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normal to reduce levels: hypertension Cannabinoids

patriotakk4
23.06.2018

Content:

  • normal to reduce levels: hypertension Cannabinoids
  • Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids
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  • Cannabis Use and Blood Pressure Levels: United States National Health and Nutrition Blood pressure was determined by an average of up to four Additional covariate adjustment did not affect the positive association. Cannabinoids (CBs) are compounds that bind to CB receptors or are . Five of 9 subjects had a lower DBP during the mental stress test, and 6. Does cannabis lower blood pressure? Anecdotally, many people report that cannabis helps them maintain healthy blood pressure levels, an.

    normal to reduce levels: hypertension Cannabinoids

    THC can linger on average up to 10 days for a casual user. It stays in your system for 2 to 4 weeks if you use marijuana often, and more than a month if you use it more often. This test needs a urine sample. You may need to give the sample with a medical staff or technician in the room. This test poses no known risks. But the results may affect your job or legal standing. The nausea medicine dronabinol gives positive test results. Tell your healthcare provider if you've been taking it.

    You may be asked to give proof you have been prescribed this medicine. You don't need to prepare for this test. Be sure your healthcare provider knows about all medicines, herbs, vitamins, and supplements you are taking.

    This includes medicines that don't need a prescription and any illicit drugs you may use. Cannabinoid Screen and Confirmation Urine Does this test have other names? Why do I need this test? What other tests might I have along with this test? What do my test results mean? How is this test done?

    Does this test pose any risks? What might affect my test results? How do I get ready for this test? Lastly, although CBD did not appear to significantly modulate the effects of THC, the authors suggested it might have attenuated the degree of the subjective "high". A dose run-up clinical study looking at the pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of THC i.

    There was also substantial variability for T max both within and between subjects with an overall median of 3. THC dose-dependently elevated heart rate, and systolic blood pressure dropped at the lower dose i. No changes were noted for diastolic blood pressure. Tolerance, as defined by the Liaison Committee on Pain and Addiction a joint committee with representatives from the American Pain Society, the American Academy of Pain Medicine, and the American Society of Addiction Medicine is a state of adaptation in which exposure to the drug causes changes that result in a diminution of one or more of the drug's effects over time Reference Tolerance to the effects of cannabis or cannabinoids appears to result mostly from pharmacodynamic rather than pharmacokinetic mechanisms Reference Pre-clinical studies indicate that pharmacodynamic tolerance is mainly linked to changes in the availability of the cannabinoid receptors, principally the CB 1 receptor, to signal.

    There are two independent but interrelated molecular mechanisms producing these changes: Studies have reported that CB 1 receptors in the caudate-putamen and its projection areas e.

    CB 1 receptors located in the striatum are also less susceptible to desensitization and downregulation relative to the hippocampus Reference One clinical study showed that chronic cannabis use was associated with a global decrease in CB 1 receptor availability in the brain with significant decreases in CB 1 receptor availability in the temporal lobe, anterior and posterior cingulate cortices, and the nucleus accumbens Reference Furthermore, a couple of clinical studies have examined the time course of changes in the availability of CB 1 receptors following chronic THC administration and abstinence Reference Reference In the second study, cannabis dependence with chronic, moderate daily cannabis smoking was associated with CB 1 receptor downregulation i.

    CB 1 receptor downregulation began to reverse rapidly upon termination of cannabis use within two days , and after 28 days of continuous monitored abstinence CB 1 receptor availability was not statistically significantly different from that of healthy controls although CB 1 receptor availability never reached the levels seen with healthy controls.

    CB 1 receptor availability was also negatively correlated with cannabis dependence and withdrawal symptoms. The observed regional variations in cellular adaptations to THC in the brain may also generalize to other tissues or organs, explaining why tolerance develops to some of the effects of cannabis and cannabinoids but not to other effects. In animal models, the magnitude and time-course of tolerance appear to depend on the species, the cannabinoid ligand, the dose and duration of the treatment, and the measures employed to determine tolerance to cannabinoid treatment Reference Tolerance to most of the effects of cannabis and cannabinoids can develop after a few doses, and it also disappears rapidly following cessation of administration Reference Tolerance has been reported to develop to the effects of cannabis on perception, psychoactivity, euphoria, cognitive impairment, anxiety, cortisol increase, mood, intraocular pressure IOP , electroencephalogram EEG , psychomotor performance, and nausea; some have shown tolerance to cardiovascular effects while others have not Reference Reference Reference There is also some evidence to suggest that tolerance can develop to the effects of cannabis on sleep reviewed in Reference As mentioned above, the dynamics of tolerance vary with respect to the effect studied; tolerance to some effects develops more readily and rapidly than to others Reference Reference However, tolerance to some cannabinoid-mediated therapeutic effects i.

    According to one paper, in the clinical setting, tolerance to the effects of cannabis or cannabinoids can potentially be minimized by combining lower doses of cannabis or cannabinoids along with one or more additional therapeutic drugs Reference One study reported that tolerance to some of the effects of cannabis, including tolerance to the "high", developed both when THC was administered orally 30 mg; q.

    There was no diminution of the appetite-stimulating effect from either route of administration. A clinical study that evaluated the effects of smoked cannabis on psychomotor function, working memory, risk-taking, subjective and physiological effects in occasional and frequent cannabis smokers following a controlled smoking regimen reported that when compared to frequent smokers, occasional smokers showed significantly more psychomotor impairment, more significant impairment of spatial working memory, significantly increased risk-taking and impulsivity, significantly higher scores for "high" ratings, for "stimulated" ratings, and more anxiety Reference Compared with frequent smokers, occasional smokers had significantly increased heart rates relative to baseline and higher systolic and diastolic blood pressure just after dosing.

    These findings suggest that frequent cannabis users can develop some tolerance to some psychomotor impairments despite higher blood concentrations of THC. Occasional smokers also reported significantly longer and more intense subjective effects compared with frequent smokers who had higher THC concentrations suggesting tolerance can develop to the subjective effects.

    A clinical study evaluated the development of tolerance to the effects of around-the-clock oral administration of THC 20 mg every 3. The morning THC dose increased intoxication ratings on day 2 but had less effects on days 4 after administration of a cumulative mg dose of THC and 6, while THC lowered blood pressure and increased heart rate over the six-day period suggesting the development of tolerance to the subjective intoxicating effects of THC and the absence of tolerance to its cardiovascular effects.

    Tolerance to the subjective intoxicating effects of THC administered orally was manifested after a total exposure of mg of THC over the course of four days Reference Another clinical study reported that while heavy chronic cannabis smokers demonstrated tolerance to some of the behaviourally-impairing effects of THC, these subjects did not exhibit cross-tolerance to the impairing effects of alcohol, and alcohol potentiated the impairing effects of THC on measures such as divided attention Reference An uncontrolled, open-label extension study of an initial five-week randomized trial of nabiximols in patients with MS and central neuropathic pain reported the absence of pharmacological tolerance measured by a change in the mean daily dosage of nabiximols to cannabinoid-induced analgesia, even after an almost two-year treatment period in a group of select patients Reference Another long-term, open-label extension study of nabiximols in patients with spasticity caused by MS echoed these findings, also reporting the absence of pharmacological tolerance to the anti-spastic effects measured by a change in the mean daily dosage of nabiximols after almost one year of treatment Reference A multi-centre, prospective, cohort, long-term safety study of patients using cannabis as part of their pain management regimen for chronic non-cancer pain reported small and non-significant increases in daily dose over a one-year study period Reference More recently, a double-blind, placebo-controlled, three-way cross-over clinical study with regular cannabis users suggested that tolerance may not develop towards some of the acute effects on neurocognitive functions despite regular cannabis use Reference One hundred and twenty-two subjects who regularly used cannabis average duration of use: Acute administration of vapourized cannabis impaired performance across a wide range of neurocognitive domains: Frequency of cannabis use correlated significantly with change in subjective intoxication following cannabis administration and also correlated and interacted with changes in psychomotor performance meaning that subjective intoxication and psychomotor impairment following cannabis exposure decreased with increasing frequency of use, however the baseline for subjective intoxication and psychomotor impairment was already higher for frequent users compared to less frequent users likely owing to already elevated THC body burden which can cause sufficient levels of intoxication and mild psychomotor impairment.

    The authors suggest that the neurocognitive functions of daily or near daily cannabis users can be substantially impaired from repeated cannabis use, during and beyond the initial phase of intoxication.

    Pharmacokinetic tolerance including changes in absorption, distribution, biotransformation and excretion has also been documented to occur with repeated cannabinoid administration, but apparently occurs to a lesser degree than pharmacodynamic tolerance Reference Dependence can be divided into two independent, but in certain situations interrelated concepts: The ECS has been implicated in the acquisition and maintenance of drug taking behaviour, and in various physiological and behavioural processes associated with psychological dependence or addiction Reference 2.

    In the former DSM-IV diagnostic and statistical manual of mental disorders fourth edition , the term 'dependence' was closely related to the concept of addiction which may or may not include physical dependence, and is characterized by use despite harm, and loss of control over use Reference There is evidence that cannabis dependence physical and psychological occurs, especially with chronic, heavy use Reference Reference Reference In the new DSM-5, the term "cannabis dependence" has been replaced with the concept of a "cannabis use disorder" CUD which can range in intensity from mild to moderate to severe with severity based on the number of symptom criteria endorsed Reference For a list of symptoms, please refer to the DSM-5 Reference Risk factors for transition from use to dependence have been identified and include being young, male, poor, having a low level of educational attainment, urban residence, early substance use onset, use of another psychoactive substance, and co-occurrence of a psychiatric disorder Reference Notably, the transition to cannabis dependence occurs considerably more quickly than the transition to nicotine or alcohol dependence Reference These increases in both month and lifetime prevalence are thought to be driven by increases in the prevalence of cannabis users.

    Higher frequency of cannabis use was associated with greater risk of disorder incidence and prevalence, supporting a dose-response association between cannabis use and risk of substance use disorders. Another study using the U. Survey respondents with month CUD differed significantly from others on all disability components of the survey, with disability increasing significantly, as cannabis disorder severity increased. Comparing data between the NESARC - Wave 1 and - Wave 2 , one study reported that the prevalence of cannabis use more than doubled between the two waves of the survey Reference Furthermore, there was a large increase in CUD during this intervening time, with nearly 3 out of 10 cannabis users reporting a CUD in - A retrospective study among a nationally representative sample of 6 Australian adults examining the initiation of cannabis use and transition to CUD found that the mean time from first use to the onset of CUD was 3.

    Younger age of initiation and other substance use were strong predictors of the transition from use to CUD.

    Social phobia and panic disorder were also associated with transition from cannabis use to CUD. Male cannabis users had greater risk of CUD than female users, but among women, those with depression were more likely to develop a CUD. Early-onset of alcohol and daily cigarette smoking were each associated with marked increased risk of early initiation of cannabis use. A handful of clinical studies have examined the differences between men and women with respect to development of dependence, withdrawal symptoms and relapse Reference Physical dependence is most often manifested in the appearance of withdrawal symptoms when use is abruptly halted or discontinued.

    Withdrawal symptoms associated with cessation of cannabis use oral or smoked appear within the first one to two days following discontinuation; peak effects typically occur between days 2 and 6 and most symptoms resolve within one to two weeks Reference - Reference Other symptoms appear to include depressed mood, chills, stomach pain, shakiness and sweating Reference Reference Reference Reference Cannabis withdrawal symptoms appear to be moderately inheritable with both genetic and environmental factors at play Reference There are also emerging reports of increased physical dependence with highly potent cannabis extracts e.

    There are no approved pharmacotherapies for managing cannabis withdrawal symptoms Reference A range of medications have been explored including antidepressants e.

    Zolpidem has also been explored as a potential pharmacotherapy to specifically target abstinence-induced disruptions in sleep Reference Reference However, agonist substitution therapy e. Self-titrated doses were lower and showed limited efficacy compared to high fixed doses and subjects typically reported significantly lower ratings of "high" and shorter duration of "high" with nabiximols and placebo compared to smoking cannabis.

    A randomized, double-blind, placebo-controlled, six-day, inpatient clinical study of nabiximols as an agonist replacement therapy for cannabis withdrawal symptoms reported that nabiximols treatment attenuated cannabis withdrawal symptoms and improved patient retention in treatment Reference However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use at follow-up.

    Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal symptoms relative to placebo including effects on irritability, depression and craving as well as a more limited effect on sleep disturbance, anxiety, appetite loss, physical symptoms and restlessness. A placebo-controlled, within-subject, clinical study demonstrated that nabilone 6 - 8 mg daily decreased cannabis withdrawal symptoms including abstinence-related irritability and disruptions in sleep and food intake in daily, non-treatment seeking cannabis smokers Reference It also decreased cannabis self-administration during abstinence in a laboratory model of relapse.

    While nabilone did not engender subjective ratings associated with abuse liability i. A follow-up study found that nabilone 3 mg, b. A double-blind, placebo-controlled, week clinical trial testing lofexidine and dronabinol for the treatment of CUD reported no significant beneficial effect compared to placebo for promoting abstinence, reducing withdrawal symptoms, or retaining individuals in treatment Reference in contrast to a previous study that showed efficacy of 40 mg dronabinol daily vs.

    A recent systematic review of the evidence of CBD as an intervention for addictive behaviours reported that to date, only 14 studies have been conducted, the majority in animals with only a handful in humans Reference The limited number of pre-clinical studies carried out to date suggest that CBD may have therapeutic potential for the treatment of opioid, cocaine and psychostimulant addiction, and some preliminary data suggest CBD may also be beneficial in cannabis and tobacco addiction in humans Reference The limited number of pre-clinical studies published thus far suggest CBD may have an impact on the intoxication and relapse phase of opioid addiction, while CBD does not appear to have an impact on the rewarding effects of stimulants e.

    With respect to cannabis dependence, pre-clinical studies show that CBD is not reinforcing on its own, but its impact on cannabis-related dependence behaviour remains unclear Reference In one clinical study, a 19 year-old female with cannabis dependence exhibiting cannabis withdrawal symptoms upon cannabis cessation was administered up to mg of CBD range: In another human study, cannabis with a higher CBD to THC ratio was associated with lower ratings of pleasantness for drug stimuli explicit "liking" , but no group difference in "craving" or "stoned" ratings was noted Reference Reference However, a multi-site, double-blind, placebo-controlled study demonstrated that CBD - mg had no effect on subjective ratings associated with cannabis abuse liability Reference A randomized, double-blind, crossover clinical study in 10 healthy volunteers examining the effects of CBD on the intoxication phase of alcohol addiction reported no differences in feelings of "drunk", "drugged", or "bad" between the alcohol only and the alcohol and CBD groups Reference Reference No pre-clinical studies exist on the use of CBD for hallucinogen-, sedative-, tobacco-, or alcohol-addictive behaviours and no human studies exist on the use of CBD for opioid-, psychostimulant-, hallucinogen-, or sedative-addictive behaviours Reference The ECS is present in early development, is critical for neurodevelopment and maintains expression in the brain throughout life Reference Furthermore, the ECS undergoes dynamic changes during adolescence with significant fluctuations in both the levels and locations of the CB 1 receptor in the brain as well as changes in the levels of the endocannabinoids 2-AG and anandamide Reference The dynamic changes occurring in the ECS during adolescence also overlap with a significant period of neuronal plasticity that includes neuronal proliferation, rewiring and synaptogenesis, and dendritic pruning and myelination that occurs at the same time Reference This period of significant neuroplasticity does not appear to be complete until at least the age of 25 Reference Thus, this neurodevelopmental time window is critical for ensuring proper neurobehavioural and cognitive development and is also influenced by external stimuli, both positive and negative e.

    Based on the available scientific evidence, youths are more susceptible to the adverse effects associated with cannabis use, especially chronic use Reference Reference Studies examining non-medical use of cannabis strongly suggest early onset i. Based on the current available evidence, it is unclear for how long some or all of the neurocognitive effects persist following cessation of use. Some investigators have found certain cognitive deficits to persist for up to one year or longer after cannabis cessation, while others have demonstrated a far shorter period of recovery i.

    Though the data from human studies do not establish causality solely from cannabis use, the pre-clinical studies in animals do indicate that adolescent exposure to cannabinoids can catalyze molecular processes leading to functional deficits in adulthood - deficits that are not found following adult exposure to cannabis. The authors note that definitive conclusions cannot be made yet as to whether cannabis use - on its own - negatively impacts the adolescent brain, and future research can help elucidate this relationship by integrating assessments of molecular, structural, and behavioral outcomes Reference Factors that may influence persistence of cognitive deficits can include age at onset of use, frequency and duration of use, co-morbidities, and use of other drugs tobacco, alcohol, and other psychoactive drugs.

    While adverse effects associated with THC-predominant cannabis use in youth have been well documented, far less is known about the adverse effects associated with CBD-predominant cannabis use. Nevertheless, as mentioned above, the ECS plays important roles in nervous system development in utero as well as during youth see Section 7.

    There is evidence to suggest that like the changes seen with the ECS during development and adolescence, there are changes in the ECS associated with ageing. In addition, the coupling of CB 1 receptors to G proteins is also reduced in specific brain areas in older animals Reference Age-related changes in the expression of components of the ECS appear similar in rodents and humans Reference Disruption of CB receptors appears to enhance age-related decline of a number of tissues suggesting an important role for the ECS in the control of the ageing process Reference In general, the elderly may be more sensitive to the effects of drugs acting on the CNS Reference A number of physiological factors may lie at the root of this increased sensitivity such as: There is very little information available on the effects of cannabis and cannabinoids in geriatric populations and based on current levels of evidence, no firm conclusions can be made with regard to the safety or efficacy of cannabinoid-based drugs in elderly patients but see below for one of the few clinical studies of safety carried out specifically in geriatric populations Reference Reference Reference Furthermore, as cannabinoids are lipophilic, they may tend to accumulate to a greater extent in elderly individuals since such individuals are more likely to have an increase in adipose tissue, a decrease in lean body mass and total body water, and an increase in the volume of distribution of lipophilic drugs Reference Lastly, age-related changes in hepatic function such as a decrease in hepatic blood flow and slower hepatic metabolism can slow the elimination of lipophilic drugs and increase the likelihood of adverse effects Reference A randomized, double-blind, placebo-controlled, cross-over clinical trial that evaluated the pharmacokinetics of THC in 10 older patients with dementia mean age 77 years over a week period reported that the median time to reach maximal concentration in the blood T max was between 1 and 2 h with THC pharmacokinetics increasing linearly with increasing dose but with wide inter-individual variation Reference Only one clinical study has thus far been carried out looking specifically at the safety of THC in an elderly population.

    In this study, 12 adults aged 65 and older who were deemed to be healthy were included, and exclusion criteria included high falls risk, regular cannabis use, history of sensitivity to cannabis, drug and alcohol abuse, compromised cardiopulmonary function, and psychiatric comorbidities.

    The most commonly reported health problems were hypertension and hypercholesterolemia and subjects reported using an average of 2 medications e. Adverse events first occurred within 20 min of dosing, with all adverse events occurring between 55 and min after dosing and resolving completely within 3. No moderate or serious adverse events were reported in this trial. While this clinical study adds important information regarding the safety and tolerability of THC in a healthy elderly population, additional studies are needed to evaluate the safety and tolerability of cannabis and cannabinoids in elderly populations having various co-morbidities.

    In humans, sex-dependent differences have been often observed in the biological and behavioural effects of substances of abuse, including cannabis Reference In male animals, higher densities of CB 1 receptors have been observed in almost all cerebral regions analyzed whereas in females a more efficient coupling of the CB 1 receptor to downstream G-protein signaling has been observed Reference In humans, sex differences in CB 1 receptor density have also been reported, with men having higher receptor density compared to women Reference Sex-dependent differences have also been noted with respect to cannabinoid metabolism.

    Pre-clinical studies in females report increased metabolism of THC to hydroxy-THC compared to males where THC was also biotransformed to at least three different, less active metabolites Reference There is also evidence to suggest that effects of cannabinoids vary as a function of fluctuations in reproductive hormones Reference Reference Together, these findings suggest that the neurobiological mechanism underlying the sex-dependent effects of cannabinoids may arise from sexual dimorphism in the ECS and THC metabolism, but also from the effects of fluctuations in hormone levels on the ECS Reference Reference There is also evidence to suggest sex-dependent differences in subjective effects and development of dependence, withdrawal symptoms, relapse and incidence of mood disorders.

    Data combined from four double-blind, within-subject studies measuring the effects of smoked "active" cannabis 3. These findings suggest that, at least among near-daily cannabis users, women may be more sensitive to the subjective effects of cannabis, especially effects related to cannabis abuse liability compared to men.

    Another study demonstrated dose-dependent sex differences in subjective responses to orally administered THC Reference In this study, women showed greater subjective effects at the lowest dose 5 mg , whereas men showed greater subjective responses at the highest 15 mg dose.

    Together, these studies suggest that while women may be more sensitive to the subjective effects of THC at lower doses, they may develop tolerance to these effects at higher doses, which could, for example, have implications for the development of dependence.

    For example, while cannabis use among men is more prevalent and men appear to be more likely than women to become dependent on cannabis, women tend to have shorter intervals between the onset of use and regular use or development of dependence commonly referred to as the "telescoping effect" Reference In addition, women abstaining from cannabis use reported more withdrawal symptoms, with some being more severe, than those seen in men and which have been linked to relapse Reference Reference Women with CUD also present with higher rates of certain comorbid health problems such as mood and anxiety disorders Reference Reference Reference The College of Family Physicians of Canada, along with other provincial medical regulatory colleges, has issued a guidance document in for authorizing the use of cannabis for medical purposes.

    Please consult these and any other official guidance documents, as applicable, for additional information regarding dosing and other matters associated with authorizing cannabis for medical purposes. Cannabis has many variables that do not fit well with the typical medical model for drug prescribing Reference While precise dosages have not been established, some "rough" dosing guidelines for smoked or vapourized cannabis have been published see below. Besides smoking and vapourization, cannabis is known to be consumed in baked goods such as cookies or brownies, or drunk as teas or infusions.

    However, absorption of these products by the oral route is slow and erratic, varies with the ingested matrix e. Other forms of preparation reported in the lay literature include cannabis-based butters, candies, edibles, oils, compresses, creams, ointments, and tinctures Reference 80 Reference - Reference but again, limited dosing information exists here with much of the information being anecdotal in nature. Dosing remains highly individualized and relies largely on titration Reference Patients with no prior experience with cannabis and initiating cannabis therapy for the first time are cautioned to begin at the very lowest dose and to stop therapy if unacceptable or undesirable side effects occur.

    Subsequent dose escalation should be done slowly, once experience with the subjective effects is fully appreciated, to effect or tolerability. If intolerable adverse effects appear without significant benefit, dosing should be tapered and stopped. Tapering guidelines have not been published, but the existence of a withdrawal syndrome see Section 2. Clinical studies of cannabis and cannabis-based products for therapeutic purposes are limited to studies carried out with dried cannabis that was smoked or vapourized and with synthetic or natural cannabis-based products that have received market authorization i.

    As such, providing precise dosing guidelines for such products is not possible although existing sources of information can be used as a reference point see below. Naturally, dosing will vary according to the underlying disorder and the many other variables mentioned above. Average daily dose of dronabinol is 20 mg and maximal recommended daily dose is 40 mg Reference Doses less than 1 mg of THC per dosing session may further avoid incidence and risks of adverse effects.

    Various surveys published in the peer-reviewed literature have suggested that the majority of people using smoked or orally ingested cannabis for medical purposes reported using between 10 and 20 g of cannabis per week or approximately 1 to 3 g of cannabis per day Reference Reference Reference An international, web-based, cross-sectional survey examining patients' experiences with different methods of cannabis intake reported that from among a group of self-selected participants, from 31 countries, the vast majority preferred inhalation over other means of administration e.

    Mean daily doses with smoked or vapourized cannabis were 3. Information regarding cannabinoid potencies of cannabis products i. Daily frequency of use for smoking was six times per day, whereas with vapourizing it was five times per day. First onset of effects for smoking were noted on average around 7 min after start of smoking, 6.

    Other data suggests that those patients who use cannabis for medical purposes use up to one gram or less per day. For example, data from the Netherlands suggests the average daily dose of dried cannabis for medical purposes stood at 0. Canadian market data collected from licensed producers under the Access to Cannabis for Medical Purposes Regulations ACMPRs showed that, from April to March , clients had been authorized by their healthcare practitioners to use, monthly, an average of 2.

    However, since this data is collected per licensed producer, it does not include cases where clients split their authorization into two or more authorizations in order to register with more than one licensed producer at a time or personal production registrations with Health Canada Reference To fulfill orders for oils, licensed producers equate oil to dried cannabis based on the formulation of their oil products.

    On average, licensed producers equate 1 g of dried cannabis to 6. Using this average conversion factor, healthcare practitioners have authorized an equivalent average of Satisfaction ratings for criteria such as onset of effects and ease of dose finding were reported to be higher for smoking and vapourizing i.

    However, prescription cannabinoid medications e. Satisfaction ratings in terms of side-effects were higher for non-prescription unregulated cannabis products, with the inhaled route rated best, although the survey did not ask specific questions about the types of side effects.

    Satisfaction ratings were only slightly higher for orally ingested cannabis products for criteria such as duration of effects. The majority of survey participants had indicated having used cannabis products prior to onset of their medical condition.

    A prospective, open-label, longitudinal study of patients with treatment resistant chronic pain reported that patients titrate their cannabis dose starting with one puff or one drop of cannabis oil per day, increasing in increments of one puff or one drop of oil per dose, three times per day until satisfactory pain relief was achieved or side effects appeared Reference Mean monthly prescribed amount of cannabis was 43 g or 1.

    Data from randomized, double-blind, placebo-controlled clinical studies of smoked or vapourized cannabis used a daily dose of up to 3. In contrast to the gram amounts of cannabis used with smoked, vapourized, and oral routes of administration, the mean daily amounts for prescription cannabinoids such as dronabinol were 30 mg, for nabilone 4.

    With respect to the relationship between dosing and psychotropic effects , it has been estimated that an inhaled dose of 0. Furthermore, it has been estimated that between one and three puffs of higher potency cannabis would be sufficient to produce significant psychoactive effects Reference One study has shown that while cannabis smokers titrate their dose of THC by inhaling lower volumes of smoke when smoking "strong" joints i.

    For oral administration, a dose of 0. Other provincial bodies may also provide guidelines on monitoring Reference The College of Family Physicians of Canada has recently published a simplified guideline for prescribing medical cannabinoids in primary care Reference The recommendations are as follows:. The majority of clinical trials with smoked cannabis for medical purposes have used joints of dried cannabis weighing between and mg.

    Estimates that are more recent suggest the mean weight of cannabis in a joint is mg Reference In addition, expectation of drug reward can also influence smoking dynamics Reference Little reliable information exists regarding conversion of a "smoked dose" of THC to an equivalent oral dose. It is also important to emphasize that this "conversion factor" appears to relate mostly to psychoactive effects e.

    Further rigorous comparative pharmacology studies are required. In addition, no comparative studies have been done with vaping. In addition, this theoretical conversion factor may or may not apply for therapeutic effects. Indeed, it is important to highlight that two studies reported that individuals using cannabis for therapeutic purposes indicated they used approximately similar gram amounts of cannabis regardless of route of administration Reference Reference A single-dose, open-label, clinical trial of patients with neuropathic pain and using very low doses of inhaled THC reported a statistically significant improvement in neuropathic pain with minimal adverse effects Reference THC administration was associated with a statistically significant reduction in baseline VAS for pain intensity of 3.

    These above-mentioned studies suggest that, at least in the case of chronic neuropathic pain, psychoactive effects can be separated from therapeutic effects and that very low doses of THC may actually be sufficient to produce analgesia while keeping psychoactive effects to a minimum.

    A review of U. Product has been discontinued by the manufacturer post-market; as of February ; not for safety reasons. Newfoundland and Labrador; NS: Prince Edward Island; QC: The pharmacokinetic information described in Section 2. Tea prepared from Cannabis flowering tops and leaves has been documented, but no data are available regarding efficacy Reference On the other hand, to reduce or prevent CINV, a dosage of 5 mg t. In either case, the dose should be carefully titrated to avoid the manifestation of adverse effects.

    The second dose is usually administered 1 to 3 h before chemotherapy. If required, the administration of nabilone can be continued up to 24 h after the chemotherapeutic agent is given. The maximum recommended daily dose is 6 mg in divided doses. Dose adjustment titration may be required in order to attain the desired response, or to improve tolerability. More recent clinical trials report starting doses of nabilone of 0. Data from an open-label longitudinal study of cannabis oil for patients with treatment-resistant chronic non-cancer pain reported that patients titrated their cannabis oil dose starting with one drop of cannabis oil per day, increasing in increments of one drop of oil per dose, three times per day, until satisfactory analgesia was achieved or until side effects appeared Reference Maximum daily dose was 5 mg b.

    On subsequent days, the number of sprays can be increased by one spray per day, as needed and tolerated. A fifteen-minute time gap should be allowed between sprays. During the initial titration, sprays should be evenly spread out over the day. If at any time unacceptable adverse reactions such as dizziness or other CNS-type reactions develop, dosing should be suspended or reduced or the dosing schedule changed to increase the time intervals between doses.

    According to the drug product monograph, the average dose of nabiximols is five sprays per day i. The majority of patients appear to require 12 sprays or less; dosage should be adjusted as needed and tolerated. Administration of four sprays to healthy volunteers total The Dutch Office of Medicinal Cannabis has published "rough" guidelines on the use of vapourizers Reference Although the amount of cannabis used per day needs to be determined on an individual basis, the initial dosage should be low and may be increased slowly as symptoms indicate.

    The amount of cannabis to be placed in the vapourizer may vary depending on the type of vapourizer used. The levels of cannabinoids released into the vapour phase increased with the temperature of vapourization Reference Participants inhaled as much of the mg dose of dried cannabis 3.

    In another study, patients followed a similar "cued-puff" procedure and inhaled 4 puffs, followed by an additional round of between 4 and 8 puffs 2 h later for a total of between 8 and 12 puffs over a 2 h period Reference Subjects inhaled 4 puffs at the beginning of the testing session, followed by an additional round of between 4 and 8 puffs 3 h later for a total of between 8 and 12 puffs over a 3 h period.

    While there are countless anecdotal reports concerning the therapeutic uses of cannabis, clinical studies supporting the safety and efficacy of cannabis for therapeutic purposes in a variety of disorders are limited, but slowly increasing in number. Furthermore, the current level of evidence for the safety and efficacy of cannabis for medical purposes does not meet the requirements of the Food and Drugs Act and its Regulations except for those products that have received a notice of compliance and market authorization from Health Canada.

    It has been repeatedly noted that the psychotropic side effects associated with the use of psychoactive cannabinoids have been found to limit their therapeutic utility Reference 23 Reference 55 Reference 57 Reference Reference A comprehensive review of 72 controlled clinical studies evaluating the therapeutic effects of cannabinoids mainly orally administered THC, nabilone, nabiximols, or an oral extract of cannabis up to the year reported that cannabinoids present an interesting therapeutic potential as anti-emetics, appetite stimulants in debilitating diseases cancer and AIDS , analgesics, and in the treatment of MS, SCIs, Tourette's syndrome TS , epilepsy, and glaucoma Reference However, a more recent systematic review and meta-analysis of randomized clinical trials of cannabinoids i.

    Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete improvement in nausea and vomiting, reduction in pain, a greater average reduction in numerical rating scale pain assessment, and average reduction in the Ashworth spasticity scale Reference There was also an increased risk of short-term adverse events with cannabinoids.

    Commonly reported adverse events included dizziness, dry mouth, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance and hallucinations Reference Overall, the review and meta-analysis conducted using the Grading of Recommendations, Assessment, Development and Evaluation GRADE approach suggested that there was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic neuropathic or cancer pain as well as MS-associated spasticity, but low-quality evidence to support use for CINV, weight gain in HIV infection, sleep disorders, and TS Reference The review and meta-analysis only included only one study with smoked cannabis and all other included clinical studies were with oral or oro-mucosal administration of cannabinoid-based medicines e.

    This comprehensive report includes information on the therapeutic effects of cannabis and the cannabinoids but also other health effects such as cancer, cardiometabolic risks, respiratory disease, immunity, injury and death, prenatal, perinatal and neonatal effects, psychosocial and mental health effects.

    It also discusses challenges and barriers in conducting cannabis research as well as recommendations to support and improve cannabis research.

    Much of the evidence included in the report came from systematic reviews and meta-analyses and selected high quality primary research. Evidence gathered from in vitro or in vivo animal studies was not included. It was available for sale in Canada in capsules containing 2.

    The drug is no longer sold in Canada post-market discontinuation of the drug product as of February ; not for safety reasons. It is available as capsules 0.

    It is also marketed with conditions as an adjunctive treatment for the symptomatic relief of neuropathic pain in adults with MS and with conditions as an adjunctive analgesic in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain Reference The existing scientific and clinical evidence for cannabis and certain cannabinoids in treating various symptoms associated with various medical conditions is summarized in the following sections beginning on the next page.

    Among the goals of palliative care described by the WHO are relief from pain and other distressing symptoms, and the enhancement of quality of life QoL Reference While integration of cannabis into mainstream medical use can be characterized as extremely cautious, its use appears to be gaining some ground in palliative care settings where the focus is on individual choice, patient autonomy, empowerment, comfort and especially QoL Reference Nevertheless, establishing the effectiveness of cannabis as a viable treatment option in a palliative care context requires a careful assessment of its effects in a wide range of conditions; such evidence is not yet abundant and further research is needed Reference Certain patient populations e.

    A prospective, non-randomized, and unblinded observational case-series study assessing the effectiveness of adjuvant nabilone therapy in managing pain and symptoms experienced by advanced cancer patients in a palliative care setting reported that those patients using nabilone had a lower rate of starting NSAIDs, tricyclic anti-depressants, gabapentin, dexamethasone, metoclopramide, and ondansetron and a greater tendency to discontinue these drugs Reference Treated patients were started on 0.

    At follow-up, the majority of patients were on a 2 mg daily nabilone dose with a mean daily dose of 1. The two primary outcomes of the study, pain and opioid use in the form of total morphine sulfate equivalents were reduced significantly in treated patients compared to untreated patients.

    Side effects from nabilone consisted mainly of dizziness, confusion, drowsiness, and dry mouth. Patients also demonstrated less tendency to initiate additional new medications and could reduce or discontinue baseline medications. One observational study that examined over self-reported cannabis-using patients in a cancer palliative care setting reported significant improvement in a variety of cancer and anti-cancer treatment-related symptoms including nausea, vomiting, mood disorders, fatigue, weight loss, anorexia, constipation, sexual function, sleep disorders, itching, and pain Reference The reported decrease in memory among a proportion of the study sample could be a function of cannabis use along with the use of other medications such as opioids, anti-depressants, or even vary with age.

    Improvements in symptom and distress scores were also noted. Limitations of the study included its observational nature, the lack of an appropriate control group, and the reliance on self-report.

    Another observational study looking at the patterns of cannabis use among adult Israeli advanced cancer patients reported that of approximately 17, cancer patients monitored at a single Israeli healthcare institution, patients were authorized to use cannabis for medical purposes; among these, the median age of patients was 60 years range: In most patients, cannabis was requested for multiple indications. Eighty-three percent of patients rated the overall efficacy of cannabis as being high.

    A handful of clinical studies have used standardized QoL instruments to measure whether the use of cannabis or prescription cannabinoids e. The evidence from these studies is summarized below.

    A two-centre, phase II, randomized, double-blind, placebo-controlled day pilot study carried out in adult patients suffering from chemosensory alterations i. Statistically significant improvements were also noted for quality of sleep and relaxation with dronabinol treatment compared to placebo. According to the study authors, negative psychoactive effects were minimized by starting patients at a low dose 2. A multi-centre, phase III, randomized, double-blind, placebo-controlled, three-arm, parallel study in adult patients with advanced incurable cancer and suffering from cancer-related anorexia-cachexia syndrome concluded that neither cannabis extract 2.

    A randomized, double-blind, placebo-controlled trial of nabilone in patients suffering from fibromyalgia reported that adjuvant nabilone therapy four weeks; maximum dose in the final week of treatment: An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel-assignment efficacy study of nabilone as an adjuvant in the treatment of long-standing diabetic peripheral neuropathic pain reported statistically significant improvements in measures of QoL Composite EuroQoL five dimensions questionnaire, EQ-5D, Index Score and overall patient status compared to placebo Reference A seven-week, randomized, placebo-controlled study comparing the effects of nabilone to placebo on QoL and side effects during radiotherapy for head and neck carcinomas reported that at the dosage used 0.

    There was also no statistically significant difference in the occurrence of adverse effects between the nabilone and placebo groups. A twelve-week, double-blind, randomized, placebo-controlled, parallel-group, enriched enrolment study of nabiximols as add-on therapy for patients with refractory spasticity concluded that there was no significant difference between active treatment and placebo on measures of QoL EQ-5D Health State Index, EQ-5D Health Status VAS, SF Reference A five-week, multi-centre, randomized, double-blind, placebo-controlled, parallel-group, graded-dose study evaluated the analgesic efficacy and safety of nabiximols in three dose ranges in opioid-treated cancer patients with poorly-controlled chronic pain Reference The study reported the lack of any positive treatment effects on overall QoL in this study population even at the highest doses of nabiximols 11 - 16 sprays per day.

    A randomized, double-blind, placebo-controlled, four-period, cross-over trial of smoked cannabis in the treatment of chronic neuropathic pain chronic post-traumatic or post-surgical etiology concluded that inhalation of smoked cannabis 25 mg of cannabis containing 2. In contrast, a cross-sectional survey examining the benefits associated with cannabis use in patients with fibromyalgia reported a statistically significant benefit in the mental health component summary score of the SF QoL questionnaire in patients who used cannabis compared to non-users Reference However, no significant differences between cannabis and non-cannabis users were found in the other SF domains, in the Fibromyalgia Impact Questionnaire, or the Pittsburgh Sleep Quality Index.

    A preliminary observational, open-label, prospective, single-arm trial in a group of 13 patients suffering from Crohn's disease or ulcerative colitis reported that treatment with inhaled cannabis over a three-month period improved subjects' QoL, caused a statistically significant increase in subjects' weight, and improved the clinical disease activity index in patients with Crohn's disease Reference Patients reported a statistically significant improvement in their perception of their general health status, their ability to perform daily activities, and their ability to maintain a social life.

    Patients also reported a statistically significant reduction in physical pain as well as improvement in mental distress. The authors attributed the null findings to the heterogeneity of study characteristics, and the limitation in which HRQoL were secondary and not primary outcomes in most studies. However, the studies showing a positive relationship between cannabinoids and HRQoL were more likely to be from pain-related symptoms neuropathic pain, multiple sclerosis, headaches, inflammatory bowel disease , while negative relationships were observed mostly in HIV patients who reported significant reductions in physical and mental HRQoL Reference CINV is one of the most distressing and common adverse events associated with cancer treatment Reference Once a patient experiences nausea, it tends to persist throughout treatment and make subsequent episodes of nausea more severe Reference Post-treatment nausea is also associated with impaired patient functioning, increased anxiety, depression, and reduced QoL which can all negatively impact treatment adherence or even cause discontinuation of treatment entirely Reference While nausea typically occurs before vomiting, the two have distinct neural circuitries and can be separated behaviourally Reference Furthermore, while the central mechanisms of vomiting are well-known, those responsible for nausea remain less well understood Reference Nevertheless, scientific studies point to the insular cortex as the seat of sensations such as nausea and disgust, with other central regions e.

    Non-specific anti-anxiety treatments e. It is important to note that excessive use of cannabis has been reported to paradoxically trigger a chronic cyclic vomiting syndrome i. Patient claims that smoked cannabis relieves CINV are widely recognized, and increasing evidence suggests a role for the ECS in the regulation of nausea and vomiting Reference Reference Reference Reference - Reference CB 1 and CB 2 receptors have been found in areas of the brainstem associated with emetogenic control Reference Reference , and results from animal studies suggest the anti-nausea and anti-emetic properties of certain cannabinoids e.

    Levels of 2-AG are increased in the visceral insular cortex during an acute episode of nausea in rats and localized blockade of 2-AG through targeted MAGL inhibition in the insular cortex reduces acute nausea Reference Similarly, infusion of 2-AG into the insular cortex dose-dependently blocks anticipatory nausea, while infusion of anandamide was without effect Reference These findings suggest that 2-AG, but not anandamide, drives acute and anticipatory nausea.

    Elsewhere, elevation of endocannabinoids such as anandamide and 2-AG by inhibition of the endocannabinoid degradative enzymes FAAH and MAGL, has been shown to suppress acute and anticipatory nausea in animal models Reference Reference and localized infusion of a peripherally-restricted CB 1 receptor agonist into the visceral insular cortex suppressed nausea-like behaviour in rats, whereas systemic administration had no effect Reference Additional work has revealed novel and important roles for cannabinoid acids i.

    In one study, when administered alone, a very low dose 0. In addition, the effective dose of CBDA that attenuated acute nausea was approximately 1 times lower than the effective dose for CBD Reference THCA at doses of 0.

    In this study, CBDA 0. Treatment with CBDA was not associated with any effects on locomotor activity at any tested dose whereas chlordiazepoxide significantly reduced locomotor activity. Co-administration of subthreshold doses of CBDA 0. Further research is needed to resolve the conflicting evidence around the mechanism of action, if any, of THCA at the CB 1 receptor.

    Additional animal studies have shown that administration of subthreshold doses of THC 0. In contrast to the effect seen for acute nausea, combined subthreshold doses of THC and CBDA did not suppress anticipatory nausea in animals Reference Higher doses of either THC 1.

    The study showed that 2. Singular administration of either 2. CBDA was not associated with any suppression of acute nausea and vomiting.

    Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids

    The scientific debate has been going on for years whether marijuana has an effect on the cardiovascular system. Marijuana CBD and blood. Cannabis may raise bp in the short-term and lower bp in the long-term. Heart rate will come back to normal in the minutes after the stimulus; however, lower blood pressure, smoking the plant with the full range of cannabinoids will have. Repeated use has actually been linked to lower blood pressure and heart rate suggests that marijuana helps users maintain healthy blood pressure levels.

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