not but ex of vivo. and CBD vitro proliferation, viability, the decreases both human sebocytes in

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03.06.2018

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  • not but ex of vivo. and CBD vitro proliferation, viability, the decreases both human sebocytes in
  • Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes
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  • CBD decreases proliferation, but not the viability, of human sebocytes both in vitro and ex vivo. Besides the above lipostatic action, another. Administration of CBD to cultured human sebocytes and human skin organ culture CBD exerts sebostatic effects in vitro and under “in vivo–like” circumstances. . CBD normalizes “pro-acne agent”–induced excessive lipid synthesis . trations of CBD did not decrease cellular viability or induce either. Our study shows that CBD induces a substantial in vivo cardioprotective effect from ischemia that is not observed ex vivo. Stroke/TBI Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes The results predominantly confirm the hypothesis of an antipsychotic activity of both cannabinoids.

    not but ex of vivo. and CBD vitro proliferation, viability, the decreases both human sebocytes in

    Bioequivalence of vapourization compared to smoking has not been thoroughly established. Inhalation of vapourized cannabis mg of 3. No statistically significant changes were reported for the AUC 12 hour area-under-the-curve for either morphine or oxycodone, but there appeared to be a statistically significant decrease in the C max of morphine sulfate, and a delay in the time needed to reach C max for morphine during cannabis exposure Reference One clinical study reported that vapourizing mg cannabis containing low-dose 2.

    Median whole-blood C max values for hydroxy-THC were 2. A different clinical study showed that inhalation of 8 to 12 puffs of vapourized cannabis containing either 2. Plasma C max of hydroxy-THC was 5. Whereas the acute effects on the CNS and physiological effects occur within minutes by the smoking route or by vapourization Reference Reference , the acute effects proceed on a time scale of hours in the case of oral ingestion Reference Reference Acute oral administration results in a slower onset of action, lower peak blood levels of cannabinoids, and a longer duration of pharmacodynamic effects compared to smoking Reference The psychotropic effect or "high" occurs much more quickly by the smoking than by the oral route, which is the reason why smoking appears to be the preferred route of administration by many, especially among non-medical users Reference Administration of a single 2.

    Twice daily dosing of dronabinol individual doses of 2. A phase I study evaluating the pharmacokinetics of three oral doses of THC 3 mg, 5 mg and 6. For those subjects who reached C max within 2 hours, the mean THC concentration was 1.

    A randomized, double-blind, placebo-controlled, cross-over trial that evaluated the pharmacokinetics of oral THC in 10 older patients with dementia mean age 77 years over a week period reported that median time to reach C max T max was between one and two hours with THC pharmacokinetics increasing linearly with increasing dose, but again with wide inter-individual variation Reference The mean C max after the first 0.

    After the second dose of 0. Consumption of cannabis-laced brownies containing 2. Peak effects occurred 2. Modest changes in pulse and blood pressure were also noted. Tea made from dried cannabis flowering tops After oral administration of chocolate cookies containing 40 mg CBD in healthy human subjects, mean plasma CBD levels ranged between 1.

    Oral intake of 5. While cannabinoids are lipophilic and anecdotal evidence suggests that cannabinoids dissolve better in fats and oils, the influence of various fats on cannabinoid absorption in vivo has been poorly studied.

    The absolute bioavailability of THC was 2. Furthermore, an in vitro lipolysis model was used to assess the mechanism by which lipids could enhance the bioavailability of THC and CBD. Chylomicrons act as carriers in the intestine and potentially transfer THC and CBD to the systemic circulation via the intestinal lymphatic system and therefore avoid hepatic first-pass metabolism, which would explain the increased bioavailability with the lipid-based formulation.

    The authors concluded that administration of cannabinoids with a fatty meal or in the form of a lipid-rich cannabis-containing cookie may increase systemic exposure and therefore change the efficacy of the drug by turning a barely effective dose into a highly effective one, or even, a therapeutic dose into a toxic one.

    In mice, it was shown that hexahydrocannabinols could, as is typically observed with THC, produce cataleptogenic effects Reference The clinical implications of this conversion of CBD to THC and hexahydrocannabinols are the subject of heated debate and currently unclear. A randomized, double-blind, placebo-controlled, double-dummy, cross-over clinical study examined the pharmacokinetics of THC and its phase I and II metabolites between frequent and occasional cannabis smokers after smoked, vapourized and oral cannabis administration Reference Cannabis plant material mg containing 6.

    Cannabis was administered orally by ingestion of cannabis-containing brownies. Mean T max was 7 min smoking , 5 min vapourization , and 2. Mean T max was 7 min smoking , 7 min vapourization , and 2. Mean T max was 13 min smoking , 11 min vapourization , and 2. Mean T max was 13 min smoking , 6 min vapourization , and 2. These findings suggest, among other things, that peak blood THC concentration THC C max was significantly lower after oral consumption compared to either route of inhalation and time to peak blood THC concentration T max occurred significantly later for oral consumption compared to inhalation for both frequent and occasional cannabis smokers.

    In addition, C max was significantly higher for the smoking route compared to vapourization, but only among frequent cannabis smokers. In addition, THC C max values were significantly greater among frequent smokers compared to occasional smokers after smoking and vapourization only, and hydroxy-THC C max values were significantly greater among frequent smokers regardless of route of administration.

    Oro-mucosal administration of nabiximols is also amenable to self-titration Reference Reference Reference Reference In humans, rectal doses of 2. Cannabinoids are highly hydrophobic, making transport across the aqueous layer of the skin the rate-limiting step in the diffusion process Reference No clinical studies have been published regarding the percutaneous absorption of cannabis-containing ointments, creams, or lotions. However, some pre-clinical research has been carried out on transdermal delivery of synthetic and natural cannabinoids using a dermal patch Reference Reference Due to its lipophilicity, it is taken up primarily by fatty tissues and highly perfused organs such as the brain, heart, lung, and liver Reference The apparent average volume of distribution of CBD is Pre-clinical studies in mice suggest a more rapid penetration of hydroxy-THC into the brain compared to the parent compound, on the order of 6: This finding lends further support to the evidence on the distribution, accumulation, and storage of THC and metabolites in the adipose tissue and the slow release of THC and metabolites from adipose tissue stores back into the bloodstream Reference Residual THC in plasma likely coming from bodily adipose stores detected weeks after last smoking episode may be associated with persisting psychomotor impairment in frequent chronic cannabis smokers according to the study authors Reference Most cannabinoid metabolism occurs in the liver, and different metabolites predominate depending on the route of administration Reference 78 Reference CBD undergoes extensive Phase I metabolism, with a reported 30 different metabolites in the urine, and the most abundant metabolites are hydroxylated 7 or 11 -carboxy derivatives of CBD, with 7 or 11 -hydroxy CBD as a minor metabolite Reference 78 Reference Reference Xenobiotics are not only metabolized by CYPs but they also modulate the expression level and activity of these enzymes; CYPs are therefore a focal point in drug-drug interactions and adverse drug reactions Reference Please see Section 6.

    While few clinical studies have specifically sought to evaluate cannabis-drug interactions per se, many, if not most, studies investigating the therapeutic effects of cannabis e.

    Cannabis smoking, as well as orally administered dronabinol may also affect the pharmacokinetics of anti-retroviral medications, although no clinically significant short-term impacts on anti-retroviral effects were noted Reference In addition, and as seen with tobacco smoke, cannabis smoke has the potential to induce CYP1A2 thereby increasing the metabolism of xenobiotics biotransformed by this isozyme such as theophylline Reference or the anti-psychotic medications clozapine or olanzapine Reference Further detailed information on drug-drug interactions can be found in Section 6.

    Similar results were obtained with intravenous THC administration Reference Following oxidation, the phase II metabolites of the free drug or hydroxylated-THC appear to be glucuronide conjugates Reference Peak plasma values of the psycho-inactive metabolite, norcarboxy THC, occur 1. The plasma levels of active hydroxy metabolite, achieved through oral administration, are about three times higher than those seen with smoking Reference Concentrations of both parent drug and metabolite peak between approximately 2 to 4 h after oral dosing, and decline over several days Reference A study that characterized cannabinoid elimination in blood from 30 male daily cannabis smokers during monitored sustained abstinence for up to 33 days on a closed residential unit found that low levels approx.

    Following oral administration, THC and its metabolites are also excreted in both the feces and the urine Reference 78 Reference A large portion of administered CBD is excreted intact or as its glucuronide Reference Reference Reference The variability in terminal half-life measurements are related to the dependence of this measure on assay sensitivity, as well as on the duration and timing of blood measurements Reference Low levels of THC metabolites have been detected for more than five weeks in the urine and feces of cannabis users Reference Like THC, the decline of CBD levels is also multi-phasic, and the half-life of CBD in humans after smoking has been estimated at 27 - 35 h, and 2 - 5 days after oral administration Reference Reference Reference More limited information is available for inhaled cannabis Reference 58 Reference A dosing interval of 1 h with this dose would give a "continuous high", and the recovery time after the last dose would be min i.

    One clinical study reported a peak increase in heart rate and perceived "good drug effect" within 7 min after test subjects smoked a 1 g cannabis cigarette containing either 1. Compared to the placebo, both doses yielded statistically significant differences in subjective and physiological measures; the higher dose was also significantly different from the lower dose for subjective effects, but not physiological effects such as an effect on heart rate.

    The equilibration half-life estimate for heart rate was approximately 7 min, but varied between 39 and 85 min for various CNS parameters Reference According to this model, the effects on the CNS developed more slowly and lasted longer than the effect on heart rate.

    Subjects reported smoking a mean of one joint per day in the previous 14 days prior to the initiation of the study range: During the study, subjects smoked one cannabis cigarette mean weight 0. According to the authors of the study, the pharmacodynamic-pharmacokinetic relationship displayed a counter-clockwise hysteresis i. THC , the pharmacological effect is greater at a later time point than at an earlier one for all measured subjective effects e.

    This particular kind of relationship demonstrates a lack of correlation between blood concentrations of THC and observed effects, beginning immediately after the end of smoking and continuing during the initial distribution and elimination phases. Following the start of cannabis smoking, heart rate increased significantly at the 30 min time point, diastolic blood pressure decreased significantly only from the 30 min to 1 h time point, and systolic blood pressure and respiratory rate were unaffected at any time.

    A study that examined the acute subjective effects associated with smoked cannabis at three different doses i. In addition, the study also showed that higher doses of THC were associated with longer duration of subjective effects.

    Findings from the study showed that the time required to reach a maximal "high" rating was slightly delayed 11 - 16 min compared to the time required to reach the peak THC serum concentration. The "high" rating declined after reaching the peak within the first 3. Scores on the VAS for "dizziness", "dry mouth", "palpitations", "impaired memory and concentration", "down", "sedated", and "anxious feelings" reached a maximum within the first 2 h post-dose and these effects were dose-dependent.

    With a dose of A dose of Finally, a THC dose of The THC-induced decrease in stimulation i. In fact, sedation was increased by almost six-fold compared to placebo. The low THC dose was associated with the highest ratings of "like the effects of the drug" and "want more of this drug". Maximal subjective "high" ratings occurred at 60 min following beginning of inhalation. One clinical study reported that ad libitum vapourization of mg cannabis containing a low-dose 2.

    Subjective effects were then measured at several time points and effects were correlated with concentrations of cannabinoids in oral fluid and blood. There were no significant differences between the effects seen with the low 2. Vapourized cannabis significantly increased measures of "stoned" and "sedated" immediately post-dose and lasted 3. Feelings of "anxious" showed significant cannabis-dose effects through 1.

    Effects and time course of effects were similar between vapourized and smoked cannabis. Another study measured 17 different psychoactive effects as a function of THC dose and time in vapourized cannabis Reference Plasma hydroxy-THC C max for the 2.

    The lower dose produced effects lower than that for the high dose and placebo effects were lower than both active doses for "any drug effect", "good drug effect", "high", "impaired", "stoned", "sedated" and "changes perceiving space".

    For "bad drug effect", "like the drug", "nauseous", "changes perceiving time", ratings with placebo were significantly lower than both active doses. The higher dose 6. There was a clear dose-response effect for the majority of psychoactive effects.

    Increases in systolic blood pressure occurred with low 5 mg and high 15 mg oral doses of THC, as well as low 5. In contrast, diastolic blood pressure decreased between 4 and 8 h after dosing.

    Heart rate increased after all active treatments. A subjective feeling of a "high" was reported to be significantly greater after 15 mg oral THC compared to placebo and to 5 mg oral THC. In contrast, neither the high nor the low doses of oro-mucosal nabiximols were reported to produce a statistically significant subjective "high" feeling.

    Study subjects reported being most "anxious" approximately 4 h after administration of 5 mg oral THC, 3 h after 15 mg oral THC, 5.

    All active drug treatments induced significantly more anxiety compared to placebo. After 15 mg oral THC, the concentration of THC in plasma was observed to have a weak, but statistically significant, positive correlation with systolic and diastolic blood pressure, "good drug effect", and "high".

    After high-dose oro-mucosal nabiximols, positive correlations were also observed between plasma THC concentrations and "anxious", "good drug effect", "high", "stimulated", and M-scale marijuana-scale scores. Consistent with other studies, the authors of this study reported that linear correlations between plasma THC concentrations and physiological or subjective effects were weak.

    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.

    Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. It should be noted, however, that CBD did not suppress the cell count below the "starting" number measured at day 1 , arguing for a "pure" antiproliferative effect. Indeed, the lack of its effects on the count of viable cells was further verified by showing that these concen- trations of CBD did not decrease cellular viability or induce either apoptosis or necrosis of SZ95 sebocytes Figure 2 , B and C.

    These hSOC assays, which mimic the human sebaceous gland function in vivo as closely as this is currently possible on the ex vivo level, clearly demonstrated that application of CBD completely prevented the lipogenic action of AEA in situ and, in line with our long-term in vitro observations Supplemental Figure 2 E , decreased basal lipogenesis as well Figure 2 , D-H.

    This suggests that CBD may also operate as a potent sebostatic agent in vivo when tested in appropriate clinical trials. Moreover, also in line with our pre- vious findings, we found that TRPV4 antagonism could success- fully prevent both alterations Figure 6C.

    CBD, without compromising viability Figure 2 , B and C , a normalized the pathologically elevated lipogenesis induced by "pro-acne" agents, both in a quantitative and qualitative manner universal lipostatic effect; Figure 1 ; b suppressed cell prolifer- ation antiproliferative effect; Figure 2 A ; and c prevented the actions of TLR activation or "pro-acne" agents to elevate proinflam- matory cytokine levels universal antiinflammatory effect; Figure 3.

    Therefore, the novel and significant antiprolif- erative activity of CBD on human sebocytes in vitro and ex vivo documented here Figure 2 , A and I is expected to greatly reduce sebum production in vivo. Moreover, it is also important to empha- size that, clinically, it is highly desirable that basal sebogenesis and viability of sebocytes are unaffected Figure 1, A-C, and Figure 2 , A-C by CBD at least in the noncytotoxic concentrations and after short-term treatments; Supplemental Figure 2 , A-E , since a suffi- cient level of sebum production is a critical factor for maintaining proper function of the epidermal barrier, one of the central com- ponents of skin homeostasis The ECS can also affect sebaceous gland function, and by acting via CB 2 , endocannabinoids positively control sebaceous lipid synthesis [64].

    Furthermore, cannabidiol, a CB1 antagonizing nonpsy- chotropic phytocannabinoid, reduced sebocyte proliferation and normalized excess sebum production that can be observed in acne lesions [65, 66]. TRPV4 interacts with intercellular adhesion proteins and thereby contributes to epidermal integrity and barrier functions Kida et al.

    In the pilosebaceous unit, TRPV4 is expressed on sebaceous gland cells, where its activation results in suppressed proliferation of sebocytes and a strong lipostatic effect Olah et al. Alpha-pinene was also a potent inhibitor of the bacterium Raman et al. Cannabis Therapeutics and the Future of Neurology. The endocannabinoid system of the skin.

    Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes

    (-)-Cannabidiol (CBD) is the most studied nonpsychotropic CBD decreases proliferation, but not the viability, of human sebocytes both in vitro and ex vivo. ((–)-cannabidiol [CBD]) exerted complex anti-acne effects by proliferation of human SZ95 sebocytes were investigated by MTT phytocannabinoids only negligibly altered the viability of the Although it is not a directly life-threatening one, it is well docu- in vitro and ex vivo in full-thickness human skin organ culture. Administration of CBD to cultured human sebocytes and human skin organ . nor quan- CBD decreases proliferation, but not the viability, of human titative Nile Red indicated changes in the basal neutral sebocytes both in vitro and ex vivo.

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