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Here are some of the known medicinal benefits associated with CBC:. CBC inhibits the uptake of anandamide, meaning that anandamide stays for longer periods of time within the blood stream. This cannabinoids has been shown to be effective against breast cancer, both in vivo and in vitro.
CBC is effective in suppressing inflammation, such as that seen in osteoarthritis. CBC has been shown to have positive effects on neurogenesis by promoting neural stem progenitor cell activity. These progenitor cells show more viability in the presence of CBC and this is vital for brain homeostasis and proper functioning.
The cells further differentiate into astroglia cells. Results from a study revealed that CBC is effective in the treatment of acne. Acne is characterized by excessive sebum production and the inflammation of sebaceous glands. CBC was shown to fight inflammation and to suppress the production of sebum. Further research is needed to confirm this findings as CBC can be a powerful remedy against acne.
This is as a result of the entourage effect which also includes terpenes, flavanoids and other cannabinoids working together synergistically. The potential medicinal benefits of the CBC cannabinoid are only just beginning to be understood. Inhibition of neurotransmitter release occurs through a retrograde signaling mechanism whereby endocannabinoids synthesized and released from the cell membrane of post-synaptic neurons diffuse backwards across the synaptic cleft and bind to CB 1 receptors located on the pre-synaptic terminals Figure 1 Reference 3.
This retrograde signaling mechanism permits the regulation of neurotransmission in a precise spatio-temporal manner Reference 3.
The CB 1 receptor is one of the most abundant G-protein coupled receptors in the central and peripheral nervous systems Reference It has been detected in the cerebral cortex, hippocampus, amygdala, basal ganglia, substantia nigra pars reticulata, internal and external segments of the globus pallidus and cerebellum molecular layer , and at central and peripheral levels of the pain pathways including the periaqueductal gray matter, the rostral ventrolateral medulla, the dorsal primary afferent spinal cord regions including peripheral nociceptors, and spinal interneurons Reference 4 Reference 23 Reference CB 1 receptor density is highest in the cingulate gyrus, the frontal cortex, the hippocampus, the cerebellum, and the basal ganglia Reference 5.
Relatively little CB 1 receptor expression is found in the thalamus and the primary motor cortex Reference 5. The CB 1 receptor is also expressed in many other organs and tissues including adipocytes, leukocytes, spleen, heart, lung, the gastrointestinal GI tract liver, pancreas, stomach, and the small and large intestine , kidney, bladder, reproductive organs, skeletal muscle, bone, joints, and skin Reference 25 - Reference CB 2 receptors are most highly concentrated in the tissues and cells of the immune system such as the leukocytes and the spleen, but can also be found in bone and to a lesser degree in liver and in nerve cells including astrocytes, oligodendrocytes and microglia, and even some neuronal sub-populations Reference 44 Reference Besides the well-known CB 1 and CB 2 receptors, a number of different cannabinoids are believed to bind to a number of other molecular targets.
For additional details on this subject please see Section 2. Modulation of these other cannabinoid targets adds additional layers of complexity to the known myriad effects of cannabinoids.
Endocannabinoid signaling is rapidly terminated by the action of two hydrolytic enzymes: Signal termination is important in ensuring that biological activities are properly regulated and prolonged signaling activity, such as by the use of cannabis, can have potentially deleterious effects Reference 52 Reference Dysregulation of the ECS appears to be connected to a number of pathological conditions, with the changes in the functioning of the system being either protective or harmful Reference However, a major and consistent therapeutic challenge confronting the routine use of THC-predominant cannabis and psychoactive cannabinoids e.
THC in the clinic has remained that of achieving selective targeting of the site of disease or symptoms and the sparing of other bodily regions such as the mood and cognitive centres of the brain Reference 23 Reference 54 - Reference The CB 1 receptor is highly expressed in the developing brain Reference For example, CB 1 receptors are highly expressed from early fetal stages, beginning as early as E Furthermore, in the adult brain, the CB 1 receptor appears to be localized on the axonal plasma membrane and in somatodendritic endosomes, whereas in fetal brain the CB 1 receptor is mostly localized to endosomes both in axons and in the somatodendritic region Reference The available evidence suggests a neurodevelopmental role for the ECS including in functions such as survival, proliferation, migration and differentiation of neuronal progenitors Reference CB 1 receptor activation, in response to stimulation by endocannabinoids, such as 2-AG and anandamide, promotes these functions but delays the transition from multipotent, proliferating, and migration-competent progenitor phenotype towards a more settled, well-differentiated, post-mitotic neuronal phenotype Reference 60 Reference In vitro studies examining the effects of CB 1 receptor activation in primary neuronal cultures suggest that the CB 1 receptor is mainly a negative regulator of neurite growth since activation of the receptor results in growth cone arrest, repulsion or collapse and thereby influences the ability of axons to reach their targets Reference However, these CB 1 receptor-mediated responses may be surmountable by the effects of local growth-promoting effectors at the growth cone and the balance between the effects of endocannabinoids and growth factors would determine the overall outcome of neuronal development.
The CB 1 receptor appears also to act as a negative regulator of synaptogenesis and in doing so can also affect the fate of neuronal communication Reference Exposure to cannabinoids that activate the CB 1 receptor such as THC during developmental periods of nervous system development such as during embryonic development in pregnancy could alter the course of normal neuronal development in offspring and negatively affect normal brain function potentially causing long-lasting impairment of a number of cognitive functions and behaviours Reference 61 and also see Sections 2.
For example, a study conducted in pregnant mice using a low dose of THC has been shown to alter the expression level of 35 proteins in the fetal cerebrum Reference Furthermore this study concretely identified a specific molecular target for THC in the developing CNS whose modifications can directly and permanently impair the wiring of neuronal networks during corticogenesis by enabling formation of ectopic neuronal filopodia and altering axonal morphology Reference Another in vitro study with retinal ganglion cell explants showed that CBD decreased neuronal growth cone size and filopodia number as well as total projection length and induced growth cone collapse and neurite retraction i.
See text for additional details. Figure adapted from Reference 64 - Reference The leaves and flowering tops of Cannabis contain over distinct compounds distributed among 18 different chemical classes, and harbor over different phytocannabinoids Reference 68 - Reference 71 The principal phytocannabinoids appear to be deltatetrahydrocannabinol i. In the living plant, these phytocannabinoids exist as both inactive monocarboxylic acids e. Furthermore, pyrolysis such as by smoking transforms each of the hundreds of compounds in cannabis into a number of other compounds, many of which remain to be characterized both chemically and pharmacologically.
Therefore, cannabis can be considered a very crude drug containing a very large number of chemical and pharmacological constituents, the properties of which are only slowly being understood. However, Canadian licensed producers of cannabis for medical purposes have now made available a large variety of cannabis strains containing varying levels of THC and CBD, including THC-predominant, CBD-predominant or balanced strains for patients who have received authorization from their healthcare practitioner to access cannabis for medical purposes.
For more information, please consult the Health Canada authorized licensed producers of cannabis for medical purposes website. The large number of compounds found in cannabis spans many chemical classes including phytocannabinoids, nitrogenous compounds, amino acids, proteins, enzymes, glycoproteins, hydrocarbons, simple alcohols, aldehydes, ketones and acids, fatty acids, simple esters and lactones, steroids, terpenes, non-cannabinoid phenols, flavonoids, vitamins, and pigments Reference Furthermore, differences in the presence and the relative abundance of some of these various components have been investigated, and differences in various components have been noted between cannabis extract, vapour, and smoke, and also between cannabis varieties Reference Of note, cannabis smoke contains many compounds not observed in either extracts or vapour, including a number which are known or suspected carcinogens or mutagens Reference 81 - Reference Moreover, comparisons between cannabis smoke and tobacco smoke have shown that the former contains many of the same carcinogenic chemicals found in the latter Reference 82 Reference 84 see Section 7.
Relatively little is known about the pharmacological actions of the various other compounds found within cannabis e. However, it is believed that some of these compounds e. Terpenes vary widely among cannabis varieties and are thought to be primarily responsible for differences in fragrance among the different Cannabis strains Reference Furthermore, it is thought that terpenes may contribute to the distinctive smoking qualities and possibly to the character of the "high" associated with smoking cannabis Reference 75 , but again, this has not been studied in any detail.
The concept that terpenes may somehow modify or enhance the physiological effects of the cannabinoids Reference 85 Reference 86 ,i.
As the temperature increases, the rate of decarboxylation increases: Heat, light, humidity, acidity and oxidation all affect the stability of cannabis and phytocannabinoids Reference 91 Reference Sevigny has provided the following formula for calculating decay of THC: For specific stability and storage conditions for cannabis provided by licensed commercial producers in Canada, please consult information provided by the licensed commercial producers.
Its effects are not well studied but it appears to have some possible immunosuppressive properties in a small number of in vitro studies Reference Cannabigerolic acid has a similar profile. CBD lacks detectable psychoactivity and does not appear to bind to either CB 1 or CB 2 receptors at physiologically meaningful concentrations, but there is some emerging evidence suggesting it may act as a non-competitive, negative, allosteric modulator of CB 1 receptors Reference There is also a considerable body of evidence suggesting CBD also affects the activity of a significant number of other targets including ion channels, receptors, and enzymes Reference 18 Reference Reference The effects of CBD at these and other molecular targets are associated with anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform effects Reference Reference Reference Much of what is known about the beneficial properties of the non-psychotropic cannabinoids e.
CBD, THCV is derived from in vitro and in vivo studies and few well-conducted, rigorous clinical studies of these substances exist. However, the results from these pre-clinical studies point to potential therapeutic indications such as psychosis, epilepsy, anxiety, sleep disturbances, neurodegeneration, cerebral and myocardial ischemia, inflammation, pain and immune responses, emesis, food intake, type-1 diabetes, liver disease, osteogenesis, and cancer Reference 18 Reference Reference For more in-depth information on the pharmacology of cannabinoids, the reader is invited to consult the following resources Reference 22 Reference 46 Reference 48 Reference Reference The limited information that exists is complex and requires further clarification through additional investigation.
The following paragraphs summarize the available information on this subject. Despite the limited and complex nature of the available information, it generally appears that pre-administration of CBD may potentiate some of the effects of THC through a pharmacokinetic mechanism. Furthermore, the ratio between the two phytocannabinoids also appears to play a role in determining whether the overall effect will be of a potentiating or antagonistic nature.
In one study, 24 healthy men and women who had reported using cannabis at least 10 times in their lifetime were subjected to a double-blind, placebo-controlled, mixed between- and within-subject clinical trial that showed that deliberate systematic variations in the levels of either CBD or CBC in smoked cannabis were not associated with any significant differences in any of the measured subjective, physiological, or performance tests Reference This double-blind, placebo-controlled, within-subject, crossover clinical study reported few reliable differences between the THC-only and whole-plant cannabis conditions Reference The authors further concluded that other cannabinoids present in the cannabis plant material did not alter the subjective effects of cannabis, but they speculated that cannabis samples with higher levels of cannabinoids or different ratios of the individual cannabinoids could conceivably produce different results, although no evidence to support this claim was provided in the study.
They also hypothesized that whole-plant cannabis and THC alone could differ on other outcome measures more relevant to clinical entities e. With the possible exception of one study Reference , see Section 4. Cancer Pain , which suggested differences between a whole-plant cannabis extract i. One study compared the subjective and physiological effects of oral THC to those of nabiximols in normal, healthy subjects Reference The authors reported the absence of any modulatory effect of CBD or other components of cannabis at low therapeutic cannabinoid doses, with the potential exception of the subjective "high" Reference An internet-based, cross-sectional study of 1 individuals with a consistent history of cannabis use reported that those individuals who had indicated using cannabis with a higher CBD to THC ratio had also reported experiencing fewer psychotic symptoms an effect typically associated with exposure to higher doses of THC Reference However, the authors noted that the effects were subtle.
The study was also hampered by a number of important methodological issues suggesting that the conclusions should be interpreted with caution. The study findings are also consistent with the rest of the literature in terms of the average daily gram dose of dried cannabis used by patients i. Taken together, the study suggests that the use of cannabis containing approximately equivalent "lower" levels of THC and "higher" levels of CBD is associated with self-reported therapeutic efficacy and satisfaction across a number of different medical conditions for which dried cannabis is typically used, and also associated with attenuated levels of mood perturbation.
The evidence also suggests that cannabis containing higher levels of THC and little CBD is not necessarily more effective than lower dose strains, except for stimulation of appetite.
However, the study findings suggest that the use of higher-THC strains is associated with greater mood perturbation than the lower-THC strains. The study carried a number of caveats being that it only looked at a small number of patients, had a limited number of medical conditions and consisted of a self-reported survey. Two in vivo studies conducted in non-human primates i. An in vivo study conducted in non-human primates i. Another in vivo study conducted in non-human primates i.
Most of the available information regarding the acute and long-term effects of cannabis use comes from studies conducted on non-medical users, with much less information available from clinical studies of patients using cannabis for medical purposes. The acute effects of smoking or eating cannabis include euphoria the marijuana "high" as well as cardiovascular, bronchopulmonary, ocular, psychological and psychomotor effects. Euphoria typically occurs shortly after smoking and generally takes longer with oral administration Reference However, some people can experience dysphoria and anxiety Reference Tachycardia is the most consistent of the acute physiological effects associated with the consumption of cannabis Reference - Reference The short-term psychoactive effects associated with cannabis smoking in non-medical users include the above-mentioned euphoria but also relaxation, time-distortion, intensification of ordinary sensory experiences such as eating, watching films, and listening to music , and loss of inhibitions that may result in laughter Reference This is followed by a depressant period Reference Driving and operation of intricate machinery, including aircraft, may be significantly impaired Reference - Reference Table 1 below , adapted from a review Reference , notes some of the pharmacological effects of cannabis in the therapeutic dosage range.
Many of the effects are biphasic, with increased activity with acute or smaller doses, and decreased activity with larger doses or chronic use Reference Reference Reference Effects differ greatly among individuals and may be greater in those who are young, severely ill, elderly, or in those taking other drugs. See Figure 2 below for a graphical representation of the pharmacokinetics of THC. Pharmacokinetics of THC and other cannabinoids.
Figure adapted from Reference THC and other cannabinoids can be administered by inhalation e. The concentration of THC and other cannabinoids in the extracellular water varies depending on serum protein binding lipoproteins, albumin , tissue storage fat, protein , metabolism hepatic microsomal, non-microsomal, extrahepatic , biliary excretion enterohepatic recirculation and renal excretion glomerular filtration, tubular secretion, passive reabsorption. The metabolism of THC and other cannabinoids produces metabolites which can also be found in the extracellular water.
The concentration of THC in the extracellular water affects the THC and other cannabinoids concentration at the site of action. The effects of THC and other cannabinoids are observed when THC and other cannabinoids interacts with cannabinoid receptors or other targets of action. THC and other cannabinoids can also be detected in hair, saliva and sweat. Smoking cannabis results in more rapid onset of action within minutes , higher blood levels of cannabinoids, and a shorter duration of acute pharmacodynamic effects compared to oral administration Reference Smoking cannabis containing 1.
Similarly, smoking cannabis joints containing 1. Smoking a 25 mg dose of cannabis in a pipe containing 2. Smoking one cannabis cigarette mg containing 6.
Compared to the data available for absorption with smoked THC, there is far less such information available for smoked CBD. Vapourization of cannabis has been explored as an alternative to smoking. In addition, the study reported that vapourization was well tolerated with no reported adverse effects, and was preferred over smoking by the test subjects Reference While vapourization has been reported to be amenable to self-titration as has been claimed for smoking Reference Reference , the proper use of the vapourizer for optimal administration of cannabis for therapeutic purposes needs to be established in more detail Reference 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
Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects
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