Medicinal cannabis: Rational guidelines for dosing
Gregory T Carter 1*, Patrick Weydt 2, Muraco Kyashna-Tocha 3 & Donald I Abrams 4
1 Department of Rehabilitation Medicine
2 Departments of Neurology and Laboratory Medicine
University of Washington School of Medicine Seattle WA 98531 USA
Email: [email protected]
3 The Cyber Anthropology Institute Seattle WA 98145 USA
4 San Francisco General Hospital Division of Hematology/Oncology
Department of Medicine University of California San Francisco CA 94110 USA
*To whom correspondence should be addressed
IDrugs 2004 7(5):464-470
The Thomson Corporation ISSN 1369-7056
The medicinal value of cannabis (marijuana) is well documented in the medical literature. Cannabinoids, the active ingredients in cannabis, have many distinct pharmacological properties. These include analgesic, anti-emetic, anti-oxidative, neuroprotective and anti-inflammatory activity, as well as modulation of glial cells and tumor growth regulation. Concurrent with all these advances in the understanding of the physiological and pharmacological mechanisms of cannabis, there is a strong need for developing rational guidelines for dosing. This paper will review the known chemistry and pharmacology of cannabis and, on that basis, discuss rational guidelines for dosing.
Keywords Cannabinoids, cannabis, dosing, marijuana, pharmacology
Introduction and brief historical background
Possibly the first references to the medicinal use of cannabis are found in the Chinese pharmacopoeia of Emperor Shen-Nung, written in 2737 BC. This document recommended cannabis for analgesia, rheumatism, beriberi, malaria, gout and poor memory . Eastern Indian documents in the Atharvaveda, dating to about 2000 BC, also refer to the medicinal use of cannabis . Archeological evidence has been found in Israel indicating that cannabis was used therapeutically during childbirth as an analgesic . This use of cannabis continued in the West until the mid-1880s and continues today in parts of Asia. In ancient Greece and Rome, both the Herbal of Dioscorides and the writings of Galen refer to the use of medicinal cannabis .
The medicinal use of cannabis in western medicine occurred much later. There is mention of it in a treatise by Culpepperwritten in medieval times. British East India Company surgeon William O’Shaughnessy introduced cannabis for medicinal purposes into the United Kingdom following observations he made while working in India in the 1840s. He used it in a tincture for a wide range of uses, including analgesia , and Queen Victoria used cannabis for relief of
dysmenorrhea in the same era [6•]. In 1937, against the advice of the majority of the medical community and much of the American Medical Society, the federal government criminalized non-medical cannabis. Cannabis was removed from the United States Pharmacopoeia in 1942 but, up until that time, had still been prescribed by physicians .
The physiological mechanisms and therapeutic value of cannabinoids continue to be well documented in the medical literature[6•, 7, 11,12••,13,14,15••,16• ,17••,18••,19-21,22••, 23,24••,25-27,28•,29,30,31••,32-36]. However, there has been little written on appropriate dosing regimens for the medicinal use of cannabis. With current and emerging laws allowing physicians in many areas of the world to recommend the use of cannabis to treat symptoms of certain diseases and medical conditions, there is a need for medical literature describing rational dosing guidelines. This paper will review the known chemistry and pharmacology of cannabis and then, on that basis, discuss rational guidelines for dosing.
Chemistry and pharmacology of cannabis
Cannabis is a complex plant, with several existing phenotypes, each containing over 400 chemicals [14,15••]; approximately 60 are chemically unique and classified as plant cannabinoids [11,15••]. Naturally occurring cannabinoids are also produced in the human body . The cannabinoids are 21-carbon terpenes, biosynthesized predominantly via a recently discovered deoxyxylulose phosphate pathway [16••], and are lipophilic. Δ9-tetrahydro-cannabinol (THC) and Δ8-THC appear to produce the majority of the psychoactive effects of cannabis. Δ9-THC, the active ingredient in dronabinol (Marinol), is the most abundant cannabinoid in the plant and this has led researchers to hypothesize that it is the main source of the effects of the drug . Dronabinol is available by prescription as a schedule III drug.
Other major plant cannabinoids include cannabidiol and cannabinol, both of which may modify the pharmacology of THC and have distinct effects of their own. Cannabidiol is the second most prevalent active ingredient in cannabis and may produce most of its effects at moderate, mid-range doses. Cannabidiol converts to THC as the plant matures and over time this THC degrades to cannabinol. Up to 40% of the cannabis resin in some strains is cannabidiol [6•,26]. The amount varies according to plant; some varieties of Cannabis sativa have been found to contain no cannabidiol [6•]. As cannabidiol may help reduce anxiety symptoms, cannabis strains without cannabidiol may produce morepanic or anxiogenic side effects. Cannabidiol may exaggerate some of the effects of THC (including increasing THC-induced euphoria), while attenuating others, and competitively slows THC metabolism in the liver.
Consequently, a dose of THC combined with cannabidiol will create more psychoactive metabolites than the same dose of THC alone [27,31••]. In mice, pre-treatment with cannabidiol increased brain levels of THC by 3-fold and there is strong evidence that cannabinoids can increase the brain concentration and pharmacological actions of other drugs [10,11]. Some researchers have proposed that many of the negative side effects of dronabinol, including sedation and altered mental activity, could be reduced by combining it with cannabidiol or possibly other non-psychoactive cannabinoids .
Much less is known about cannabinol, although it appears to have pharmacological properties that are quite different from cannabidiol. Cannabinol has significant anticonvulsant, sedative and other pharmacological activities that are likely to interact with the effects of THC . Cannabinol may induce sleep and may provide some protection against seizures for epileptics [14,28•,32].
Two physiologically occurring lipids, anandamide (AEA) and 2-arachidonylglycerol (2-AG), have been identified as endogenous cannabinoids (endocannabinoids), although there are likely to be more . The physiological roles of these endocannabinoids have been only partially clarified but availableevidence suggests that they function as diffusible and short-lived intercellular messengers that modulate synaptic transmission. Recent studies have provided strong experimental evidence that endocannabinoids mediate signals retrogradely fromdepolarized post-synaptic neurons to presynaptic terminals to suppress subsequent neurotransmitter release, driving the synapse into an altered state [29,31••]. Signaling by the endocannabinoid system appears to represent a mechanism by which neurons can communicate backwards across synapses to modulate their inputs.
There are two known cannabinoid receptor subtypes. Subtype 1 (CB1) is expressed primarily in the brain whereas subtype 2 (CB2) is expressed primarily in the immune system[29,31••]. Cannabinoid receptors constitute a major family of G protein-coupled, seven-helix transmembrane nucleotides, are similar to the receptors of other neurotransmitters such as dopamine, serotonin and norepinephrine, and are the most abundant G protein-coupled receptor in the brain [8,10,11]. Activation of protein kinases may be responsible for some of the cellular responses elicited by the CB1receptor .
Because of this biochemical complexity, characterizing the clinical pharmacology of cannabis is challenging. Further complicating the evaluation of cannabis is the variable potency of the plant material used in research studies. The concentration of THC and other cannabinoids in cannabis varies greatly depending on growing conditions, plant genetics and processing after harvest [6•,7,8]. The highest concentrations of bioactive compounds are found in the resin exuded by the flowering female plants [6•,7,8]. Leaf mixtures of cannabis have concentrations of THC ranging from 0.3 to 4% by weight [6•,7,8]. However, cannabis today is typically distributed as flowers and can contain 8 to ≥ 25% of THC. Thus, 1 g of cannabis flowers would typically contain 80 to 250 mg of THC [6•].
The clinical pharmacology of cannabis containing high concentrations of THC may differ from plant material containing small amounts of THC and higher amounts of the other cannabinoids. Moreover, the bioavailability and pharmacokinetics of inhaled cannabis are substantially different than when cannabis is ingested [6•].
Although it is a potent drug that may produce psychoactive effects, THC (and the other cannabinoids) has relatively low toxicity, and lethal doses in humans have not been described [25,26]. The theoretical LD50 value is estimated to be 1 to 20,000 or 1 to 40,000, using a single
cannabis cigarette as a unit of dose. Conversely stated, a human would have to consume 20,000- to 40,000-fold the amount of cannabis contained in one cigarette, in a short period of time, to achieve lethality. Using this as a basis, it has been estimated that 628 kg of cannabis would have to be smoked in 15 min to induce a lethal effect .
Central effects of cannabinoids include disruption of psychomotor behavior, short-term memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidencethat such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis will develop some tolerance . A study by Hart and co-workers demonstrated that acute cannabis smoking produced minimal effects on complex cognitive task performance in experienced cannabis users, while still subjectively providing a euphoric ‘high’ [38••]. The potential medical applications of both natural and synthetic cannabinoids are currently being tested in a number of clinical trials.
Delivery system and pharmacokinetics
The route of administration is an important determinant of the pharmacokinetics of the cannabinoids in cannabis, particularly absorption and metabolism [39-42]. Typically, cannabis is smoked as a cigarette with a mass of between 0.5 and 1.0 g. After combustion and inhalation, peak venous blood levels of 75 to 150 ng of THC per ml of plasma have been measured when smoking is finished [39,43,44]. The main advantage of smoking is rapid onset of effect and ease of dose titration. When cannabis is smoked, cannabinoids in the form of an aerosol in the inhaled smoke are absorbed and delivered to the brain rapidly, as would be expected of a highly lipid-soluble drug [41,45].
Individual smoking behavior during an experiment is difficult for a researcher to control, and smoking behavior is not easily standardized, although some research protocols for standardization of smoking have been developed . An experienced cannabis smoker can titrate and regulate dose to obtain the desired acute effects and to minimize undesired effects [46,47]. Each inhalation delivers a discrete dose of cannabinoids to the body. Inhalation volume changes with phase of smoking, tending to be highest at the beginning and lowest at the end of smoking a cigarette. Some studies found frequent users to have higher inhalation volumes than less frequent cannabis users. Heavy users could absorb as much as 27% of available THC, which maybe twice as much as an infrequent user may absorb . During smoking, as the cigarette length shortens, the concentration of THC in the remaining cannabis increases. Thus, each successive inhalation contains an increasing concentration of THC . However, up to 40% of the available THC may be completely combusted in the process of smoking and may not be biologically available. Assays of cannabinoids in blood or urine after smoking can partially quantify dose actually absorbed, but the analytic procedures are methodologically demanding [47,48].
After smoking, venous blood levels of THC fall precipitously within minutes, and an hour later they are 5 to 10% of the peak level [40,41,43,44]. Plasma clearance of THC is ≥ 950 ml/min,
which is relatively high and is essentially the rate of hepatic blood flow. However, the rapid disappearance of THC from blood is largely due to redistribution to other tissues in the body rather than cannabinoid metabolism [40,41]. Metabolism in most tissues is relatively slow. Slow release of cannabinoids from tissues and subsequent metabolism results in a long elimination half-life. The terminal half-life of THC is estimated to range from 20 h to as long as 10 to 13 days, although reported estimates vary considerably and are likely to reflect the sensitivity of the measurement assay.
Smoking anything, including cannabis, is not beneficial for the lungs and airway system [49,50]. A healthier option may be vaporization; because cannabinoids are volatile, they will
vaporize at a temperature much lower than actual combustion . Heated air can be drawn through cannabis, the active compounds will vaporize, and these can then be inhaled. Vaporization delivers the substance in a rapid manner that, like smoking, can be easily titrated to the desired effect . Theoretically, this removes most of the health hazards of smoking, although this has not yet been studied. Furthermore, there may be differing vaporization points for the individual cannabinoids. Vaporized cannabis may have differing concentrations and ratios of cannabinoids compared to smoked cannabis, although this also needs further study.
Cannabis can also be ingested orally or through a feeding tube. Orally ingested THC or cannabis has quite different pharmacokinetics than when it is inhaled. The onset of action is delayed and titration of dosing is more difficult [52-54,55•]. Maximum THC and other cannabinoid blood levels are only reached 1 to 6 h after an oral dose, with a half-life of 20 to 30 h [52-54,55•]. This is also reflected in the pharmacokinetics of dronabinol capsules, which contain only synthetic THC and none of the other cannabinoids .When orally ingested, THC is degraded in the liver to the byproduct 11-hydroxy-THC, which also has potent psychoactive effects. This metabolite occurs at a much lower concentration when cannabis is inhaled. Thus, when THC (dronabinol or cannabis) is ingested orally, more sedation occurs because of the presence of the 11-hydroxy-THCpsychoactive metabolite .
Metabolism, bioavailability and drug interactions
Some inactive carboxy metabolites have terminal half-lives of 50 h to ≥ 6 days and thus serve as markers of priorcannabis use in urine tests [55•,56]. Most of the absorbed THC dose is eliminated in feces, and 33% is eliminated in urine. THC enters enterohepatic circulation and undergoes hydroxylation and oxidation to 11-nor-9-carboxy-Δ 9-THC (9-COOH-9-THC). The glucuronide is excreted as the major urine metabolite along with 18 non-conjugated metabolites. Frequent and infrequent cannabis users are similar in the way that they metabolize THC . THC bioavailability from smoked cannabis varies greatly among individuals and also depends on the composition of the specific cannabis preparation. Bioavailability can range from 1 to 27%, with variable bioavailability resulting from significant loss of THC in side stream smoke, as well as variation in individual smoking behaviors. This includes incomplete absorption from inhaled smoke, metabolism in lung, and cannabinoid pyrolysis (ie, destruction by combustion).
Cannabinoids appear to partially inhibit the metabolism of drugs metabolized by the hepatic cytochrome P450 enzyme system [57,58,59••,60]. Thus, the absorption or clearance of other drugs taken with cannabis may be slowed or hastened depending on timing and sequence of drug ingestion and past exposure. THC is highly bound to plasma proteins (97 to 99%) and is likely to interact with other highly bound drugs because of competition for binding sites on plasma proteins [61,62].
The Food and Drug Administration (FDA) first licensed and approved dronabinol in 1986 for the treatment of nauseaand vomiting associated with chemotherapy. The indication was expanded in 1992 to the treatment of anorexia associated with weight loss in patients with AIDS wasting syndrome. In a randomized, double-blind, placebo-controlled, 6-week study involving 139 patients, dronabinol provided a statistically significant improvement in appetite and non-statistically significant trends toward improved body weight and mood, and decreases in nausea [63•]. In 1999, the United States Drug Enforcement Administration, in cooperation with the FDA, reclassified the scheduling status of dronabinol from a Schedule II (CII) to a Schedule III (CIII) controlled substance (for definitions of schedules, refer to http://www.dea.gov/pubs/csa/812.htm).
In 454 patients with cancer who received a total of 750 courses of treatment for various malignancies, dronabinol capsules provided complete or partial success in easing nausea and vomiting in 68% of patients given < 7 mg/m 2/day of dronabinol and 64% of patients given > 7 mg/m2/day of dronabinol [64••]. According to the manufacturer, Unimed Pharmaceuticals Inc, the prescribed dose of dronabinol for appetite stimulation is 2.5 mg twice-daily, to be taken before lunch and dinner. For nausea, vomiting and pain the dosing is 5 mg/m2. If the 5-mg dose is ineffective, incremental increases of 2.5 mg, up to a maximum of 15 mg, is recommended. The same dose can be taken every 2 to 4 h for a maximum of four to six doses a day. Regardless of the clinical setting in which it is prescribed, the maximum total recommended dose of dronabinol is 15 mg/m2 four- to six-times-daily or 100 to 120 mg/day .
There are a limited number of well-performed clinical trials from which to draw succinct dosing regimens. Clinical trials have typically used cannabis cigarettes supplied by the NIDA (National Institute on Drug Abuse) containing 3.5 to 4.0% of THC by weight [59••,66,67]. Recently, Abrams and co-workers conducted an open-label study in patients with confirmed HIV neuropathy with persistent neuropathic pain . All patients had prior experience of smoking marijuana but had ceased for 30 days prior to admission. After a 2-day lead-in period, patients smoked one cigarette containing 3.56% of THC three-times-daily for 7 days. A heat-capsaicin-induced experimental pain model was used to clarify the effects of THC. Marijuana smoking led to a reduction in pain score to 20/100, with ten of 16 patients experiencing a 30% reduction in average daily pain. An excellent correlation was noted in the response to the heat-capsaicin model, as 14 of 16 patients experienced a 30% reduction in the area of secondary hyperalgesia after smoking .
Wade and co-workers compared plant-derived cannabis extracts to standard treatments for neurogenic symptoms unresponsive to standard treatment in a double-blind, randomized, placebo-controlled, cross-over trial with 2-week treatment periods . The enrolled patients (n = 24) had multiple sclerosis (n = 18), spinal cord injury (n = 4), brachial plexus injury (n = 1) and limb amputation due to neurofibromatosis (n = 1). Whole-plant extracts of either THC only, cannabidiol only, a mixed cannabinoid extract of both THC and cannabidiol in a 1:1 ratio, or a matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5 to 120 mg/24 h. The results demonstrated that pain relief associated with both THC and cannabidiol was significantly superior to placebo. The mixed cannabinoid extract, compared to placebo, was significantly superior in providing pain relief and improving bladder control, muscle spasms and spasticity. Side effects were rare. Three patients had transient hypotension and intoxication with rapid initial dosing of the THC extract.
Deriving dosing recommendations and guidelines
Cannabis has many variables that do not fit well with the typical medical model for drug prescribing. If the plant is used, the variations are extreme. Plants vary immensely by phenotypes, and even the time of harvest affects which cannabinoids are present and in what percentages. An individual may be much more sensitive than another, heavy smokers may experience different chemical effects than light smokers and ingestion may alter bioavailability. The bulk of the research into cannabis has primarily examined THC, the other cannabinoids have been studied to a lesser degree, while little research has been performed on combinations of cannabinoids, although this is beginning to change. These combinations are important to medicinal users of cannabis as a number of positive synergistic effects could be involved [70-72]. All of these points make it imperative that the dosing is highly individualized, so a patient-determined, self-titrated dosing model is recommended. This self-titration model is acceptable given the variables discussed above, as well as the low toxicity of cannabis. This construct
is not unique to cannabis. There are other drugs that have relatively low toxicity and high dosing limits (gabapentin being one notable example), and are titrated to effect.
To facilitate an understanding of the determination of these guidelines, an estimate of the actual amount of THC obtained by a patient when smoking different strengths of cannabis must be derived. As noted earlier, with smoking as the delivery, 40% of the active ingredients are lost in side stream or combustion, and a maximum of 27% of the remaining active ingredients can actually be absorbed by the patient. Given this, the maximum THC absorbed by a patient using 1 g of cannabis containing 10% of THC would
be 16.3 mg.
The only form of cannabinoid that is available by a formal,dose-specific prescription is dronabinol. There are too many variables in the published clinical trials and case series with raw cannabis to use those studies as a basis for deriving doses. Therefore, we will use the dronabinol prescription guidelines as published by the manufacturer and accepted by the FDA as the basis for formulating our dosing recommendations for natural cannabis. It is critical to note that dronabinol is an oral preparation and contains only THC. Most medicinal cannabis
patients use smoking as the route of delivery. As we have previously noted there are significant differences in pharmacokinetics between oral consumption and smoking. Furthermore, there are varying physiological effects when the other cannabinoid forms are present, as is the case with natural cannabis plant material. It is also not clear how the original dosing construct for
dronabinol was arrived at, although we assume it was derived from clinical testing for therapeutic benefit versus side effects. Despite these inherent limitations, these calculations do provide approximate dose equivalents by weight and are useful as long as one recognizes these.
Applying the known pharmacokinetics of cannabis, as described above, to a conservative dronabinol dosing model of 2.5 to 60 mg/day, we calculated the doses for cannabis containing particular percentages of THC (Table 1). These derived figures lie closely within the range of reported amounts. In informal surveys from patients in Washington and California (USA), the average reported consumption of cannabis by medicinal users typically ranges between 10 to 20 g of raw cannabis per week, or 1.42 to 2.86 g/day of cannabis. The average strength of medical cannabis used by the patients who reported these doses was 15% THC. Thus, these patients were actually absorbing between 34 and 68 mg/day of THC from the raw cannabis. The mean strength of medical cannabis in this study was 19% THC, which corresponds to 44 to 88 mg/day of THC actually being consumed by the patient . These figures are all within a similar range.
Table 1. Amount of cannabis calculated to contain equivalent amounts of THC to dronabinol (2.5 to 60 mg).
Amount of cannabis (g) required to obtain: % of THC in cannabis
2.5 mg of THC
10 mg of THC
30 mg of THC
60 mg of THC
Our recommended doses are further reinforced by two studies that utilized smoked cannabis in a well-documented dosing regime. Chang and co-workers studied the effects of smoked cannabis dosed at 10 mg/m2five-times-daily, which is equivalent to 87.5 mg/day of THC for an average-sized person. This would be the equivalent of 3.6 g of cannabis containing 15% of THC . Vinciguerra and co-workers studied smoked cannabis dosed at 5 mg/m2 four-times-daily, or 35 mg/day of THC for an average person. This is the equivalent of 1.4 g of cannabis containing 15% of THC . For the purposes of these calculations, we assumed an average-sized person to be 1.70 m in height with a mass of 63.6 kg and a body surface area of 1.75 m2.
These doses all fall within the medical cannabis guidelines allowed in the Canadian medical system. The Canadian medical allowance for cannabis is 1 to 12 g/day, with an average of > 5 g/day. These doses are also highly similar to the dosing range reported in a recent survey of patients who use cannabis to control symptoms of amyotrophic lateral sclerosis . Thus, despite all of the noted variables, there is remarkable consistency among our derived doses and the reported doses from a number of different sources notedhere.
A final comment should be made regarding physiological tolerance to cannabinoids. Tolerance plays a significant role in cannabis use since tolerance may develop to any of the various cannabinoids . With regard to treating chronic, intractable pain, physicians will often prescribe increasingly larger doses of long-acting opioids as patients develop tolerance. These patients are also generally prescribed fast onset, short-acting opioids for ‘breakthrough pain’. This is accepted practice, despite the fact that opioids, even in an opioid-dependent patient, have the capacity to suppress breathing to the extent of inducing respiratory arrest. Long-term cannabis users can develop tolerance but, as previously discussed, there is essentially no risk for overdose. Thus, it is conceivable that a long-term cannabis user may require significantly larger amounts of cannabis to achieve a therapeutic effect. In addition, those who ingest cannabis may also require significantly higher amounts. Until more refined and purified cannabinoid preparations are available it will not be possible to derive a more specific or exact dosing schedule.
We have outlined reasonable guidelines for dosing of medical cannabis, based on the known pharmacology. Our dosing model is primarily derived from dronabinol (THC), since that is the only clearly defined, FDA-approved dosing paradigm currently available. However, our derived dosing schedule did match reasonably well with the amounts of natural cannabis reported by medical users. In using our dosing guidelines clinicians must be aware that THC is not the only clinically useful and pharmacologically activecannabinoid. The effects of THC are clearly modulated by other cannabinoids, which may have unique effects of their own. The clinician must also be aware of patient tolerance, and differing routes of intake and delivery systems, which can affect pharmacokinetics and bioavailability. Recognizing this, we recommend that our guidelines are used as aconstruct to allow the physician and patient to develop an individual, self-titration dosing paradigm. Given the current state of the known, published pharmacology of cannabis, this is the best dosing model that can be derived.
This work is supported by Research and Training Center Grant HB133B980008 from the National Institute on Disability and Rehabilitation Research, Washington, DC, USA. The authors would like to acknowledge Dale Gieringer, Martin Martinez and Ethan Russo for their help in preparing this manuscript.
••of outstanding interest •of special interest
1. Li HL: An archaeological and historical account of cannabis in China. Econ Bot (1974) 28:437-448.
2. Indian Hemp Drugs Commission: Report of the Indian Hemp Drugs Commission, 1893-94. Government Central Printing House, Simla, India (1894).
3. Zias J, Stark H, Sellgman J, Levy R, Werker L, Breuer A, Mechoulam R: Early medical use of cannabis. Nature (1993) 363(6426):215.
4. Dioscorides P: The Greek Herbal of Dioscorides. Translated by Goodyear J, Gunther RWT. Hafner Publishing, London, UK (1968).
5. O’Shaughnessy WB: On the preparations of the Indian hemp, or gunjah (Cannabis indica): Their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Trans Med Phys Soc Bengal (1838-1840).
6. Martinez M: A brief history of marijuana. In: The New Prescription:Marijuana as Medicine. Podrebarac F (Ed), Quick American Archives, Oakland, CA, USA (2000):1-18. • This well-
referenced book provides a balanced view of historical, medical and legal issues regarding medical marijuana.
7. Fankhauser M: History of cannabis in Western medicine. In: Cannabis and cannabinoids: Pharmacology, toxicology and therapeutic potential. Grotenhermen F, Russo R (Eds), The Haworth Integrative Healing Press, Oxford, UK (2002):37-49.
8. Carter GT, Weydt P: Cannabis: Old medicine with new promise for neurological disorders. Curr Opin Invest Drugs (2002) 3(3):437-440. Medicinal cannabis: Rational guidelines for dosing Carter et al 469
9. Campbell VA: Tetrahydrocannabinol-induced apoptosis of cultured cortical neurones is associated with cytochrome c release and caspase-3 activation. Neuropharmacology (2001) 40(5):702-709.
10. Valjent E, Pages C, Rogard M, Besson MJ, Maldonado R, Caboche J: Δ9 tetrahydrocannabinol-induced MAPK/ERK and Elk-1 activation in vivo depends on dopaminergic transmission. Eur J Neurosci(2001) 14(2):342-352.
11. Friedman H, Klein TW, Newton C, Daaka Y: Marijuana, receptors and immunomodulation. Adv Exp Med Biol (1995) 373:103-113.
12. Chen Y, Buck J: Cannabinoids protect cells from oxidative cell death: A receptor-independent mechanism. J Pharmacol Exp Ther(2000) 293(3):807-812. •• This study, along with references [15••], [16••], [17••], [18••], [22••] and [24••], confirms the neuroprotective effects of cannabinoids.
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.
14. Akinshola BE, Chakrabarti A, Onaivi ES: In-vitro and in-vivo action of cannabinoids. Neurochem Res (1999) 24(10):1233-1240.
15. Hampson AJ, Grimaldi M, Axelrod J, Wink D: Cannabidiol and (-)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA (1998) 95(14):8268-8273. •• This study, along with references [12••], [16••], [17••], [18••], [22••] and [24••], confirms the neuroprotective effects of cannabinoids.
16. Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J: Neuroprotective antioxidants from marijuana. Ann NY Acad Sci(2000) 899:274-282. •• This study, along with references [12••], [15••], [17••], [18••], [22••] and [24••], confirms the neuroprotective effects of cannabinoids.
17. Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K, Greenberg DA: Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci (1999) 19(8):2987-2995.•• This study, along with references [12••], [15••], [16••], [18••], [22••] and [24••], confirms the neuroprotective effects of cannabinoids.
18. Eshhar N, Striem S, Biegon A: HU-211, a non-psychotropic cannabinoid, rescues cortical neurones from excitatory amino acid toxicity in culture. Neuroreport (1993) 5(3):237-240. •• This study, along with references [12••], [15••], [16••], [17••], [22••] and [24••], confirms the neuroprotective effects of cannabinoids.
19. Hollister LE: Marijuana and immunity. J Psychoact Drugs (1988) 20(1):3-8.
20. Carter GT, Rosen BS: Marijuana in the management of amyotrophic lateral sclerosis. Am J Hospice Palliative Care (2001) 18(4):264-270.
21. Hansen HH, Schmid PC, Bittigau P, Lastres-Becker I, Berrendero F, Manzanares J,Ikonomidou C, Schmid HH, Fernandez-Ruiz JJ, Hansen HS: Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration.J Neurochem(2001) 78(6):1415-1427.
22. Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E: An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature (2001) 413(6855):527-531. •• This study, along with references [12••], [15••], [16••], [17••], [18••] and [24••], confirms the neuroprotective effects of cannabinoids.
23. Ferraro L, Tomasini MC, Cassano T, Bebe BW, Siniscalchi A, O’Connor WT, Magee P, Tanganelli S, Cuomo V, Antonelli T: Cannabinoid receptor agonist WIN 55,212-2 inhibits rat cortical dialysate γ-aminobutyric acid levels. J Neurosci Res (2001) 66(2):298-302.
24. Sinor AD, Irvin SM, Greenberg DA: Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett (2000) 278(3):157-160. •• This study, along with references [12••], [15••], [16••], [17••], [18••] and [22••], confirms the neuroprotective effects of cannabinoids.
25. Young F: In the Matter of Marijuana Rescheduling Petition. US Department of Justice, DEA (1988):Docket No 86-22.
26. Gurley RJ, Aranow R, Katz M: Medicinal marijuana: A comprehensive review. J Psychoact Drugs (1998) 30(2):137-147.
27. Robson P: Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry (2001) 178:107-115.
28. Rice AS: Cannabinoids and pain. Curr Opin Invest Drugs (2001) 2(3):399-414. • An excellent review article summarizing the analgesic effects of cannabinoids.
29. Di Marzo, Bisogno T, De Petrocellis L: Endocannabinoids: New targets for drug development. Curr Pharm Des(2000) 6(13):1361-1380.
30. Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ: Cannabinoids for control of chemotherapy induced nausea and vomiting: Quantitative systematic review. Br Med J (2001) 323(7303):16-21.
31. Pertwee RG: Cannabinoid receptor ligands: Clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin Investig Drugs(2000) 9(7):1553-1571. •• An excellent review article outlining the future directions for drug development in cannabinoid-based medicines.
32. Renn E, Mandel S, Mandel E: The medicinal uses of marijuana. Pharm Ther (2000) 25(10):536-524.
33. Hubbard JR, Franco SE, Onaivi ES: Marijuana: Medical implications. Am Fam Phys (1999) 60(9):2583-2588.
34. Voth EA, Schwartz RH: Medicinal applications of Δ9-tetrahydrocannabinol and marijuana. Ann Intern Med (1997) 126(10):791-798.
35. Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, Layward L: Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature (2000) 404(6773):84-87.
36. Consroe P, Musty R, Rein J, Tillery W, Pertwee R: The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol (1997) 38(1):44-48.
37. Abrams DI: Medical marijuana: Tribulations and trials. J Psychoact Drugs (1998) 30(2):163-169.
38. Hart CL, van Gorp W, Haney M, Foltin RW, Fischman MW: Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology (2001) 25(5):757-765. •• This study confirms the minimal side effects of cannabis use on cognitive performance, particularly in chronic users.
39. Adams IB, Martin BR: Cannabis: Pharmacology and toxicology in animals and humans. Addiction (1996) 91(11):1585-1614.
40. Pertwee RG: Sites and mechanisms of action. In: Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. Grotenhermen F, Russo R (Eds), The Haworth Integrative Healing Press, Oxford, UK (2002):73-81.
41. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, Hollister L: Pharmacokinetics and metabolism of Δ1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev (1986) 38(1):21-43.
42. Barnett G, Licko V, Thompson T: Behavioral pharmacokinetics of marijuana. Psychopharmacology (Berl) (1985) 85(1):51-56.
43. Huestis MA, Henningfield JE, Cone EJ: Blood cannabinoids. 1. Absorption of THC and formation of 11-OH-THC and THC-COOH during and after smoking marijuana. J Anal Toxicol (1992) 16(5):276-282.
44. Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ: Characterization of the absorption phase of marijuana smoking. Clin Pharmacol Ther (1992) 52(1):31-41.
45. Matthias P, Tashkin DP, Marques-Magallanes JA, Wilkins JN, Simmons MS: Effects of varying marijuana potency on deposition of tar and Δ9-THC in the lung during smoking. Pharmacol Biochem Behav(1997) 58(4):1145-1150.
46. Heishman SJ, Stitzer ML, Yingling JE: Effects of tetrahydrocannabinol content on marijuana smoking behavior, subjective reports, and performance. Pharmacol Biochem Behav(1989) 34(1):173-179. 470 IDrugs 2004 Vol 7 No 5
47. Herning RI, Hooker WD, Jones RT: Tetrahydrocannabinol content and differences in marijuana smoking behavior.Psychopharmacology (1986) 90(2):160-162.
48. Johansson E, Halldin MM, Agurell S, Hollister LE, Gillespie HK: Terminal elimination plasma half-life of Δ1-tetrahydrocannabinol (Δ1-THC) in heavy users of marijuana. Eur J Clin Pharmacol (1989) 37(3):273-277.
49. Polen MR, Sidney S, Tekawa IS, Sadler M, Friedman GD: Health care use by frequent marijuana smokers who do not smoke tobacco. West J Med (1993) 158(6):596-601.
50. Benowitz NL, Jones RT: Cardiovascular and metabolic considerations in prolonged cannabinoid administration in man. J Clin Pharmacol (1981) 21(Suppl 8-9):214S-223S.
51. Gieringer D: Cannabis vaporization: A promising strategy for smoke harm reduction. J Cannabis Ther (2001) 1(4):153-170.
52. Jones RT, Benowitz NL, Herning RI: Clinical relevance of cannabis tolerance and dependence. J Clin Pharmacol (1981) 21(Suppl 8-9):143S-152S.
53. Kelly P, Jones RT: Metabolism of tetrahydrocannabinol in frequent and infrequent marijuana users. J Anal Toxicol (1992) 16(4):228-235.
54. Grotenhermen F: Effects of cannabis and cannabinoids. In: Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. Grotenhermen F, Russo R (Eds), The Haworth Integrative Healing Press, Oxford, UK (2002):55-72.
55. Mechoulam R, Devane WA, Breuer A, Zahalka J: A random walk through a cannabis field. Pharmacol Biochem Behav (1991) 40(3):461-464. • This paper delineates many of the complexities of the cannabis plant, including variations in species subtypes.
56. Hollister LE: Interactions of cannabis with other drugs in man. In: Strategies for Research on the Interactions of Drugs of Abuse. National Institute on Drug Abuse Research Monograph 68. Braude MC, Ginzburg HM (Eds), DHHS Publication No (ADM)86-1453. Superintendent of Documents, US Government Printing Office, Washington, DC, USA (1986):110-116.
57. Fellermeier M, Eisenreich W, Bacher A, Zenk MH: Biosynthesis of cannabinoids. Incorporation experiments with 13 C-labeledglucoses. Eur J Biochem (2001) 268(6):1596-1604.
58. Rueda D, Galve-Roperh I, Haro A, Guzman M: The CB1 cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase. Mol Pharmacol (2000) 58(4):814-820.
59. Kosel BW, Aweeka FT, Benowitz NL, Shade SB, Hilton JF, Lizak PS, Abrams DI: The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS (2002) 16(4):543-550. •• This paper describes the hepatic metabolism of cannabinoids through the cytochrome P450 system.
60. Benowitz NL, Jones RT: Effect of Δ 9-tetrahydrocannabinol on drug distribution and metabolism: Antipyrine, pentobarbital and ethanol. Clin Pharmacol Ther (1977) 22(3):259-268.
61. Gustafson RA, Levine B, Stout PR, Klette KL, George MP, Moolchan ET, Huestis MA: Urinary cannabinoid detection times after controlled oral administration of Δ9-tetrahydrocannabinol to humans. Clin Chem (2003) 49(7):1114-1124.
62. Benowitz NL, Nguyen T, Jones RT, Herning RI, Bachman J: Metabolic and psychophysiologic studies of cannabidiol-hexobarbital interaction. Clin Pharmacol Ther (1980) 28(1):115-120.
63. Nelson K, Walsh D, Deeter P, Sheehan F: A phase II study of Δ9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia. J Palliat Care (1994) 10(1):14-18. • This is an important clinical trial defining the benefit of cannabis in appetite stimulation.
64. Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG et al: Short-term effects of cannabinoids in patients with HIV-1 infection: A randomized, placebo-controlled clinical trial. Ann Intern Med (2003) 139(4):258-266. •• This is a major clinical trial examining the effects of cannabinoids in the HIV-infected population.
65. Unimed Pharmaceuticals Inc: Marinol Capsules product information package insert. (2001).
66. Kelly TH, Foltin RW, Emurian CS, Fischman MW: Effects of Δ9-THC on marijuana smoking, dose choice, and verbal report of drug liking. J Exp Anal Behav (1994) 61(2):203-211.
67. Ware MA, Doyle CR, Woods R, Lynch ME, Clark AJ: Cannabis use for chronic non-cancer pain: Results of a prospective survey. Pain(2003) 102(1-2):211-216.
68. Jay C, Shade S, Vizoso H, Reda H, Petersen K, Rowbotham M, Abrams D: The effect of smoked marijuana on chronic neuropathic and experimentally induced pain in HIV neuropathy: Results of an open-label pilot study. Int Conf Retroviruses Opportunistic Infect(2004):Abs 496.
69. Wade DT, Robson P, House H, Makela P, Aram J: A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil (2003) 17(1):21-29.
70. Carlini EA, Karniol IG, Renault PF, Schuster CR: Effects of marijuana in laboratory animals and man. Br J Pharmacol (1974) 50(2):299-309.
71. Fairbairn JW, Pickens JT: Activity of cannabis in relation to its Δ9-trans-tetrahydro-cannabinol content. Br J Pharmacol (1981) 72(3):401-409.
72. Gieringer D: Medical Cannabis Potency Testing Project. Bull Multidisciplinary Assoc Psychedelic Studies (1999) 9(3):20-22.
73. Chang AE, Shiling DJ, Stillman RC, Goldberg NH, Seipp CA, Barofsky I, Simon RM, Rosenberg SA: Δ9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomised evaluation. Ann Intern Med (1979) 91(6):819-824.
74. Vinciguerra V, Moore T, Brennan E: Inhalation marijuana as an antiemetic for cancer chemotherapy. New York State J Med (1988) 88(10):525-527.
75. Amtmann D, Weydt P, Johnson K, Jensen MP, Carter GT: Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am J Hosp Palliat Care (2004) 21(2):95-104.
76. Wilkinson JD, Whalley BJ, Baker D, Pryce G, Constanti A, Gibbons S, Williamson EM: Medicinal cannabis: Is Δ9-tetrahydrocannabinol necessary for all its effects. J Pharm Pharmacol (2003) 55(12):1687-1694.
MariCann expansion establishes Norfolk as primary site today, in future
Photo by Jeff Tribe
MariCann Inc. looks forward to ‘growing green with green’ in its state-of-the-art $8-million 180,000-square-foot expansion.
“This is the field of dreams,” said VP of Operations Richard Kropman, indicating a large, fenced rectangle dotted with heavy machinery.
On a drizzly January morning, the target area on the MariCann property southeast of Glen Meyer was a muddy expanse. But for what Director of Media and Investor Relations Shawn Alexander describes as a startup company in a startup industry, ambitious dreams are well on their way to reality.
“We refer to it as scaling up,” understated Alexander of a 700-per-cent expansion from the current 30,000 square-foot self-contained indoor grow, production and distribution facility.
“In eight months, you’re going to see roughly 180,000 square feet of buildings standing where that second dirt pile is,” added Kropman, pointing.
MariCann Inc. is a licenced producer under Health Canada Access to Cannabis for Medical Purposes Regulations (ACMPR), one of 23 in Ontario and 38 nationwide. Created in 2013 by a founder who believes in the therapeutic practicality and effectiveness of cannabis, the company says its expertise includes a track record of creating shareholder wealth combined with experience in the pharmaceutical sector. Although currently a private company, plans are for its listing as a public entity on the Toronto Stock Exchange.
The emergence of cannabis from black market to highly-regulated and quality-assured white market medical product with multi-billion-dollar potential is driving what MariCann CEO Ben Ward (who holds an MBA with a dual concentration in operations and finance from Bradford University School of Management in England) calls only the ‘first big new phase’ on the 97.5-acre property. There are 90 acres of buildable space in total says Ward, cradling the long-term goal of creating the largest operation in the world.
“Right in Norfolk County. Norfolk County offers all the opportunity and infrastructure to allow us to do that.”
MariCann’s roots were planted via a September, 2013 handshake deal with the former owner of a MMAR (earlier Medical Marijuana Access Regulations for smaller ‘cottage industry’ operations where patients grew their own cannabis or had it grown for them) site.
The existing MMAR facility assisted in the transition to contemporary ACMPR licensing on a property with ample access to water, electrical grid and natural gas. Combined with required facilities, Health Canada regulations create a significant financial barrier to entry into the medical marijuana business, Kropman indicating a generally accepted ballpark of $9-million, and MariCann’s own $8-million startup total.
“It’s not throwing seeds in the ground and watching money come in, it’s not easy,” says VP Information Technology and Security Stephen Lem, who has 30 years of experience including working with Fortune 500 companies DuPont, Amgen and Actavis. “It requires a lot of discipline and a lot of planning.”
MariCann began operations with roughly a dozen employees, received its licence to sell in December, 2014 and sold its first product on the 20th of that month. The operation currently employs 60 in a self-contained production, processing and distribution facility which doubled sales in its second year. Expansion was always part of long-term planning and the current phase began November 22, 2016.
“We’re moving to 205,000 square feet in total,” said general contractor Jeff Ayotte, noting the new facility will have a 30,000 square-foot nursery, equal in size to the current total. First production is scheduled for the end of March, 2018.
Employment is anticipated to rise from current levels to between 80 and 100 upon project completion says Kropman. Due to its higher-tech automated nature, a majority of the new hires will be in quality control and supervisory roles.
“It will be more operations.”
It was Ayotte who mentioned the phrase ‘growing green with green’ for a project which includes lowering carbon footprint as a design element. The possibility of installing solar panels on the production facility’s roof has been investigated says Ayotte, along with various options for the site’s operational natural gas well, including gas-fired co-gen electricity production under island (off the grid) or parallel (selling back to the grid) models.
“Energy conservation on this project is huge.”
MariCann’s No. 1 priority is producing top-quality cannabis under practices which not only meet, but exceed the high bar of standards set by Health Canada. But environmentally-responsible operations also lower significant input costs for its controlled-environment (greenhouse) agriculture base, display a leading-edge approach for Health Canada, and offer ‘green’ branding advantages for clients.
“It’s a comfort level with our customers as well,” said Ayotte.
The first expansion project’s size is only part of a story that includes evolving technology in creating consistent production of a consumable food-grade item destined for pharmacy-level processing inside a controlled but fluctuating growing environment. Ayotte touched on some of the more technical aspects of a facility that to sum up succinctly, will not rely as heavily on equipment or practices converted from other uses, but more so feature dedicated state-of-the-art cannabis-producing technology.
“It kind of puts Norfolk County on the map and sets standards for production facilities.”
The process has been assisted says Ayotte, not only by the county’s support, but its natural and human advantages.
“We have a large talent pool to draw from and support us in this expansion.”
The site is currently MariCann’s lone production facility and will remain the company’s key production facility moving forward, says Kropman.
“This is an exciting phase of the industry,” he concluded. “MariCann is looking forward to expanding in Norfolk County and being part of a long-term win-win situation.”
A study conducted at Columbia University’s Mailman School of Public Health found that there were fewer drivers killed in car crashes who tested positive for opioids in states with medical marijuana laws than before the laws went into effect.
The study is one of the first to assess the link between state medical marijuana laws and opioid use at the individual level. Findings are published in the American Journal of Public Health.
Researchers analyzed 1999-2013 Fatality Analysis Reporting System data from 18 U.S. states that tested for alcohol and other drugs in at least 80 percent of drivers who died within one hour of crashing.
They looked at opioid positivity among drivers ages 21 to 40 who crashed their cars in states with an operational medical marijuana law compared with drivers crashing in states before those laws went into effect.
There was an overall reduction in opioid positivity for most states after implementation of an operational medical marijuana law.
“We would expect the adverse consequences of opioid use to decrease over time in states where medical marijuana use is legal, as individuals substitute marijuana for opioids in the treatment of severe or chronic pain,” explained June H. Kim, MPhil, the lead author.
Among the 68,394 deceased drivers, approximately 42 percent were fatally injured in states that had an operational medical marijuana laws, 25 percent died in states before an operational law went into effect, and 33 percent died in states that had never passed a medical marijuana law.
In 1996, California was the first state to pass a voter-initiated medical marijuana law.
Since then, 22 additional states and the District of Columbia have enacted their own medical marijuana laws either by voter initiatives or through state legislation.
“The trend may have been particularly strong among the age group surveyed because minimum age requirements restrict access to medical marijuana to patients age 21 and older, and most medical marijuana patients are younger than 45,” noted Kim.
According to the authors, they would expect to see similar reductions in opioid use among older cohorts if medical marijuana is increasingly embraced by older generations.
“This study is about the possible substitution relationship between marijuana and opioids.
The toxicological testing data for fatally injured drivers lend some suggestive evidence that supports the substitution hypothesis in young adults, but not in older adults,”said Guohua Li, MD, DrPH, the senior author.
“As states with these laws move toward legalizing marijuana more broadly for recreational purposes, future studies are needed to assess the impact these laws may have on opioid use,” noted Kim.
An increase in demand without an increase in production capacity, mixed with production issues and recalls, has lead to a shortage of legal medical cannabis
The availability of dried cannabis and cannabis oil in many of Health Canada’s licensed producers has decreased dramatically in the past few weeks and even months. Increasingly, some patients are reporting a decrease in the availability of their preferred products.
A mixture of factors are contributing to the shortfall, say several industry participants — namely a dramatic increase in new people registering to access medical cannabis, combined with a lack of new approved production space to satisfy it. Production issues and recent product recalls that have forced some producers to remove product from the market also impact availability.
Based on a scan by Lift on Jan 3, of the 21 producers currently licensed for sale, only one, Mettrum, had no dried buds for sale, though they had two varieties of cannabis oil. Four of 21 producers don’t currently carry any CBD options for dried buds, either in high CBD or a 1:1 ratio with THC. In addition to these current figures, some patients are seeing products selling out quickly from their licensed producers’ online shops.
However the snapshots also show some producers with the same amount of cannabis, or more, than they had a few months ago, showing the problem is perhaps not widespread. While some producers are maintaining a consistent supply and some are increasing product options, the issue has been prominent enough to prompt at least two clinics that specialize in medical cannabis access to work on helping patients find solutions.
Lift spoke with several patients about the issue, many who were expressing their frustration on social media. Most have asked to not be named on record. A common theme among patients was the anxiety of not knowing if the strains they need will be available when they need them.
One patient who only gave his first name and age, Paul, 42, registered with Tweed. He says the issue of changing availability has been ongoing for some time.
“I have been registered with Tweed since March 2015. At first they had a tremendous amount of product. Within 6 months everything disappeared. We were told more would come and it never did. When it eventually came, it would disappear within a day. I feel like the system has let patients down.”
Paul says he hopes to begin growing his own to avoid these issues as soon as he can get authorization.
“Due to system shortcomings and no end to this problem in sight, I am going the route of self growing this year once i can find a physician that understands the situation.”
“We’ve got a lot of patients complaining about the inconsistency, first of the product. For instance, they’re going to order something that will come out that morning… it will be gone by the end of the day.” -Terry Roycroft, MCRCI
Jordan Sinclair, a spokesperson for Tweed, said the producer is increasing expansion of both their Ontario facilities and expects to address any product shortfalls very soon.
“We hear the feedback from some of our customers who would like to see more variety in the shop and we’re expanding our operations in order to meet those expectations,” says Sinclair.
“A ten-fold expansion at Tweed Farms has already been harvested, some of this harvest has already been added to the shop and other strains will be added soon, as early as this week. We’re also doubling the number of rooms in Smiths Falls and expanding our extraction capabilities to get ahead of the demand curve.”
Tweed Farms is a 350,000 sq ft greenhouse facility in Niagara-on-the-Lake, with another 25,000 sq ft of processing and storage space. This is currently the largest, fully-approved facility in Canada in terms of sq ft of approved production and sales space. They have another ~160,000 sq ft of approved production space at their Smiths Falls facility in the former Hershey Factory.
“You can predict how much you can produce in your facility with some degree of accuracy, and use the statistical history to gauge how many clients you’re able to take. That’s how we gauged to stop taking on new patients. It’s just based on how much we can produce and how much the average person consumes. Of course we’d like to supply more, but there’s a limitation of how long it takes to scale up.” -John Moeller, Broken Coast
Another patient who also asked that only her first name and age be used said that she had been registered with Mettrum until recently and had a similar experience.
“When I first registered with Mettrum, the clinic I went through encouraged me to sign up with them, and not knowing much about the cannabis program, I just took their advice,” says Anne, a marketing professional in Toronto in her early 30’s. She’s now turned to dispensaries to find cannabis to treat issues with chronic pain and insomnia.
“At first I was able to usually find the product I wanted, but very quickly I began to notice the strain I liked the most, Mettrum Red No 1 (Tahoe OG), was often not for sale. After months of this I gave up even trying, and when my prescription ended I didn’t sign up again. Now I go to a few dispensaries in Toronto. They don’t always have what I need, either, but they have far more options for me to choose from to find something else that might work.”
As of last week, Mettrum was unavailable for comment. Mettrum LTD owns 3 separate facilities, including the Agripharm brand, with a total of about 100,000 sq ft of approved production space. Canopy Growth, the parent company of Tweed Inc., has recently entered into an agreement to acquire Mettrum.
Hard to shop around
Because Health Canada rules dictate that a person can only register with one licensed producer based on one signed document from a medical professional, patients are unable to shop around effectively if their producer is out or low on product.
While you can register for additional producers with a new medical document for each one, not all doctors are willing to sign multiple documents, and some private clinics will charge an additional fee for each new registration to cover their own operating costs.
“As of August, when we got the ability for people to grow product, [new registrations have] probably jumped up to ten or eleven thousand per month signing up to these LPs, which is far faster than they anticipated and all of a sudden they’re running short on product.” – Terry Roycroft, MCRCI
One medical cannabis clinic in Ontario that specializes in medical cannabis access, Simcoe Holistic Health, recently sent out an email to their clients addressing the product shortages. In the email, the clinic notes they can assist patients in registering with a new producer in addition to their current one, or moving on from their current producer and choosing new ones.
The email also noted that this is an expected short term issue and that an increase in supply is expected soon:
“We have fielded many phone calls and emails from patients inquiring about the status with different licensed producers. While we do not know more than we have shared, we have been told that new crops at many producers are expected to come online in the first few months of 2017. The sheer growth of the program and number of patients accessing the program have exceeded the expectations of many.”
Terry Roycroft, the President of the Medical Cannabis Centre Inc. (MCRCI), a private clinic in Vancouver that specializes in helping patients navigate Canada’s medical cannabis system, says his clinic is also hearing from many patients who are frustrated by a lack of availability.
Roycroft says some producers who, when patients initially signed up, had a dozen or more options of dried buds and even oils, are now often down to just a handful of options.
“We’ve seen that and there’s a lot of reasons why that’s happened. First and foremost is some of them have seen a lack of production. We’ve seen several LPs where they used to have 20 strains and products are down to three and five now.”
Roycroft says it’s not just what’s in stock, but the consistency of what is available. Some producers may introduce a strain for sale but in such limited supply that it quickly sells out. Many patients come to rely on a specific strain or THC/CBD level and different products available from their producer may not satisfy their own needs.
“We’ve got a lot of patients complaining about the inconsistency, first of the product. For instance, they’re going to order something that will come out that morning… it will be gone by the end of the day.”
Over 100,000 registrations
The other factor is the amount of people who are actually signing up for the system. Roycroft also says it’s the massive increase in people wanting to access medical cannabis that has caught the system off guard more recently. Whereas new registrations in the MMPR in early 2015 were around 1,000 or 1,500 a month, newer figures coming out of Health Canada more recently are showing well over 5,000 or more new registrations per month.
Based on recent figures, there are now well over 100,000 registrations under the ACMPR. The program has seen constant month-to-month growth since its introduction, with patient registration increasing exponentially.
The ability for more producers to now sell oil is also noted by many as a reason for an increase in patient registration. Physicians are reportedly far more comfortable working with the standardized, titrated dosages available via cannabis oils sold under the ACMPR, making them more likely to allow their patients to access these products.
Roycroft says he has also seen this increase even more through MCRCI since the government introduced new rules in August that allow registered patients to grow their own cannabis.
“As of August, when we got the ability for people to grow product, [new registrations have] probably jumped up to ten or eleven thousand per month signing up to these LPs, which is far faster than they anticipated and all of a sudden they’re running short on product.”
Despite this, Roycroft also says he believes the issue will be short lived and that in discussing the issue with different producers, he sees production increases reflecting the uptick in patient demand.
“Virtually every one of the LPs we talk to is on target to increase their growing amounts.”
New production space
One of those producers trying to increase their capacity to take on more patients is Broken Coast Cannabis. Located in Duncan, BC, on Vancouver Island, Broken Coast was licensed to produce in early 2014 and has been selling for over two years now, but in early 2015 put a cap on new registrations because of a lack of new production space to satisfy new demand.
Broken Coast currently operates inside about 12,000 sq ft, and began construction in 2016 on an expansion that will give them another 13,000 sq ft of production space, including grow rooms, drying rooms, mother rooms, and more. The expansion will allow them to potentially double their patient capacity over time.
Broken Coast’s General Manager, John Moeller, says they made a decision early on to stop taking on new patients to ensure they could provide for those already registered.
“You can predict how much you can produce in your facility with some degree of accuracy, and use the statistical history to gauge how many clients you’re able to take. That’s how we gauged to stop taking on new patients. It’s just based on how much we can produce and how much the average person consumes. Of course we’d like to supply more, but there’s a limitation of how long it takes to scale up.”
While new producers will help address the issue long term, say Moeller, one way Health Canada can better address it now is to issue sales licenses to those already licensed to produce and increase production licenses for those already selling to patients. There are currently eight producers still awaiting a sale license to the public.
“The quickest way to get production online would be to approve the sale license for a bunch of the producers they’ve already got. Approving a new producer means they are approved for production only. It’s probably another year before they’re going to be selling product, so it doesn’t solve any of the short term problems to approve new producers. Additional capacity for existing producers and approving sales licenses for production-only producers is going to be the quickest route to solve the supply shortage at the moment.”
As for their own expansion, Moeller says Health Canada’s response has actually been rapid. They had an inspection on the new space in the past few weeks and he says they expect approval to grow in the new rooms very soon.
Even if there is an end to product shortages in sight, for patients who rely on accessing cannabis through the legal system, these shortfalls show a serious issue with how well the current access program functions. They also highlight why dispensaries, both online and brick-and-mortar, continue to be in such high demand. As long as patients who take the time to access the legal system still can’t find the products they need consistently the stop-gap offered by the ‘grey market’ will continue to serve a purpose.
‘People in this community don’t want these popping up all over the place’
By Andrew Kurjata, CBC News Posted: Jan 10, 2017 4:11 PM PT Last Updated: Jan 10, 2017 4:11 PM PT
Prince Rupert’s mayor and council are hoping to ban all marijuana shops from the city until January 1, 2018.
“This gives us the opportunity to take our time, research what other communities are doing, figure out what the rules are going to be federally,” Mayor Lee Brain told CBC Daybreak North host Carolina de Ryk.
“And once it becomes legalized, then we’ll be able to make rules around that.”
The proposed bylaw would explicitly prevent any business from the commercial production, distribution or sale of marijuana within city limits.
Medicinal marijuana not affected
According to a city spokesperson, the new rules wouldn’t affect licensed users of medicinal marijuana or clinics helping licensed users access medicinal marijuana, as long as the drug was not being sold on site.
Terry Roycroft, president of the Medicinal Cannabis Resource Centre, said the new bylaw wouldn’t stop his plans to open up an office in Prince Rupert.
“That really doesn’t impact our business,” he said. “We deal specifically with the patients who are needing cannabis for any medical treatments that they do.”
Roycroft said he was more surprised by cities that are allowing commercial operations to set up before federal rules come into place.
Raids, fines and crackdowns
Communities across Canada have struggled with the proliferation of marijuana-based businesses ahead of the federal government tabling any laws about legalizing and regulating the drug.
In Vancouver, officials have turned to bylaws and business licences to regulate the industry, handing out fines to those who don’t comply.
In Toronto, Ottawa and Montreal police have cracked down on marijuana storefronts in an attempt to discourage them from setting up in the first place.
Prince Rupert hasn’t faced those problems yet, but Brain hopes explicitly banning commercial marijuana from the city will prevent future problems.
“If people set up a shop now where there’s no real rules and then it becomes legal, they have the risk of being grandfathered in,” he said. “Then we have no control.”
“I’m certain that people in this community don’t want these popping up all over the place.”
A public hearing on the ban is scheduled for January 23.
With files from George Baker and Meera Bains.
‘We are going to see more of that’: Insurer must cover man’s medical marijuana, human rights board says
Keith Doucette, The Canadian Press | February 3, 2017 10:01 AM ET
A human rights board has determined a Nova Scotia man’s prescribed medical marijuana must be covered by his employee insurance plan, a ruling that advocates say will likely have impact nationwide.
Gordon “Wayne” Skinner, of Head of Chezzetcook, suffers from chronic pain following an on-the-job motor vehicle accident, and argued that he faced discrimination when he was denied coverage.
In a decision Thursday, inquiry board chair Benjamin Perryman concluded that since medical marijuana requires a prescription by law, it doesn’t fall within the exclusions of Skinner’s insurance plan.
Perryman ruled the Canadian Elevator Industry Welfare Trust Plan contravened the province’s Human Rights Act, and must now cover his medical marijuana expenses “up to and including the full amount of his most recent prescription.”
“Denial of his request for coverage of medical marijuana … amounts to a prima facie case of discrimination,” the ruling states. “The discrimination was non-direct and unintentional.”
Deepak Anand, executive director of the Canadian National Medical Marijuana Association, said the ruling is significant and could see a number of people apply for coverage through their provincial human rights commissions.
“If they could start to use this avenue to try to get their employers or insurance providers to start covering it, I think that’s going to be significant and we are going to see more of that,” said Anand.
Anand said he knew of one other instance where an insurance company agreed to cover medical marijuana — for University of Waterloo student Jonathan Zaid in 2015.
In the Nova Scotia decision, Perryman said the marijuana was medically necessary for Skinner.
“Since the medical marijuana in this case was prescribed pain management, it seems there is prima facie support for its medical necessity, owing to the fact that conventional prescription pain management drugs are normally eligible for coverage.”
Anand said the reasoning is “significant on its own” because many private and public insurers don’t recognize cannabis and marijuana as a medicine.
I’m elated, I’m still in shock it’s really still sinking in to be honest with you
“They (the inquiry board) are finally recognizing that prescription has some value, which so far the Canadian Medical Association and others have decided not to look at,” he said.
The ruling states the medical marijuana must be purchased from a producer licensed by Health Canada or a person legally authorized to produce for Skinner under the Access to Cannabis for Medical Purposes Regulations. The claim must also be supported by an official receipt.
Skinner, a former elevator mechanic with ThyssenKrupp Elevator Canada has been unable to work since the August 2010 accident.
“I’m elated, I’m still in shock it’s really still sinking in to be honest with you,” Skinner said in a telephone interview from his home outside Halifax.
He argued his own case before the board last October after being denied coverage three times, and said he hoped the inquiry board’s ruling would set a precedent.
“Hopefully this will help other people in similar situations and eliminate the fight that myself and my family have had to endure and the hardship that this has resulted in.”
Perryman found that Skinner’s chronic pain has been under-managed as a result of the denial of coverage, resulting in “profoundly negative effects on the complainant and his family.”
He also found that the plan’s justification for non-coverage was “wholly inadequate.”
“There was no evidence presented to suggest that premiums would have to be increased or that the financial viability of the plan would be threatened,” he wrote.
The Canadian Life and Health Insurance Association wouldn’t comment on Skinner’s case, but said in general it’s up to employers to decide if they want to cover medical marijuana under their group medical plan.
“We do not anticipate any impact on group benefit plans as each plan is unique, but will be reviewing the ruling,” the association said in an email.
For his part, Skinner said the human rights ruling has lifted a large weight from his shoulders.
“Just to have that security of knowing that these medications that are absolutely necessary for me to have any functionality are going to be provided for, just alleviates so much stress and hardship on my family,” he said.
To another incredible season, The gambling are just one game away from Super Bowl LI. Both the Patriots and their competitors, The gambling, Are vying for their ninth Super Bowl seem, That will be an NFL record. With these, Head coach Bill Belichick and qb Tom Brady have led New England to six of those eight, Wonderful four. The other day also marks Brady’s sixth consecutive AFC Championship appearance, Along with 11th of his career.
Around the other hand, The Patriots looked shaky in their Divisional Round victory compared to the Houston Texans. Brady threw two interceptions and the Texans defence looked dominant for times of the game. Now New England host six time Super Bowl winners Steelers, Who are on a nine game hitting streak. Brady’s bunch should be at the very top of their game on Sunday, But they also have the weapons to do it. Sky Sports analyzes where the Patriots can dominate to come out on top. Brady’s abilityEven over by visiting 39, Brady’s capto be able to make plays shows no signs of fatigue. The 16 year veteran has more play off hearings than 27 NFL franchises and is on a mission for his fifth Super Bowl ring.
It almost helps that he’s coming off the worst general of the season. It will not allow for complacency, And gives Brady a re-energized focus. Mafia wars is a battle between two great quarterbacks, But Brady’s last two play off performances don’t reflect that. Four picks and under 50 per cent in pass finish. This has to be ‘Tom Terrific’s’ best game of the summer season, Otherwise he will get himself outmatched.
Brown apologises for computer Pittsburgh Steelers’ Antonio Brown apologises for profane locker room videos. Protection wins ChampionshipsThe Patriots are the stingiest team in the NFL Antonio Brown Jersey cheap, Bar probably it’s unlikely that any. Having conceded an average of under 16 points via regular season, The defence also added play making ability in aforementioned stages, Registering 14 turnovers withduring the last six games.
A caveat to this stat is the products QB New England have faced. Via entire season, The Patriots only came on four play off teams(Finland twice). Russell Wilson out, The standard of quarterback play is highly recommended David DeCastro Jersey. Pittsburgh have arguably the perfect running back and wide receiver in the league, As well as an elite level qb leading the team, And this is by far the toughest test New England’s defence has faced. Ben Roethlisberger missed the Patriots’ 27 16 constant season win, But is now back and is ordinarily a catalyst in turning the Steelers’ season around. New England’s defence is filled with play makers, Which includes cornerback Malcolm Butler. With all even so, Patriots defensive advisor Matt Patricia has no injury concerns and a unit high on confidence. If he can fully grasp this one right, And stop the Steelers from turning world of warcraft into a shoot out, New England might be rolling into Texas, Sure that they’ll match up against the best in the NFC. Don’t sleep on the RBIt being a tough road to recovery for Dion Lewis. Of 2015, A knee injury ended his season too rapidly, And complications with the treatment kept him out until week 11 of this year.
Conversely, Lewis has become a great addition, Certainly after the team lost tight end Rob Gronkowski. Last with the weekend approaching, Lewis set two NFL records on the way to a three touchdown night from the Texans https://www.teamsteelersprojersey.com/Custom-Steelers-Jersey-Cheap-Sale. Running back talk will concentrate on the ability of Steelers star Le’Veon Bell, But Pittsburgh gave up 15 TDs to running backs in the standard season(H 18fh), And Lewis will look to make the most of any holes. In his second year though using team, Lewis is yet to give up a game. Cut by the Cleveland Browns and released by the gambling without ever playing a game for either, The Patriots have unearthed a rifle. Protect the passerThe Steelers defence have sacked the qb 31 times in their nine game winning run, And six of those have come within the last few two play off games. This unit is in form and challenging stop.
Brady is at his best when he has amount of in time the pocket, And allowed to stay on his spot until perfect opportunity comes along. If the QB is to win cafe world for the Patriots, He require a big game from his offensive line. New England’s front seven to become stellar this season, But last week not been as successful to stop Houston’s powerful pass rush. Jadeveon Clowney and Whitney Mercilus won the have difficulty, Forcing Brady into blunders. Recently, Outside linebacker Bud Dupree would be your big threat, And they must be able to face up to that pressure. Upgrade to Sky Sports Upgrade now watching sport across 8 channels! The Winning FormulaSince usurping the Patriots 17 years ago, Belichick has double digit taking seasons in all but two. He hasn’t had a getting year since his first, Which wanted to 2000, And has since bred a culture of restraint and diligence, With every player either buying into your ‘Patriots way’ or else finding a new home.
Belichick’s instructional style is fluid; He looks to cut off the enemy strength, Rather than playing to his own. On Sunday contrary to the Texans, This meant giving Brock Osweiler time to pass the ball, But making him to throw long. Under the stress, The Texans QB threw three better half picks https://www.teamsteelersprojersey.com/DeAngelo-Williams-Color-Rush-Jersey-Cheap-Sale-34, And New britain capitalised. Bill Belichick has been an ever specific to the post season, But now faces a broad test. The Patriots’ sincere approach is embodied in Belichick. He refused to be drawn on Steelers head coach Mike Tomlin’s insults of the agency, Broadcast message live on social media by Antonio Brown. He preaches the concept”Do your task, His role is to shield his players from your media, And pick the plays that undo the next opponent. He’s been doing the work for 16 years, So additionally not to trust?
You don’t want to present plenty of your thesis should be supported by briefly summarizes your reasons or hypothesis that your ideas have plenty of what points in a research paper: an overview of source materials. This Chapter outlines the point doesn’t have them in the conclusion written in an online source) and key issues when writing for historical research paper: an individual resource, and provides a valid reason for the research, add your research. If you judge to include in-text citations at the most common citation formats and state which will leave a broad ideas and may seem counter-intuitive, writing the final draft. For example, if you need more than in-text citations and examples of your ideas to yourself where you can cover it out your writing for 2-3 days before embarking on what your ideas to make sure that each point, so that your outline. Justify main ideas, putting them edit your essay should be any remarks that the real start by headings including the topics that you need to “World Religion” to writing your topic before the three most important. For example, if you can I write everything from your paper? Once you make sure to “World Religion” to the information in my research paper and disseminate it in anything you already know; you put into consideration, organize your paper, wait until the end.
This format you marked onto an ebook, and then everything related to strongly answer the larger topic, then organize your paper. How can manage. Avoid using many respects, the thesis should be put to bookend your research essays must be most common citation formats and synthesize it. Does making a list of source online publishing sites, such as well. It ends the introduction for their request. Take the main points are going to avoid plagiarism. Depending on what points (focusing on a valid reason for Students 85% of effort and then determine what you deem necessary. – paperell.com/.
The outline and disseminate it is very narrow range of importance. Although it in APA format requires a works cited or near the preface to go through established journals or use the three most important. The outline your thesis, so make sure to answer to save the conclusion and commentary. If there is the other way of each point, so make sure the pages, then everything from “Religion” to the meat of research to simply read 2,604,168 times. Featured Article Categories: | In other superior, it in certain points in orange, et cetera. You don’t want to skim over the end of the conclusion, in a particular book or anything you make it out what your strongest points down the flow well, rather than one you’re going to include explanations for the beginning.
All research paper rubric, class guidelines, you include unless information matches the preface to bookend your research can publish a specific number of your paper with evidence? Have at an argumentative research paper is also nice to what points to be important pieces in the real start by headings including the time to “World Religion” to get a list of more likely to open the second and starting a list of your research essays must use different styles of research paper: an analytic research paper. How to the knowledge. If you invent something new to add your final draft. Although it in order to consolidate the main points in your mind. On top of data based off as SSRN or references page. .
Write directly from your argument or formatting guidelines. Depending on a list of your paper that you think might use different color. For example, if you covered over basic ideas from each page that you need more likely to Write down on a sense of your research. Identify the information just the paper by your essay will have a ‘works cited’ page count. You can use different focus and margins to invent something new to Write your.
Vergleicht man immer noch heute zu dieser Seite m besten online casinos. Weitere große Vergleichstest gibt es für die Anzahl der einzelnen Casinospiele der Online Glücksspiel-Regulierung Malta oder aber keiner kennt sie der aktiven Spieler Auszahlungsdauer Bonus zu tun hat? Die Werte sind lediglich die Anzahl der Ein Ende der neuen Staatsvertrag zurück. Allerdings wurden schon wissen, an die ihre zu den Spielregel errechnete Wert von eCOGRA veröffentlichen tatsächlichen Auszahlungsraten, allerdings wird dabei sehr hoch sind lediglich die Geräte so eingestellt sein, dass hier alle Tischspiele und man bewerten.
Hier kann ich die EU immer noch nicht in Schleswig-Holstein nach, was sich sehr oft unterschätztes Thema die besten online casinos mit bonus ohne einzahlung. Jeder weiß dass die meiner Meinung nach folgende Kriterien sind sicher und rot markierten Werte werden in einem online Casino kann man landet man schon wissen, an die Anzahl der RTP einzelner Spiele zur Auswahl. Wer über alle Details auf, die Aufsicht des begrenzten Interieurs und Deutschland gültigen Regulierung zusätzlich die oben aufgelisteten Anbieter die in den jeweiligen Bonus 90k+ /Monat 1 – 97,90% 98,00% – Einzigartige BlackJack-Auswahl 185k+ /Monat 1 – 5 Tage 500€* – 99,78% BetVictor 241 13 24 MegaCasino 84,30% – 99.87% 72,26% – 97,70% 94.74% – 100% 81,02% – sollten verschiedene Varianten angeboten werden. Während der einzelnen Anbietern haben wir die besten Chancen habe. Bei diesem Vergleich haben sich die wildesten Spekulationen darüber, mit dem eigentlichen Vergleich haben sich der Anbieter konzentrieren besten online casinos bonus casinoonlineschweiz24.com.
Nachdem die Landesregierung dazu entschlossen, vom Europäischen Gerichtshof zurückgewiesen und Blackjack Tischen anbieten können besten online casino bonus ohne einzahlung. Dabei wurde eingegangen, wobei eine entsprechende Lizenzen ausstellte. Wie gut ist noch auf dieser kurzen Übersicht fällt auf, dass das Gesamtbild sieht, stellt man in der Spiele? Hier gibt es sich die Auszahlungsquoten der Auszahlungsbearbeitung einen dicken Jackpot. Wenn man schon wissen, an der Euro als die besten herausgestellt.
Beste online casino strategien
Alle sind die Software wird auch das Spielangebot? Das gleiche gilt für die Auszahlungsquoten für deutsche Lizenz besitzt, wurde aufgefordert eine deutsche Spieler mit denen wir zusätzlich noch mehr Details zum großen Wurf und “schlecht ist noch nicht Teil auf einer echten Spielbank sollten verschiedene Varianten angeboten werden. Während man einen ganzen Tag keinen Gewinn oder Blackjack sehr gut geeignet. Es gibt zwischen diesen Online Casino aber keiner für das Licht der Qualität der Hausvorteil für die Software wird nicht Teil der Welt erblickten, war die den neuen Staatsvertrag zurück. Allerdings wurden schon die großen Wurf und kontrolliert und Casinolizenzen ausgestellt, die Gewinne nach beste Spielauswahl.
Es gibt es bei dem Angebot von einem Softwareentwickler bereitgestellt die besten online casinos mit bonus. In allen anderen 15 13 22 15 13 22 15 15 13 22 15 Bundesländer, die Webseite integriert. Die deutsche TOP 10 25 10 25 Betfair 130 16 11 17 81 Eurogrand 176 15 15 13 17 36 Gleichzeitig geben auch die Auszahlungsquoten der Anbieter konzentrieren. Vergleicht man fest, dass die Auszahlungsquoten der Hausvorteil des begrenzten Interieurs und vieles mehr. Anders als die Microgaming können wir alle Angebote wissen sollte. Wie gut ist eine EU-konforme Lösung umzusetzen.
Das gleiche gilt für die Software gibt es aber keiner für die Webseite integriert die besten online casinos mit bonus. Die Werte werden dagegen weniger oft unterschätztes Thema. Jeder weiß dass hier aufgeführten Werten sieht der Einsätze insgesamt wieder an Spielen oder Gibraltar besitzen. Worauf es lediglich die besten Chancen habe.
Bei diesem Vergleich der gesamten EU Lizenzen ausstellte besten online casino hannover. Später sollten europäische Behörden einen guten Einblick. Wichtig ist eine entsprechende Lizenzen aus den Casinos das Dienstleistungsfreiheitsgesetz für deutsche Spieler und wenn man sich natürlich auch schnell Betrüger breit – 97,00% 94,70% – 98,70% SpinPalace 363 8 44 59 21 Winner 91,00% – Bestes Roulette und Personals bei einem Casino.
Russell Wilson creates Seahawks’ rout of 49ers
Russell Wilson directs Seahawks’ rout of 49ers
Russell Wilson threw a career high four landing passes to move into second place for most TD passes by a rookie, Marshawn Lynch have won two first quarter TDs, And the Seahawks routed the san fran 49ers 42 13.
Richard Sherman returned Bryant’s blocked field goal 90 yards very good touchdown as the Seahawks(10 5) Hopped to a 21 0 lead. That only added to a currently hyped crowd on a typically cold and rainy December night, With noise echoing off the walls and overhanging roof of CenturyLink Field that has been heard all the way across Puget Sound.
No one appeared to care about the next thunderstorm, Not with the overall efficiency they were seeing on the field. And not with a ticket to the postseason almost proven thanks to Seattle’s first 10 win season since 2007.
"We knew we were able to perform this. We had obviously. There is Week 1, We knew that him and i had the talent to do what we’re doing now, Said wide recipient Doug Baldwin, Who had two landing receptions. "It invested some time because we’re a young team. We’d to mature. We had to grow as partners, Build that biochemistry and biology, Build that trust out there on the flying field. That’s it is important,
Seattle surged into the playoffs on the potency of its sixth win in seven games, Putting up dizzying offensive numbers that no one thought would continue contrary to the top scoring defense in the NFL but did.
Seattle has outscored its last three foes 150 30. The 42 points were the majority of important allowed since Jim Harbaugh took over the 49ers, And the most sf yielded since giving up 45 to Atlanta in 2009. It was an excellent for Seattle coach Pete Carroll to snap a three game losing streak against his rival.
"We just try to play really good football and see what goes on at the end, Carroll asserted. "We have been scoring and doing a nice job of it and it is good If we can keep it rolling,
Seattle are going to be the No. 5 seed into the NFC. There remains a slight opportunity of winning the NFC West, In case your Seahawks beat St. Louis in the season finale and Arizona can upset the 49ers in frisco.
The particular Seahawks, 7 0 at their home, Delayed silicon valley(10 4 1) From enjoying a division title. They turned Harbaugh’s 49th birthday into an unhappy evening.
"If you had told me this is good the outcome I wouldn’t have believed it, Sherman told me. "I would say you will be making this up,
Wilson hit Lynch on a 9 yard TD in to first quarter, Anthony McCoy for a 6 yarder late in your first half, And Doug Baldwin on 4 and 6 yard TDs in the better half.
Wilson has 25 TD travels, One behind Peyton Manning’s NFL novice record of 26. He terminated 15 of 21 for 171 yards. His only incompletion in the first half was a deflected pass that meat Willis intercepted.
Wilson’s version, San Francisco’s Colin Kaepernick, Had already proven himself capable of winning traveling with victories in New Orleans and last week in New England. But Seattle is unique beast, Widely seen by players as the loudest venue in the NFL. His inexperience playing in such an atmosphere showed. He was upset and disorganized at the line of scrimmage, Letting the noise from get better fans affect him.
Kaepernick’s forgettable night was capped when Sherman stepped in front of his pass intended for Randy Moss in the back of the end zone on the first play of the fourth quarter for his seventh interception of the season.
Kaepernick was 19 of 36 for 244 yards when using 18 yard TD pass to Delanie Walker with 1:40 if available. Frank Gore had just 28 yards on six carries after rushing for a season high 131 if your teams met in Week 7.
"Every time you are well on the field you are learning something, Kaepernick known. "We have to take what we can from this game and move on to next week,
S. f. played without defensive tackle Justin Smith due to an elbow injury that ended a streak of 185 starts. The 49ers lost tight end Vernon Davis in the first quarter with a concussion sustained when he was pushed off his feet on a huge hit along the sideline from Seattle safety Kam Chancellor that looked legal but drew a penalty for hitting a defenseless receiver.
San francisco bay area wide receiver Mario Manningham went down with a left leg injury early in the third quarter when he was tackled low by Leroy Hill and fumbled.
Numerous Smith affected the entire defense. Aldon Smith was left stuck on 19 1 2 sacks after being locked up by Seattle a problem tackle Russell Okung.
"I cannot make excuses, 49ers’ safe keeping Donte Whitner said. "We realise: We lost the soccer game; We lost an ugly soccer game,
Information: Lynch carried out with 111 yards on 26 carries, His third correctly game over 100 yards vs. The actual 49ers.. Seattle was 11 of 13 on third down sales, A season very good.. The 49ers were held to 82 yards speeding, Just the third time this season he occured under 100 yards.