• cites [9] Svizenska I Dubovy P Sulcova A Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures–a short review Pharmacol Biochem Behav 2008 90 4 501 511 18584858Not checked yet

  Not checked in the free run.

May combine two claims.

CB-2 receptor activation also inhibits adenylyl cyclase, but does not influence ion conductance.

“CB-2 receptor activation also inhibits adenylyl cyclase, but does not influence ion conductance [15].”

• cites [15] Howlett AC Breivogel CS Childers SR Cannabinoid physiology and pharmacology: 30 years of progress Neuropharmacology 2004 47 Suppl 1 345 358 15464149Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

The variability in cell signaling induced by cannabinoids in neuronal and non-neuronal cells suggests that the effect of cannabinoids will need to be examined for both their anti-nociceptive activity and the peripheral effect for individual pathological condition.

“Importantly, this variability in cell signaling induced by cannabinoids in neuronal and non-neuronal cells suggests that the effect of cannabinoids will need to be examined for both their anti-nociceptive activity and the peripheral effect for individual pathological condition.”

May combine two claims.

Clinical and experimental studies show that cannabis-derived compounds act as anti-emetic, appetite modulating and analgesic agents.

“Clinical and experimental studies show that cannabis-derived compounds act as anti-emetic, appetite modulating and analgesic agents.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Smoking results in rapid absorption and onset of psychoactive effects, and is the preferred mode of recreational use.

“Smoking results in rapid absorption and onset of psychoactive effects, and is the preferred mode of recreational use.”

• cites [9] Svizenska I Dubovy P Sulcova A Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures–a short review Pharmacol Biochem Behav 2008 90 4 501 511 18584858Not checked yet

  Not checked in the free run.

May combine two claims.

Cannabinoids mainly act via CB-1 receptors, predominantly expressed on neurons, and CB-2 receptors, predominantly expressed on cells of the immune system.

“Cannabinoids mainly act via 2 different receptors: (i) the cannabinoid-1 (CB-1) receptor, predominantly expressed on the neurons; and (ii) the cannabinoid-2 (CB-2) receptor, predominantly expressed on cells of the immune system [9].”

• cites [9] Svizenska I Dubovy P Sulcova A Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures–a short review Pharmacol Biochem Behav 2008 90 4 501 511 18584858Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

When Δ9-THC enters the bloodstream, it is metabolized to 11-hydroxy Δ9-THC, which is absorbed into adipose tissue, stays for 30 minutes, and is then released back into circulation and reaches the brain.

“When Δ9-THC enters the bloodstream, it is metabolized to 11-hydroxy Δ9-THC, which is absorbed into the adipose tissue, where it stays for 30 minutes before being released back into circulation and reaching the brain. [2].”

• cites [2] Booth M Cannabis: A History Thomas Dunne Books 1 2004Not checked yet

  Not checked in the free run.

May combine two claims.

Cannabinoid signaling is cell-specific and may also be dependent upon specific agonists used.

“However, it appears that the cannabinoid signaling is cell-specific and may also be dependent upon specific agonists used.”

Probably not a substantial claim: may not pass S2 (checkable).

There is a need to explore alternative or adjunct medications to opioids in management of severe pain.

“In view of these side- effects and the decrease in analgesic efficacy over time [8], there is a need to explore alternative or adjunct medications to opioids in management of severe pain”

• cites [8] Ballantyne JC Shin NS Efficacy of opioids for chronic pain: a review of the evidence Clin J Pain 2008 24 6 469 478 18574357Not checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Opioids are the only analgesics for treating severe pain.

May combine two claims.

Cannabinoids modulate both cell proliferation and cell survival pathways, sometimes with opposite effects depending on the cell type.

“Cannabinoids modulate both the cell proliferation as well as cell survival pathways, albeit sometimes effects may be opposite depending on the cell type”

• cites [18] Ozaita A Puighermanal E Maldonado R Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain J Neurochem 2007 102 4 1105 1114 17484726Not checked yet

  Not checked in the free run.

• cites [19] Molina-Holgado F Pinteaux E Heenan L Neuroprotective effects of the synthetic cannabinoid HU-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase/AKT signaling Mol Cell Neurosci 2005 28 1 189 194 15607953Not checked yet

  Not checked in the free run.

• cites [20] Lee YM Uhm KO Lee ES AM251 suppresses the viability of HepG2 cells through the AMPK (AMP-activated protein kinase)-JNK (c-Jun N-terminal kinase)-ATF3 (activating transcription factor 3) pathway Biochem Biophys Res Commun 2008 370 4 641 645 18406347Not checked yet

  Not checked in the free run.

May combine two claims.

The efficacy of individual cannabinoid products is variable and dependent upon the route of administration.

“However, the efficacy of individual products is variable and dependent upon the route of administration.”

May combine two claims.

Cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy.

“Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy.”

May combine two claims.

Overall, cannabinoids appear to be effective in treating pain in MS, and would need to be further evaluated for their optimum use in MS.

“Overall, cannabinoids appear to be effective in treating pain in MS, and would need to be further evaluated for their optimum use in MS.”

May combine two claims.

Pretreatment with HU-210 increased the antinociceptive effect of morphine injected into the periaqueductal gray and prevented the development of tolerance.

“Pretreatment with HU-210 also increased the antinociceptive effect of morphine injected into the periaqueductal gray and prevented the development of tolerance [53].”

• cites [53] Wilson AR Maher L MM Morgan MM Repeated cannabinoid injections into the rat periaqueductal gray enhance subsequent morphine antinociception Neuropharmacology 2008 55 7 1219 1225 18723035 PMC2743428Not checked yet

  Not checked in the free run.

May combine two claims.

Since inflammatory pain is a hallmark of several chronic diseases including sickle cell disease and cancer, cannabinoids appear to be a promising therapy to treat severe pain in these diseases.

“Since, inflammatory pain is a hallmark of several chronic diseases including sickle cell disease and cancer, cannabinoids appear to be a promising therapy to treat severe pain in these diseases.”

May combine two claims.

Studies using smoked cannabis in HIV associated sensory neuropathy and other types of neuropathic pain have found that it offers clinically significant analgesia to a large number of subjects, but often with associated neurocognitive and psychoactive effects, especially at higher doses.

“Studies using smoked cannabis in HIV associated sensory neuropathy and other types of neuropathic pain have found that it offers clinically significant analgesia to a large number of subjects [112], [114, 115] but often with associated neurocognitive and psychoactive effects, especially at higher doses [115].”

• cites [112] Ellis RJ Toperoff W Vaida F Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial Neuropsychopharmacology 2009 34 3 672 680 18688212 PMC3066045Not checked yet

  Not checked in the free run.

• cites [114] Abrams DI Jay CA Shade SB Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial Neurology 2007 68 7 515 521 17296917Not checked yet

  Not checked in the free run.

• cites [115] Wilsey B Marcotte T Tsodikov A A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain J Pain 2008 9 6 506 521 18403272 PMC4968043Not checked yet

  Not checked in the free run.

May combine two claims.

Δ9-THC, both by itself and in combination with morphine, provides better anti-nociception in diabetic mice than in non-diabetic arthritic mice, correlated to lower endogenous opioid levels in diabetic mice.

“Δ9-THC (both by itself and in combination with morphine) has been shown to provide better anti-nociception in diabetic mice than in non-diabetic arthritic mice, and this has been correlated to the lower endogenous opioid levels in diabetic mice [63].”

• cites [63] Williams J Haller VL Stevens DL Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception Eur J Pharmacol 2008 584 1 78 86 18313663Not checked yet

  Not checked in the free run.

May combine two claims.

Cannabinoid withdrawal symptoms were decreased in double μ and κ opioid receptor knockout mice, suggesting a relationship between opioid and cannabinoid receptor activities.

“Conversely, cannabinoid withdrawal symptoms were decreased in double μ and κ opioid receptor knockout mice [66], suggesting a relationship between opioid and cannabinoid receptor activities.”

• cites [66] Castane A Robledo P Matifas A Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice Eur J Neurosci 2003 17 1 155 159 12534979Not checked yet

  Not checked in the free run.

May combine two claims.

Many HIV infected patients smoke marijuana for symptom relief and reducing symptom frequency; users report improvement in appetite (97%), muscle pain (94%), nausea (93%), anxiety (93%), nerve pain (90%), depression (86%), and paraesthesia (85%).

“Many HIV infected patients smoke marijuana for a variety of reasons, including symptom relief and reducing symptom frequency; the users report improvement in appetite (97%), muscle pain (94%), nausea (93%), anxiety (93%), nerve pain (90%), depression (86%), and paraesthesia (85%).”

• cites [92] Woolridge E Barton S Samuel J Cannabis use in HIV for pain and other medical symptoms J Pain Symptom Manage 2005 29 4 358 367 15857739Not checked yet

  Not checked in the free run.

May combine two claims.

A 2 yr open label study as a follow up of this trial using Sativex in 63 MS patients showed it to be effective in decreasing pain, however less than half of the subjects completed the trial.

“A 2 yr open label study as a follow up of this trial using Sativex® in 63 MS patients showed it to be effective in decreasing pain, however less than half of the subjects completed the trial [99].”

• cites [99] Rog DJ Nurmikko TJ Young CA Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial Clin Ther 2007 29 9 2068 2079 18035205Not checked yet

  Not checked in the free run.

May combine two claims.

Nabilone is superior to placebo, domperidone and prochlorperazine in the management of CINV, but not superior to metoclopramide and chlorpromazine.

“A recent systematic review concluded that nabilone is superior to placebo, domperidone and prochlorperazine in the management of CINV, but not superior to metoclopramide and chlorpromazine [88].”

• cites [88] Davis MP Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain Expert Opin Investig Drugs 2008 17 1 85 95 18095921Not checked yet

  Not checked in the free run.

May combine two claims.

Both CB-1 and CB-2 receptors appear to be involved in pain modulation, and selective agonists may be useful when the specific role of each receptor is fully characterized in each type of pain.

“Both CB-1 and CB-2 receptors appear to be involved in pain modulation, and selective agonists may be useful when the specific role of each receptor is fully characterized in each type of pain.”

May combine two claims.

Many studies have shown dronabinol to improve mood, appetite and decrease nausea in patients with AIDS or advanced cancer, but a recent study comparing cannabis extracts, Δ9-THC and placebo in patients with cancer related anorexia cachexia syndrome found no significant advantage of CE or Δ9-THC over placebo with regard to appetite, quality of life or toxicity.

“While many studies have shown dronabinol to improve mood, appetite and to decrease nausea in patients with AIDS or advanced cancer [90], a recent study comparing cannabis extracts (CE), Δ9-THC and placebo in patients with cancer related anorexia cachexia syndrome found no significant advantage of CE or Δ9-THC over placebo with regard to appetite, quality of life or toxicity [91].”

• cites [90] Kogan NM Mechoulam R Cannabinoids in health and disease Dialogues Clin Neurosci 2007 9 4 413 430 18286801 PMC3202504Not checked yet

  Not checked in the free run.

• cites [91] Strasser F Luftner D Possinger K 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 J Clin Oncol 2006 24 21 3394 3400 16849753Not checked yet

  Not checked in the free run.

May combine two claims.

Ultra-low dose naltrexone enhances the anti-nociceptive action of WIN 55,212-2, while high dose naltrexone does not.

“However, ultra-low dose naltrexone has also been shown to enhance the anti-nociceptive action of WIN 55,212-2, while high dose naltrexone does not [60].”

• cites [60] Paquette J Olmstead MC Ultra-low dose naltrexone enhances cannabinoid-induced antinociception Behav Pharmacol 2005 16 8 597 603 16286810Not checked yet

  Not checked in the free run.

May combine two claims.

CB1 receptor knockout mice appear to have lesser opioid addiction and withdrawal, suggesting a role for cannabinoid receptors in opioid signaling pathways.

“Also, CB1 receptor knockout mice appear to have lesser opioid addiction and withdrawal [65], suggesting a role for cannabinoid receptors in opioid signaling pathways.”

• cites [65] Ledent C Valverde O Cossu G Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice Science 1999 283 5400 401 404 9888857Not checked yet

  Not checked in the free run.

May combine two claims.

Marijuana offered slightly better overall relief than prescription/OTC medications for a number of symptoms including anxiety, depression, nausea, vomiting, diarrhea, neuropathy.

“Marijuana offered slightly better overall relief then the prescription/OTC medications for a number of symptoms (including anxiety, depression, nausea, vomiting, diarrhea, neuropathy).”

• cites [93] Corless IB Lindgren T Holzemer W Marijuana effectiveness as an HIV self-care strategy Clin Nurs Res 2009 18 2 172 193 19377043Not checked yet

  Not checked in the free run.

May combine two claims.

Different cannabinoids may offer pain relief in cancer by both systemic and peripheral routes, primarily via CB-1 receptors, and the route of administration may be tailored to the specific need.

“These studies suggest that different cannabinoids may offer pain relief in cancer by both systemic and peripheral routes, primarily via CB-1 receptors, and the route of administration may be tailored to the specific need.”

May combine two claims.

Sativex was found to decrease mean pain intensity and reduce sleep disturbance in MS.

“It was found to decrease mean pain intensity and reduce sleep disturbance in MS [98].”

• cites [98] Rog DJ Nurmikko TJ Friede T Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis Neurology 2005 65 6 812 819 16186518Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The preclinical studies provide a rationale for further evaluation of cannabinoid receptor agonists in different types of pain.

“The preclinical studies described above provide a rationale for further evaluation of cannabinoid receptor agonists in different types of pain.”

May combine two claims.

In other conditions, the addition of a cannabinoid may confer no additional benefit, so the optimal therapy for pain management in specific conditions remains an area for future research.

“However, in other conditions, the addition of a cannabinoid may confer no additional benefit, so the optimal therapy for pain management in specific conditions remains an area for future research.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Opioids and cannabinoids both provide antinociception through G-protein coupled mechanisms.

“Opioids and cannabinoids both provide antinociception through G-protein coupled mechanisms, and many studies have explored synergistic interactions between them.”

May combine two claims.

Cannabinoids have a role in relieving pain, spasticity, tremor, nocturia and improving general well being in MS.

“Cannabinoids have a role in relieving pain, spasticity, tremor, nocturia and improving general well being in MS (Table 5).”

May combine two claims.

A randomized controlled trial with 667 MS patients using oral Δ9-THC or a cannabis extract Cannador found subjective improvement in subjects' self-reported sense of spasticity and pain, but no objective improvement in spasticity by the Ashworth scale.

“A randomized controlled trial with 667 MS patients using oral Δ9-THC or a cannabis extract Cannador®; found subjective improvement in subjects’ self-reported sense of spasticity and pain, but no objective improvement in spasticity [95] by the Ashworth scale, [96].”

• cites [95] Zajicek J Fox P Sanders H Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial Lancet 2003 362 9395 1517 1526 14615106Not checked yet

  Not checked in the free run.

• cites [96] Herndon RM Handbook of Neurological rating scales Demos Medical Publishing 2 2006Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable).

In cases of pain attributable wholly or partly to inflammation, it may be worthwhile to explore a local route of administering the cannabinoid and thus avoid systemic side effects.

“Especially in cases of pain attributable wholly or partly to inflammation, it may be worthwhile to explore a local route of administering the cannabinoid and thus avoid systemic side effects.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Sativex is an oromucosal spray containing Δ9-THC (27 mg/mL) and cannabidiol (25 mg/mL), with a dosage of 100 μL/spray.

“Sativex® is an oromucosal spray containing Δ9-THC (27 mg/mL) and cannabidiol (CBD)(25 mg/mL), with a dosage of 100 μL/spray [97].”

• cites [97] Russo EB Guy GW PJ Robson PJ Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine Chem Biodivers 2007 4 8 1729 1743 17712817Not checked yet

  Not checked in the free run.

May combine two claims.

Adjunct use of cannabinoids may permit the use of lower doses of opioids than otherwise required, thus acting as an opioid sparing agent in similar situations.

“Thus, adjunct use of cannabinoids may permit the use of lower doses of opioids than otherwise required, thus acting as an opioid sparing agent in similar situations.”

May combine two claims.

Marijuana users reported better overall medication effectiveness than non-users, however it is unclear whether it is attributable to the euphoric effect of marijuana or a real synergism with the medications.

“Marijuana users reported better overall medication effectiveness than non-users, however it is unclear whether it is attributable to the euphoric effect of marijuana or a real synergism with the medications [93].”

• cites [93] Corless IB Lindgren T Holzemer W Marijuana effectiveness as an HIV self-care strategy Clin Nurs Res 2009 18 2 172 193 19377043Not checked yet

  Not checked in the free run.

May combine two claims.

CB-2 receptor activation by AM1241 causes the release of β-endorphin from keratinocytes, and the antinociceptive effect of AM1241 in rats is blocked by antagonism of the μ opioid receptor and by antiserum to β-endorphin.

“CB-2 receptor activation by AM1241 causes the release of β-endorphin from keratinocytes, and the antinociceptive effect of AM1241 in rats is blocked by antagonism of the μ opiod receptor and by antiserum to β-endorphin [64].”

• cites [64] Ibrahim MM Porreca F Lai J CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids Proc Natl Acad Sci USA 2005 102 8 3093 3098 15705714 PMC549497Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

A case-control study showed no increase in risk of head and neck cancer with cannabis use.

“A case-control study showed no increase in risk of head and neck cancer with cannabis use [130].”

• cites [130] Aldington S Harwood M Cox B Cannabis use and cancer of the head and neck: case-control study Otolaryngol Head Neck Surg 2008 138 3 374 380 18312888 PMC2277494Not checked yet

  Not checked in the free run.

May combine two claims.

Studies regarding the use of cannabinoids for post-operative analgesia suggest that cannabis extract Cannador might potentially be beneficial, while Δ9-THC offers no benefit and may actually provoke hyperalgesia.

“Studies regarding the use of cannabinoids for post-operative analgesia suggest that while cannabis extract Cannador® might potentially be beneficial [108], Δ9-THC offers no benefit and may actually provoke hyperalgesia [84], [109].”

• cites [108] Holdcroft A Maze M Dore C A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management Anesthesiology 2006 104 5 1040 1046 16645457Not checked yet

  Not checked in the free run.

• cites [84] Beaulieu P Effects of nabilone, a synthetic cannabinoid, on postoperative pain Can J Anaesth 2006 53 8 769 775 16873343Not checked yet

  Not checked in the free run.

• cites [109] Buggy DJ Toogood L Maric S Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain Pain 2003 106 1–2 169 172 14581124Not checked yet

  Not checked in the free run.

May combine two claims.

Studies in healthy human volunteers using oral cannabis extracts in acute pain models do not show any analgesic effect, but rather suggest a hyperalgesic action.

“Interestingly, studies in healthy human volunteers using oral cannabis extracts in acute pain models do not show any analgesic effect, but rather suggest a hyperalgesic action [85].”

• cites [85] Kraft B Frickey NA Kaufmann RM Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers Anesthesiology 2008 109 1 101 110 18580179Not checked yet

  Not checked in the free run.

May combine two claims.

Some studies show higher lung cancer rates in marijuana smokers, while some do not find any such association.

“Some studies show higher lung cancer rates in marijuana smokers [131], [132], while some do not find any such association [133].”

• cites [131] Aldington S Harwood M Cox B Cannabis use and risk of lung cancer: a case-control study Eur Respir J 2008 31 2 280 286 18238947 PMC2516340Not checked yet

  Not checked in the free run.

• cites [132] Voirin N Berthiller J Benhaim-Luzon V Risk of lung cancer and past use of cannabis in Tunisia J Thorac Oncol 2006 1 6 577 579 17409920Not checked yet

  Not checked in the free run.

• cites [133] Hashibe M Morgenstern H Cui Y Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study Cancer Epidemiol Biomarkers Prev 2006 15 10 1829 1834 17035389Not checked yet

  Not checked in the free run.

May combine two claims.

A systematic review in 2001 of all randomized controlled trials done with cannabinoids in various types of pain concluded that in cancer pain, cannabinoids were of the same efficacy as codeine, while being associated with dose limiting CNS depressant effects.

“A systematic review in 2001 of all randomized controlled trials done with cannabinoids in various types of pain concluded that in cancer pain, cannabinoids were of the same efficacy of codeine, while being associated with dose limiting CNS depressant effects [119].”

• cites [119] Campbell FA Tramer MR Carroll D Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review BMJ 2001 323 7303 13 16 11440935 PMC34324Not checked yet

  Not checked in the free run.

May combine two claims.

Sativex and a THC predominant cannabis extract GW-2000-02 both offered significant analgesia in subjects with neuropathic pain from brachial plexus avulsion.

“Sativex® and a THC predominant cannabis extract GW-2000-02 both offered significant analgesia in subjects with neuropathic pain from brachial plexus avulsion [113].”

• cites [113] Berman JS Symonds C Birch R Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial Pain 2004 112 3 299 306 15561385Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Pain in SCD is a result of vascular occlusion, tissue infarction and inflammation, and is widely prevalent and often undertreated.

“Pain in SCD is a result of vascular occlusion, tissue infarction and inflammation [121], and is widely prevalent and often undertreated [122].”

• cites [121] Ballas SK Pain management of sickle cell disease Hematol Oncol Clin North Am 2005 19 5 785 802 16214644Not checked yet

  Not checked in the free run.

• cites [122] Smith WR Penberthy LT Bovbjerg VE Daily assessment of pain in adults with sickle cell disease Ann Intern Med 2008 148 2 94 101 18195334Not checked yet

  Not checked in the free run.

May combine two claims.

Cannabis use was not found to vary with the severity of the disease, and 52% of users said they used it to reduce or prevent acute or chronic pain; other reasons were to improve sleep, mood or to aid relaxation.

“While cannabis use was not found to vary with the severity of the disease, 52% of the users said they used it to reduce or prevent acute or chronic pain; other reasons were to improve sleep, mood or to aid relaxation [120].”

• cites [120] Howard J Anie KA Holdcroft A Cannabis use in sickle cell disease: a questionnaire study Br J Haematol 2005 131 1 123 128 16173972Not checked yet

  Not checked in the free run.

May combine two claims.

Marijuana smoke has been shown to be mutagenic, while THC by itself is not mutagenic.

“Marijuana smoke has been shown to be mutagenic [135, 136], while THC by itself is not mutagenic [137, 138].”

• cites [135] Wehner FC van Rensburg SJ Thiel PG Mutagenicity of marijuana and Transkei tobacco smoke condensates in the Salmonella/microsome assay Mutat Res 1980 77 2 135 142 6990238Not checked yet

  Not checked in the free run.

• cites [136] Busch FW Seid DA Wei ET Mutagenic activity of marihuana smoke condensates Cancer Lett 1979 6 6 319 324 378366Not checked yet

  Not checked in the free run.

• cites [137] Van Went GF Mutagenicity testing of 3 hallucinogens: LSD, psilocybin and delta 9-THC, using the micronucleus test Experientia 1978 34 3 324 325 631257Not checked yet

  Not checked in the free run.

• cites [138] Zimmerman AM Stich H San R Nonmutagenic action of cannabinoids in vitro Pharmacology 1978 16 6 333 343 353830Not checked yet

  Not checked in the free run.

May combine two claims.

CB-2 receptor activation and CB-1 receptor inhibition has beneficial effects in cerebral ischemia.

“CB-2 receptor activation and CB-1 receptor inhibition has beneficial effects in cerebral ischemia [128], [129].”

• cites [128] Hillard CJ Role of cannabinoids and endocannabinoids in cerebral ischemia Curr Pharm Des 2008 14 23 2347 2361 18781985 PMC2581413Not checked yet

  Not checked in the free run.

• cites [129] Zhang M Martin BR Adler MW Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke J Neuroimmune Pharmacol 2009 4 2 249 259 19255856 PMC2855650Not checked yet

  Not checked in the free run.

May combine two claims.

As an adjuvant drug added to opioids, nabilone improved pain control and the quality of sleep in patients with chronic non-cancer pain.

“As an adjuvant drug added to opioids, it also improved pain control and the quality of sleep in patients with chronic non-cancer pain [107].”

• cites [107] Narang S Gibson D Wasan AD Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy J Pain 2008 9 3 254 264 18088560Not checked yet

  Not checked in the free run.

May combine two claims.

CB-2 receptor activation by JWH-133 has been found to protect from cardiac ischemia reperfusion injury and may help in SCD.

“CB-2 receptor activation by JWH-133 has been found to protect from cardiac ischemia reperfusion injury [126], [127] and may help in SCD as well.”

• cites [126] Montecucco F Lenglet S Braunersreuther V CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion J Mol Cell Cardiol 2009 46 5 612 620 19162037Not checked yet

  Not checked in the free run.

• cites [127] Defer N Wan J Souktani R The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy FASEB J 2009 23 7 2120 2130 19246487Not checked yet

  Not checked in the free run.

May combine two claims.

A study comparing escalating daily doses of nabilone (maximum 2 mg) and dihydrocodeine (maximum 240 mg) in patients with severe neuropathic pain found dihydrocodeine to offer clinically significant pain relief to more patients than nabilone; no subject responded to both agents.

“However, a study comparing escalating daily doses of nabilone (maximum 2 mg) and dihydrocodeine (maximum 240mg) in patients with severe neuropathic pain found dihydrocodeine to offer clinically significant pain relief to more patients than nabilone; interestingly, no subject responded to both agents [117].”

• cites [117] Frank B Serpell MG Hughes J Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study BMJ 2008 336 7637 199 201 18182416 PMC2213874Not checked yet

  Not checked in the free run.

May combine two claims.

A recent review of clinical trials conducted with Sativex and other cannabis extracts in various types of pain observed a benefit in a range of conditions, including MS, cancer, irritative urinary symptoms, neuropathy, peripheral nerve injury and spinal cord injury; the only condition where benefit was not noted was post-herpetic neuralgia.

“A recent review of the clinical trials conducted with Sativex® and other cannabis extracts in various types of pain observed a benefit in a range of conditions, including MS, cancer, irritative urinary symptoms, neuropathy, peripheral nerve injury and spinal cord injury. The only condition where benefit was not noted was post-herpetic neuralgia [97].”

• cites [97] Russo EB Guy GW PJ Robson PJ Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine Chem Biodivers 2007 4 8 1729 1743 17712817Not checked yet

  Not checked in the free run.

May combine two claims.

Cannabinoids could possibly be used as adjunct agents along with opioids to decrease opioid dose and achieve better pain control.

“Cannabinoids could possibly be used as adjunct agents along with opioids to decrease opioid dose and achieve better pain control.”

May combine two claims.

Cannabinoids, endocannabinoids and non-cannabinoid derivatives of the cannabis plant have anti-inflammatory properties, which may be helpful in SCD.

“Cannabinoids, endocannabinoids and non-cannabinoid derivatives of the cannabis plant have also been found to have anti-inflammatory properties [124], which may be helpful in SCD.”

• cites [124] Burstein SH Zurier RB Cannabinoids, endocannabinoids, and related analogs in inflammation AAPS J 2009 11 1 109 119 19199042 PMC2664885Not checked yet

  Not checked in the free run.

May combine two claims.

Cannabinoids are commonly used to control nausea and vomiting in other settings, and could be potentially beneficial in SCD.

“Cannabinoids are commonly used to control nausea and vomiting in other settings, and could be potentially beneficial in this scenario as well.”

• AssumptionRests on an assumption: Cannabinoids are commonly used to control nausea and vomiting in other settings.

May combine two claims.

Sativex was found to offer significant pain relief, as well as improvement in sleep and allodynia in neuropathic pain of various etiologies.

“Sativex® was found to offer significant pain relief, as well as improvement in sleep and allodynia in neuropathic pain of various etiologies [116].”

• cites [116] Nurmikko TJ Serpell MG Hoggart B Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial Pain 2007 133 1–3 210 220 17997224Not checked yet

  Not checked in the free run.

May combine two claims.

Δ9-THC has analgesic and other beneficial effects in fibromyalgia and rheumatoid arthritis.

“Δ9-THC has analgesic and other beneficial effects in fibromyalgia and rheumatoid arthritis as well [110], [111].”

• cites [110] Skrabek RQ Galimova L Ethans K Nabilone for the treatment of pain in fibromyalgia J Pain 2008 9 2 164 173 17974490Not checked yet

  Not checked in the free run.

• cites [111] Blake DR Robson P Ho M Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis Rheumatology (Oxford) 2006 45 1 50 52 16282192Not checked yet

  Not checked in the free run.

May combine two claims.

Past conflicting epidemiological data regarding the association of marijuana smoking and cancer may not necessarily apply to Δ9-THC and other cannabis derivatives during therapeutic use via a non-inhalational route; however, caution may still be exercised while awaiting conclusive data.

“It appears that past conflicting epidemiological data regarding association of marijuana smoking and cancer may not necessarily apply to Δ9–THC and other cannabis derivatives during therapeutic use via a non-inhalational route; however, caution may still be exercised while awaiting conclusive data.”

May combine two claims.

THC was found to increase apoptosis and improve survival in murine cancer models and in human lymphoma and leukemia.

“In contrast, THC was found to increase apoptosis and improve survival in murine cancer models and in human lymphoma and leukemia [141].”

• cites [141] McKallip RJ Lombard C Fisher M Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease Blood 2002 100 2 627 634 12091357Not checked yet

  Not checked in the free run.

May combine two claims.

The cannabinoid HU-331 is anti-angiogenic in vivo and in vitro, suggestive of an inhibitory effect on cancer progression.

“Moreover, the cannabinoid HU-331 is anti-angiogenic in vivo and vitro, suggestive of an inhibitory effect on cancer progression [142].”

• cites [142] Kogan NM Blazquez C Alvarez L A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells Mol Pharmacol 2006 70 1 51 59 16571653Not checked yet

  Not checked in the free run.

May combine two claims.

Cannabinoids may have two opposite effects on cancer: tumor regression via promotion of apoptosis, and tumor promotion via suppression of immunogenicity.

“It appears that cannabinoids may have two opposite effects on cancer: tumor regression via promotion of apoptosis, and tumor promotion via suppression of immunogenicity [13].”

• cites [13] Guzman M Sanchez C Galve-Roperh I Control of the cell survival/death decision by cannabinoids J Mol Med 2001 78 11 613 625 11269508Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The legalization of medical marijuana would enable development of cannabis-derived drugs for multiple disease processes, in addition to treating severe pain.

“The legalization of medical marijuana would also enable more clinical trials in humans, and development of cannabis-derived drugs for multiple disease processes, in addition to treating severe pain.”

• AssumptionRests on an assumption: Legal barriers are a principal obstacle to conducting clinical trials of medical marijuana.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The legalization of medical marijuana would enable more clinical trials in humans.

“The legalization of medical marijuana would also enable more clinical trials in humans, and development of cannabis-derived drugs for multiple disease processes, in addition to treating severe pain.”

• AssumptionRests on an assumption: Legal barriers are a principal obstacle to conducting clinical trials of medical marijuana.

Probably not a substantial claim: may not pass S3 (load-bearing).

WIN-55,212-2 and other cannabinoid agonists have been suggested as potential therapeutic options in prostate cancer.

“WIN-55,212-2 and other cannabinoid agonists have been suggested as potential therapeutic options in prostate cancer [144].”

• cites [144] Sarfaraz S Afaq F Adhami VM Cannabinoid receptor as a novel target for the treatment of prostate cancer Cancer Res 2005 65 5 1635 1641 15753356Not checked yet

  Not checked in the free run.