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A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray
Abstract
Purpose:
To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, when administered to healthy male subjects.
Methods:
Twelve subjects took part in this fed-fasted cross-over study and received a single dose of THC/CBD spray (4 sprays = 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time-points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC).
Results:
Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80-14.91 ng/ml) and lower in 5 subjects (2.81-3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97-9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0-t), AUC(0-inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2-2.5 h. Only mild adverse events were reported.
Conclusions:
The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.
... This study was largely an exploratory pilot study and as such a sample size of 5 participants was considered adequate for a limited assessment of the Stage I single dose PK study with no sample size calculation a priori. This was similar in design to a phase I study that assessed the single and multiple dose PKs and safety and tolerability of a mouth spray that administered Δ9-THC/CBD [21]. For Stage II sample size of n = 25 was sufficient to detect a moderate effect size of 0.5 with alpha set at 0.05 (one-tail) and power set at 80%. ...
... ng/mL and 2.99/0.82 ng/ mL.h, respectively [21]. With half that dose from MDCNB-01 (2.5 mg Δ9-THC/2.5 mg CBD), we found C max and AUC (0-t) of 1.31/058 ng/mL and 1.71/0.65 ng/mL.h, ...
... For oro-buccal sprays there is a risk that with high volumes administered that some of the volume will be swallowed prior to absorption, especially when the dose is high. Yet, the nanoparticle water-soluble delivery technology provided one peak consistent with mostly mucosal delivery, whereas a 50% ethanol mouth spray provided two peaks and inconsistent plasma levels [21], indicating inefficient mucosal absorption and swallowing of the medicine and less effective gastrointestinal absorption. ...
This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n = 5) [2.5 mg Δ9-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n = 25). During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD, was 1.71 ng mL.h⁻¹ (1.1, 6.6) and 0.65 ng mL.h⁻¹ (0.49, 4.1), respectively). During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastases, had the highest mean pain score improvement from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients. The water-soluble cannabis-based medicine provided acceptable bioavailability for Δ9-THC/CBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.
... A sample size of n=5 was considered adequate for a limited assessment of the Stage I SAD PK study, which was similar in design to a phase I study that assessed the single and multiple dose PKs and safety and tolerability of an oro-mucosal administered Δ9-THC/CBD spray [23]. Pharmacokinetic parameters were presented as medians within the range of minimum and maximum values. ...
... The water-soluble nanoparticle cannabis formulation has appropriate pharmacokinetics of cannabinoids for a maintenance analgesic, with peak plasma concentration in less than an hour and efficacy durable enough to support dosing every four hours (with multiple dosing). Oromucosal delivery using 50% ethanol (and propylene glycol) [23] does not seem to be as effective as the nanoparticle water-soluble spray. For example, comparing the PK data with that reported for an ethanol-based Δ9-THC/CBD spray, NanaBis TM achieved an approximate equivalent AUC (0-t) and C max with half the Δ9-THC/CBD administered dose. ...
... ng mL.h -1 and 1.48/0.39 ng mL -1 respectively [23]. A comparison with half the dose from NanaBis TM 2.5 mg Δ9-THC/2.5 mg CBD), the calculated means for AUC (0-t) and C max were 2.79/1.46 ...
... Lastly, there is evidence that a fed over-fasted state may delay and/or increase absorption of cannabinoids. 18,19 Thus, differences in fed states could explain the variation in reported values between trials. ...
... Data presented from our PK study on THC capsules support the wider literature that reports consumption of cannabinoids in the presence of food leads to altered PK parameters in comparison to administration under a fasting condition. 18,19 Our data align with these previous findings showing that the mean absorption of THC was increased by 2-to 3-fold (depending on dose), whereas the mean levels of 11-OH-THC were enhanced *1.3fold for both doses. The increased mean absorption of THC in the presence of food is possibly due to the slowed transit time through the gastrointestinal tract when fat is present. ...
... However, the exact mechanism of this enhanced absorption has yet to be investigated. In contrast to Stott et al., 18 we did not find a significant increase in C max fed and fasted conditions. As peak plasma concentration after oral administration of a drug is influenced by both absorption and metabolism, these differences could be the result of the polymorphic nature of the CYP450 enzymes and/or heterogeneity of the participant populations. ...
Background: There is variability in the reported Δ9-tetrahydrocannabinol (THC) and 11-hydroxy-tetrahydrocannabinol (11-OH-THC) pharmacokinetic (PK) and pharmacodynamic (PD) parameters between studies and there is limited investigation into how the presence of food or sex affect these parameters. In this study, we examined the PK and PD parameters of an encapsulated THC extract and its major active metabolite, 11-OH-THC, under different fed states. Methods: The study was a single-dose, randomized, double-blinded, four-way crossover investigation. THC capsules (1 or 2×5 mg) were administered to 28 healthy adults (13 females: 15 males) under a fasted condition or after a high-fat meal. Blood samples were collected and PK parameters were determined through noncompartmental analysis. Adverse events (AEs), cognitive function (through completion of digit symbol substitution tests), blood pressure, and heart rate were also recorded. Results: The presence of high-fat food significantly enhanced time to peak plasma concentration (Tmax) and area under the curve (AUC0-24) for both THC and 11-OH-THC and reduced THC's apparent volume of distribution (Vz/F) and apparent clearance (Cl/F). Females had a significantly greater peak plasma concentration (Cmax) compared with males after 5 mg THC in a fasted state. No cardiovascular or cognitive effects and only mild AEs (somnolence, fatigue, and euphoric mood) were reported. Conclusion: These findings may help to inform the guidelines provided by governing health bodies on the effects of cannabis, such as time to onset and duration of action, and aid health care practitioners in their prescribing practices. Furthermore, the doses used in this study are safe to consider for future interventional studies in disease conditions where THC has been shown to have therapeutic efficacy.
... Furthermore, an effect of food, meaning food/fat-dependent absorption has been shown. Food intake was found to increase area under the curve (AUC) and maximum plasma concentration (C max ) but also time to reach maximum plasma concentration (T max ) (delayed absorption) [16]. ...
... As reference formulation the same Hemp-Extract diluted with MCT (medium-chain triglycerides) oil (MTC-CBD) was used. To control for confounding factors, especially the possible influence of the described food effect [16] on the pharmacokinetics of CBD, the study was conducted under fasted conditions and strict after dosing diet. Fasting conditions are considered to be the most sensitive conditions to detect a potential difference between formulations. ...
... Second, the current study and the study by Cherniakov et al. [23] were conducted under fasted conditions whereas the study by Atsmon et al. [22] was carried out under fed conditions. The relevance of these dietary conditions for CBD's pharmacokinetics was recently demonstrated by Stott et al. who reported an increase in CBD bioavailability under fed vs. fasted states in 12 men after a single 10 mg dose of CBD administered as oromucosal spray (Sativex ® ) [16]. Mean AUC and C max were 4-and 3-fold higher during fed compared to fasted conditions (AUC 0-t , 20.2 vs. 4.5 ng/mL*h; C max 3.7 vs. 1.2 ng/mL). ...
Cannabidiol (CBD), a phytocannabinoid compound of Cannabis sativa, shows limited oral bioavailability due to its lipophilicity and extensive first-pass metabolism. CBD is also known for its high intra- and inter-subject absorption variability in humans. To overcome these limitations a novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology incorporating CBD, as Hemp-Extract, was developed (SEDDS-CBD). The study objective was to evaluate the pharmacokinetic profile of SEDDS-CBD in a randomized, double-blind, cross-over design in 16 healthy volunteers under fasted conditions. As reference formulation, the same Hemp-Extract diluted with medium-chain triglycerides (MCT-CBD) was used. CBD dose was standardized to 25 mg. Pharmacokinetic parameters were analyzed from individual concentration-time curves. Single oral administration of SEDDS-CBD led to a 4.4-fold higher Cmax and a 2.85-/1.70-fold higher AUC0–8h/AUC0–24h compared to the reference formulation. Tmax was substantially shorter for SEDDS-CBD (1.0 h) compared to MCT-CBD (3.0 h). Subgroup analysis demonstrated a higher bioavailability in women compared to men. This difference was seen for MCT-CBD while SEDDS-CBD mitigated this gender effect. Overall, SEDDS-CBD showed a significant improvement for all determined pharmacokinetic parameters: increased CBD plasma values (Cmax), favorably enhanced bioavailability (AUC) and fast absorption (Tmax). No safety concerns were noted following either administration.
... 1,3,10,11 CBD half-life (t 1/2 ) ranges from 18 to 60 hours. 1,[10][11][12][13] Evidence exists for a large food effect with lower doses (approximately 40 mg single dose) of tetrahydrocannabinol (THC) and CBD (1:1) delivered as an oromucosal spray, resulting in a threefold higher C max and fivefold higher area-under-the-concentration-time curve (AUC 0-∞ ) for fed compared to fasting states. 12 A similar food effect for the currently approved FDA liquid formulation (Epidiolex) has also been reported. ...
... 1,[10][11][12][13] Evidence exists for a large food effect with lower doses (approximately 40 mg single dose) of tetrahydrocannabinol (THC) and CBD (1:1) delivered as an oromucosal spray, resulting in a threefold higher C max and fivefold higher area-under-the-concentration-time curve (AUC 0-∞ ) for fed compared to fasting states. 12 A similar food effect for the currently approved FDA liquid formulation (Epidiolex) has also been reported. 11 Liquid formulations are associated with a higher possibility of inconsistent dosing, which complicates the characterization of drug pharmacokinetics. ...
... Our estimates are in agreement with literature values for CBD CL/F and V/F. 1,3,[10][11][12] It is important to note that these are apparent values after an oral dose, which can explain higher values of both V/F and CL/F for fasting states owing to lower bioavailability. To put these values into clinical perspective, for a 300 mg total daily oral dose of CBD, the average steady-state plasma concentration would be 32.2 ng/ mL for fed compared to 6.6 ng/mL for fasting. ...
Objective
To evaluate the pharmacokinetics of a purified oral cannabidiol (CBD) capsule administered with and without food in adults with refractory epilepsy.
Methods
Adult patients who were prescribed CBD for seizures, had localization‐related intractable epilepsy with ≥4 seizures per month, and qualified for Minnesota cannabis were enrolled. A single dose of 99% pure CBD capsules was taken under both fasting (no breakfast) and fed (high fat 840‐860 calorie) conditions. Blood sampling for CBD plasma concentrations was performed under each condition between 0 and 72 hours post‐dose and measured by a validated liquid chormatography‐mass spectometry assay. CBD pharmacokinetic profiles including maximum concentration (Cmax), area‐under‐the‐curve from zero to infinity (AUC0‐∞), and time‐to‐maximum concentration (Tmax) were calculated. The confidence intervals (CIs) for log‐transformed Cmax and AUC0‐∞ ratios between fed and fasting states were calculated. Seizure and adverse events information was collected.
Results
Eight patients completed the study. On average Cmax was 14 times and AUC0‐∞ 4 times higher in the fed state. The 90% CI for the ratio of fed versus fast conditions for Cmax and AUC0‐∞ were 7.47‐31.86 and 3.42‐7.82, respectively. No sequence or period effect for Cmax and AUC0‐∞ was observed. No adverse events were reported.
Significance
Administering CBD as a capsule rather than a liquid allows for more precise determination of pharmacokinetics parameters and is more representative of CBD swallowed products. The fat content of a meal can lead to significant increases in Cmax and AUC0‐∞ and can account for variability in bioavailability and overall drug exposure within patients with oral products.
... Improved absorption of oral formulations of CBD has been observed when administered with a meal, or in a postprandial state, or in nano-emulsion formulations (Atsmon et al., 2018;Cherniakov et al., 2017). Studies in humans showed a 14-fold increase in plasma concentration (C max ) of CBD when ingested with a high-fat meal, compared to ingestion in a fast state (Birnbaum et al., 2019), and a 3-5fold higher C max , and longer half-life when CBD was taken under fed conditions (Birnbaum et al., 2019;Stott et al., 2013). While systemic absorption of CBD is often the spotlight of most studies (Millar et al., 2018), the estimation of intestinal absorption of other cannabinoids has been mostly carried out by physiologic based pharmacokinetic modeling (PBPK) (Liu and Sprando, 2023). ...
... Absorption of orally ingested hydrophobic compounds is complex and dissolution in gastrointestinal fluids is critical. CBD is broken down in the stomach, but the oral ingestion with a high-fat food has been shown to significantly increase its bioavailability (Birnbaum et al., 2019;Stott et al., 2013;Mozaffari et al., 2021). Also, human studies with various CBD formulations showed that oily oral formulations increased CBD bioavailability, while the presence of protein in products decreased its bioavailability (Silmore et al., 2021;Zgair et al., 2016). ...
... In a human study, the administration of CBD with a high-fat meal increased both the concentration peak and the area under the concentration-time curve (AUC) by more than four times compared to its administration in fasted status (14). Food is thought to promote the absorption of lipophilic drugs by increasing their time spent in the gastrointestinal tract, their solubilization, and their lymphatic transport by lymphatic lipoproteins (15). It has been observed that the oral bioavailability of drugs can also be influenced by the meal in the equine species (16). ...
... While in a human study, a high-fat meal caused a four-fold increase of C max and AUC values compared to those obtained in fasted conditions (14), in the present study, the feeding status did not influence the C max and AUC values of both CBD formulations. It should be underlined that horses were fed with a polyphite hay, with a low fat content; consequently, no CBD solubilization and no lymphatic absorption related to the lipid content of the meal could have been promoted (15). ...
Pain management in horses plays a pivotal role in the therapeutic approach to several diseases. Horses have cannabinoid receptors at the level of dorsal root ganglia, blood vessels, and synoviocytes that can be up or down- regulated by inflammatory conditions, justifying the possible efficacy of exogenous cannabinoids (i.e., phytocannabinoids) in managing several painful pathologies in this animal species. However, the current use of supplements containing cannabidiol (CBD) in equines is based on anecdotal evidence, without the support of sufficient pharmacokinetic studies. In humans, the concentration peak of CBD and the area under the concentration-time curve (AUC) are both strongly influenced by food administration. Also, in equids, the oral bioavailability of some drugs can be influenced by the meal but no information is available about CBD. This study investigated the pharmacokinetics of CBD following single oral administration of two different formulations of pure CBD (oil and paste), dosed at 1 mg/kg, at two different times about food administration. CBD oil and CBD paste were administered orally at 1 mg/kg to eight healthy horses according to a cross over design, and blood samples were taken at pre-fixed time-points for the pharmacokinetic analyses. The obtained pharmacokinetic data did not allow for statistically significant differences between formulations (paste or oil) and feeding time (fed and fasted status). However, following treatment with the paste, the Cmax was achieved in a shorter time range compared to the oily formulation, indicating that it could be a better formulation to consider in future equine studies.
... In addition, a significant number of reports have conducted studies on the pharmacokinetics of CBD using extracts of Cannabis sativa, and the content of THC incorporated in addition to CBD varies widely. Table 1 shows a summary of reported results (Nadulski et al. 2005;Stott et al. 2013a;Taylor et al. 2019;Crockett et al. 2020;Sholler et al. 2022) to assess the effects of diet on CBD pharmacokinetics. Regarding oral exposure to CBD, the mean absorption rate of CBD into the blood stream through the gastrointestinal tract under fasted and fed conditions was inconsistent and varied between reports. ...
... According to a report by Crockett et al. (Crockett et al. 2020), when a high fat diet was combined with oral administration of CBD, the mean T max (3.38 h) was lower than that of the fasted diet (3.75 h), but when it was combined with low fat (5.26 h), milk (5.88 h), and alcohol (5.76 h), the mean T max values increased. There was also a difference between fasted and fed states in the rate of CBD absorption through the transdermal (oromucosal), with mean T max lower in fasted (1.39 h) than fed (4.00 h) (Stott et al. 2013a). However, considering that the T max mean values in both fasted and fed states ranged from 1.39 to 5.88 h, and that the mean difference between fasted and fed states in the intra-study comparison was within approximately 2.5 h, it was suggested that the effect of diet on T max of CBD is unlikely to be very significant. ...
Cannabidiol (CBD) is a non-psychoactive substance that exerts numerous pharmacological benefits, including anti-inflammatory and antioxidant properties. It has received attention as a useful substance for the treatment of intractable pain, seizures, and anxiety, and related clinical trials have continued. However, the CBD pharmacokinetic results between reports are highly variable, making it difficult to clearly identify the pharmacokinetic properties of CBD. The main purpose of this study was to identify CBD clinical pharmacokinetic properties through meta-analysis. In particular, we sought to derive valid, interpretable independent variables and interpret their pharmacokinetic parameter correlations in relation to the large inter-individual and inter-study variability in CBD pharmacokinetics. For this study, CBD-related clinical trial reports were extensively screened and intercomparisons were performed between internal data sets through systematic classification and extraction of pharmacokinetic parameter values. The candidate independent variables associated with interpretation of CBD pharmacokinetic diversity established and explored in this study were as follows: diet, tetrahydrocannabinol (THC) combination, sample matrix type, liver and renal function, exposure route, dosage form, CBD exposure dose, cannabis smoking frequency, multiple exposure. The results of this study showed that CBD pharmacokinetics were influenced (increased plasma exposure by approximately 2–5 times) by diet immediately before or during CBD exposure, and that THC was not expected to have an antagonistic effect on the CBD absorption. The influence of changes in liver function would be significant in CBD pharmacokinetic diversity. Due to decreased liver function, the plasma exposure of CBD increased 2.57–5.15 times compared to healthy adults, and the half-life and clearance showed a 2.58-fold increase and a 5.15-fold decrease, respectively. CBD can be rapidly absorbed into the body (time to reach maximum concentration within 3.18 h) by oral, transdermal, and inhalation exposures, and lipid emulsification and nanoformulation of CBD will greatly improve CBD bioavailability (up to approximately 2 times). The pharmacokinetics of CBD generally follow linear kinetic characteristics. The importance of this study is that it suggests key factors that should be considered in terms of pharmacokinetics in further clinical trials and formulations of CBD in the future.
Graphical Abstract
... On the first day, participants believed they experienced symptoms each month, participants consumed their assigned dose daily for 5 consecutive days (given normal periods average between 2 and 7 days; Cleveland Clinic, 2022). Additionally, we encouraged participants to consume CBD with food high in fat to promote bioavailability (Mozaffari et al., 2021;Stott et al., 2013). In total, participants received 120 (160 mg) or 240 softgels (320 mg). ...
... Second, participants were not compensated for this study and to limit participant burden, the present study relied on individuals' self-reported consumption of CBD at prescribed doses and times; future work should consider verification of consumption using more rigorous verification method such as video confirmation of CBD consumption. Future work may also implement video confirmation of a provided high-fat snack to promote the bioavailability of CBD during consumption (Mozaffari et al., 2021;Stott et al., 2013). Third, the present study did not implement a placebo control. ...
Some individuals attempt to alleviate menstrual-related symptoms (MRS) by using cannabis and report having expectations that cannabis can improve MRS; however, no study has examined the effect of cannabinoids on MRS. The present study is a pre–post, randomized, open-label trial that aimed to examine the effects of oral cannabidiol (CBD) isolate for alleviating MRS. Participants were assigned randomly to one of two open-label dosing groups of CBD softgels (160 mg twice a day, BID, n = 17; 320 mg BID, n = 16) and completed a 1-month baseline period. Following baseline, participants were instructed to consume CBD starting the first day they believed they experienced symptoms each month and to take their assigned dose daily for 5 consecutive days for three CBD-consumption months. We examined differences in MRS and related outcomes between baseline and 3 months of CBD consumption. Results revealed reductions (in both dosing groups) in MRS, irritability, anxiety, global impression of change, stress, and subjective severity scores when comparing baseline to all 3 months of CBD consumption. Depression scores did not change in either dosing group. Findings suggest that CBD may have the potential for managing MRS. Importantly, changes in symptoms appeared in the first month of CBD consumption and persisted over the 3 consumption months. Further research is warranted comparing the effects of CBD to placebo (a limitation of the study) and examining the potential to optimize CBD consumption for reducing MRS (e.g., combining CBD with terpenes; varying routes and timing of administration).
... Specifically, we observed a higher C max and AUC 0-t across all the models for fed condition compared with fasted status, which is in line with within-study direct comparisons. 12,19,34,40 The lack of a significant effect of diet status on T max , is in line with two multiple-arm comprehensive studies, 19,34 but inconsistent with two other studies where T max was considerably longer in the fed group. 12,40 Although we would expect a significant effect of diet on AUC 0-inf , both theoretically and based on withinstudy comparisons, 19,34,40 we did not detect such an effect in our models. ...
... 12,19,34,40 The lack of a significant effect of diet status on T max , is in line with two multiple-arm comprehensive studies, 19,34 but inconsistent with two other studies where T max was considerably longer in the fed group. 12,40 Although we would expect a significant effect of diet on AUC 0-inf , both theoretically and based on withinstudy comparisons, 19,34,40 we did not detect such an effect in our models. This could in part be attributed to the lower number of studies that reported AUC 0-inf and thus lower power of these models. ...
Background: In this review, we provide an updated assessment of available evidence on the pharmacokinetics (PK) of CBD and explore the impact of different factors on PK outcomes. Materials and Methods: This systematic review and meta-regression analysis was preregistered (PROSPERO: CRD42021269857). We systematically searched Medline, Embase, PsycInfo, and Web of Science Core Collection up to November 19, 2022. Trials of CBD in healthy adults were included if they reported at least one of the PK parameters of interest, including Tmax, Cmax, AUC0-t, AUC0-inf, and T1/2, in serum or plasma. Studies of patient populations or CBD co-administration with other medications were excluded. The National Heart, Lung, and Blood Institute's Quality Assessment Tool for Before-After Studies with no Control Group was used. Random-effects multivariable meta-regression analysis was conducted. Results: A total of 112 trial arms from 39 studies were included; 26 trial arms had a "Good" quality, 70 "Fair," and 16 "Poor." Eight arms used inhalation CBD, 29 oromucosal, 73 oral, and 2 intravenous. CBD formulations could be categorized to nanotech (n=14), oil-based (n=21), alcohol-based (n=10), water-based (n=12), Sativex (n=17), and Epidiolex® (n=22). For single-dose studies, CBD doses ranged between 2 and 100 mg in inhalation, 5-50 mg in oromucosal, and 0.42-6000 mg in oral administration. Sixty-six trial arms had only male participants or a higher number of male than female participants. The duration of the PK session was between 4 and 164 h. A higher CBD dose was associated with higher Cmax, AUC0-t, and AUC0-inf. Compared with oral administration, oromucosal administration was associated with lower Cmax, AUC0-t, and AUC0-inf. Fed status was associated with higher Cmax and AUC0-t when compared with the fasting status. A higher ratio of female participants was associated with lower Tmax in oral administration and higher Cmax. Conclusion: As expected, CBD dose, route of administration, and diet were major determinants of CBD PK with oral routes providing higher bioavailability and nanotechnology formulations a faster onset. Although CBD appeared to have a faster onset and longer duration in women, more studies are required to delineate the role of biological sex. Factors that influence CBD PK have implications for medication development and appropriate dosing in clinical practice.
... With regard to bioavailability, an increase in the maximum concentration (in plasma) by a factor of one to three can be observed for dron abinol (administered as a spray) when a highfat diet is taken. 65 According to Stott et al. 65 this inter action seems to be clinically less relevant due to interindividual variability. Nevertheless, the doctor should recommend taking dronabinolcontaining drugs outside mealtimes in order to avoid possible fluctuations in effect. ...
... With regard to bioavailability, an increase in the maximum concentration (in plasma) by a factor of one to three can be observed for dron abinol (administered as a spray) when a highfat diet is taken. 65 According to Stott et al. 65 this inter action seems to be clinically less relevant due to interindividual variability. Nevertheless, the doctor should recommend taking dronabinolcontaining drugs outside mealtimes in order to avoid possible fluctuations in effect. ...
Background
Multiple sclerosis (MS) is the most common immune-mediated demyelinating disease in younger adults. Patients with MS (PwMS) are vulnerable to the presence of potential drug–drug interactions (pDDIs) and potential drug–food interactions (pDFIs) as they take numerous medications to treat MS, associated symptoms and comorbidities. Knowledge about pDDIs and pDFIs can increase treatment success and reduce side effects.
Objective
We aimed at determining the frequency and severity of pDDIs and pDFIs in PwMS, with regard to polypharmacy.
Methods
In the cross-sectional study, we analysed pDDIs and pDFIs of 627 PwMS aged ⩾18 years. Data collection was performed through patient record reviews, clinical examinations and structured patient interviews. pDDIs and pDFIs were identified using two DDI databases: Drugs.com Interactions Checker and Stockley’s Interactions Checker.
Results
We identified 2587 pDDIs (counted with repetitions). Of 627 PwMS, 408 (65.1%) had ⩾ 1 pDDI. Polypharmacy (concomitant use of ⩾ 5 drugs) was found for 334 patients (53.3%). Patients with polypharmacy (Pw/P) were found to have a 15-fold higher likelihood of having ⩾ 1 severe pDDI compared with patients without polypharmacy (Pw/oP) (OR: 14.920, p < 0.001). The most frequently recorded severe pDDI was between citalopram and fingolimod. Regarding pDFIs, ibuprofen and alcohol was the most frequent severe pDFI.
Conclusion
Pw/P were particularly at risk of severe pDDIs. Age and educational level were found to be factors associated with the occurrence of pDDIs, independent of the number of medications taken. Screening for pDDIs/pDFIs should be routinely done by the clinical physician to increase drug safety and reduce side effects.
... The single-dose half-life of THC and CBD is 2-3 h (Lunn et al. 2019;Millar et al. 2018;Stott et al. 2013); however, THC and CBD accumulate in tissues, especially adipose tissues, due to their lipophilicity, and after multiple doses, their half-life is 2-5 days (Millar et al. 2018;Huestis 2007). THC and CBD bind to blood cells and proteins and have a high apparent volume of distribution of 6.4 L/kg and 32 L/kg, respectively (Fasinu et al. 2016;Ohlsson et al. 1986). ...
... THC and CBD bind to blood cells and proteins and have a high apparent volume of distribution of 6.4 L/kg and 32 L/kg, respectively (Fasinu et al. 2016;Ohlsson et al. 1986). Administration of oral, sublingual and oro-buccal THC and/or CBD at therapeutic doses for chronic pain, stress, anxiety, and insomnia provide plasma THC and CBD levels in the order of 1-10 ng/ml for THC, and 1-30 ng/mL for CBD (Britch et al. 2021;Crippa et al. 2021;Guy and Flint 2004;Henson et al. 2021;Millar et al. 2018;Prieto González and Vila Silván 2021;Silmore et al. 2021;Stott et al. 2013;Torres-Moreno et al. 2018;Vitetta et al. 2021). ...
Combination tetrahydrocannabinol (THC)/cannabidiol (CBD) medicines or CBD-only medicines are prospective treatments for chronic pain, stress, anxiety, depression, and insomnia. THC and CBD increase signaling from cannabinoid receptors, which reduces synaptic transmission in parts of the central and peripheral nervous systems and reduces the secretion of inflammatory factors from immune and glial cells. The overall effect of adding CBD to THC medicines is to enhance the analgesic effect but counteract some of the adverse effects. There is substantial evidence for the effectiveness of THC/CBD combination medicines for chronic pain, especially neuropathic and nociplastic pain or pain with an inflammatory component. For CBD-only medication, there is substantial evidence for stress, moderate evidence for anxiety and insomnia, and minimal evidence for depression and pain. THC/CBD combination medicines have a good tolerability and safety profile relative to opioid analgesics and have negligible dependence and abuse potential; however, should be avoided in patients predisposed to depression, psychosis and suicide as these conditions appear to be exacerbated. Non-serious adverse events are usually dose-proportional, subject to tachyphylaxis and are rarely dose limiting when patients are commenced on a low dose with gradual up-titration. THC and CBD inhibit several Phase I and II metabolism enzymes, which increases the exposure to a wide range of drugs and appropriate care needs to be taken. Low-dose CBD that appears effective for chronic pain and mental health has good tolerability and safety, with few adverse effects and is appropriate as an initial treatment.
... As discussed previously, several studies have also been done concerning differences in absorption for cannabinoid oromucosal sprays in the fasted or fed state. Stott et al. (2013) studied the pharmacokinetic profile of Sativex oromucosal spray on 6 volunteer subjects who either fasted for 10 h pre-dose or were fed a standard high fat breakfast 30 minutes pre-dose. The pharmacokinetic profile demonstrated an enhanced 3-fold increase in Cmax for CBD and THC for the fed group, but Tmax was delayed from 1.5 h in fasted subjects to 4 h in fed subjects. ...
... Food components may also physically or chemically interact with a delivery system or drug. An example of this is co-administration of lipids with cannabinoids increasing the solubilization and transport into the lymphatic system (Stott et al. 2013). ...
Emulsions, hydrogels and emulgels have attracted a high interest as tools for the delivery of poorly soluble hydrophobic nutraceuticals by enhancing their stability and bioavailability. This review provides an overview of these delivery systems, their unique qualities and their interactions with the human gastrointestinal system. The modulation of the various delivery systems to enhance the bioavailability and modify the release profile of bioactive encapsulates is highlighted. The application of the delivery systems in the delivery of cannabinoids is also discussed. With the recent increase of cannabis legalization across North America, there is much interest in developing cannabis edibles which can provide a consistent dose of cannabinoids per portion with a rapid time of onset. Indeed, the long time of onset of psychoactive effects and varied metabolic responses to these products result in a high risk of severe intoxication due to overconsumption. Sophisticated emulsion or hydrogel-based delivery systems are one potential tool to achieve this goal. To date, there is a lack of evidence linking specific classes of delivery systems with their pharmacokinetic profiles in humans. More research is needed to directly compare different classes of delivery systems for the gastrointestinal delivery of cannabinoids.
... Oromucosal spray administration of doses ranging from 5 to 20 mg yields apparent plasma clearance (CL′) ranging from 2500 to 4700 L/h. 88,103,104 This decreases to 533 L/h for the same concentration range in a fed state. 103 In contrast, the mean elimination rate (K el ) does not change significantly between the fed and fasted states. ...
... 88,103,104 This decreases to 533 L/h for the same concentration range in a fed state. 103 In contrast, the mean elimination rate (K el ) does not change significantly between the fed and fasted states. There is some variation in elimination rate depending on the route of administration. ...
This Miniperspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labelled health products, and associated health claims, lack a rigorous scientific foundation. CBD's reputation as a cure-all puts it in the same class as other “natural” panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the “natural” label. Literature evidence associates CBD with certain semi-ubiquitous, broadly-screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.
... A total of nine published clinical reports focusing on pharmacokinetic cannabis-drug interactions were entered into the repository (Dalton et al., 1976;Jusko et al., 1978;Perez-Reyes et al., 1988;Kosel et al., 2002;Haney et al., 2003;Engels et al., 2007;Kleinloog et al., 2012;Stott et al., 2013;Manini et al., 2015). Only one study reported an interaction involving smoked Cannabis sativa, which was observed to increase the clearance of the CYP1A2 substrate theophylline (Jusko et al., 1978). ...
... Clinical pharmacokinetic interactions between cannabis and docetaxel, fentanyl, indinavir, irinotecan, nelfinavir, or secobarbital were not evident based on bioequivalence limits (Dalton et al., 1976;Kosel et al., 2002;Engels et al., 2007;Manini et al., 2015). One clinical study compared the plasma concentrations of THC and CBD under fasting and fed conditions (Stott et al., 2013), while another study reported estimated pharmacokinetic parameters for THC (Kleinloog et al., 2012). Figure 5 provides an overview of pharmacokinetic NPDI data for kratom from both NaPDI Center studies and peer-reviewed published reports. ...
There are many gaps in scientific knowledge about the clinical significance of pharmacokinetic natural product–drug interactions (NPDIs) in which the natural product (NP) is the precipitant and a conventional drug is the object. The National Center for Complimentary and Integrative Health created the Center of Excellence for NPDI Research (NaPDI Center) (www.napdi.org) to provide leadership and guidance on the study of pharmacokinetic NPDIs. A key contribution of the Center is the first user-friendly online repository that stores and links pharmacokinetic NPDI data across chemical characterization, metabolomics analyses, and pharmacokinetic in vitro and clinical experiments (repo.napdi.org). The design is expected to help researchers more easily arrive at a complete understanding of pharmacokinetic NPDI research on a particular NP. The repository will also facilitate multidisciplinary collaborations, as the repository links all of the experimental data for a given NP across the study types. The current work describes the design of the repository, standard operating procedures used to enter data, and pharmacokinetic NPDI data that have been entered to date. To illustrate the usefulness of the NaPDI Center repository, more details on two high-priority NPs, cannabis and kratom, are provided as case studies.
SIGNIFICANCE STATEMENT
The data and knowledge resulting from natural product–drug interaction (NPDI) studies is distributed across a variety of information sources, rendering difficulties to find, access, and reuse. The Center of Excellence for NPDI Research addressed these difficulties by developing the first user-friendly online repository that stores data from in vitro and clinical pharmacokinetic NPDI experiments and links them with study data from chemical characterization and metabolomics analyses of natural products that are also stored in the repository.
... However, food can increase the AUC for THC and CBD in Sativex approximately 3-and 5-fold, respectively; and the intersubject variability for AUC after 4 sprays of Sativex can be up to 8-fold for THC and 11-fold for CBD. 22,40 In addition, other studies with Sativex found high intersubject variability with resulting high standard deviations for AUC. 41 In our study, the intersubject variability was high in all groups, where AUC varied with up to a factor 18 for AUC CBD in the controls. ...
Introduction
Chronic kidney disease (CKD) affects approximately 10% of the global population and is associated with a large symptom burden. Medicinal cannabis is advised against in patients with severe CKD. However, pharmacokinetic and pharmacodynamic knowledge regarding their use in patients with CKD is lacking.
Methods
We aimed to investigate the pharmacokinetics and side effects of a single dose of Sativex, corresponding to 5.4 mg Δ⁹-tetrahydrocannabinol (THC) and 5 mg cannabidiol (CBD), in patients with CKD stages 4 and 5 compared with healthy volunteers (controls). The study was a nonrandomized and unblinded clinical study.
Results
Twenty controls and 29 patients with CKD completed the study. The area under the curve (AUC) for THC (median [interquartile range]) was 2.76 (1.77–3.48), 4.16 (3.35–5.28), and 4.31 (3.16–5.42) h × ng/ml for controls, and for patients with CKD stages 4 and 5, respectively, with significant differences between patients with CKD and controls. AUC for CBD and metabolites, and other pharmacokinetic parameters, such as maximum concentration (Cmax) and excretion of metabolites in urine were also significantly different between patients with CKD and controls. After 1.5 hours, numeric rating scale (NRS) scores for dizziness were significantly higher for each CKD group compared with controls (mean NRSscores: 0.7 and 1.5 vs. 0.1).
Conclusion
Total exposure to THC, CBD, and metabolites was higher in patients with CKD stages 4 and 5 compared with controls, and side effects may be more pronounced; however, the intersubject variability was high. If cannabis products are administered to patients with severe CKD, caution is needed.
... Oral THC absorption is highly influenced by food, particularly by a high fat meal, which can slow gastric emptying and reduce THC metabolism to the 11-OH-THC metabolite. [60][61][62] THC taken with food may be better tolerated than under fasted conditions, as one study observed a greater number of AEs after 10 mg THC administered under fasted conditions compared with the fed state. 60 The differing food conditions in the studies we evaluated may have contributed to the extensive PK variability observed, and also affected tolerability. ...
Background: Δ9-tetrahydrocannabinol (THC), the primary intoxicating compound in cannabis, has been tested extensively in controlled administration human studies. Some studies require a high THC dose that may induce adverse events (AEs), such as those testing novel treatments for cannabinoid overdose. Although there are ethical concerns related to administering high THC doses, there is no systematic analysis on studies utilizing these doses. In this review, we examine studies that administered oral THC doses ≥30 mg ("high-dose THC"), focusing on reported tolerability, subjective effects, and pharmacokinetics (PK), with the objective to inform the design of future studies. Methods: A comprehensive PubMed search was performed to identify studies meeting pre-specified criteria. Results: Our search identified 27 publications from 17 high-dose oral THC laboratory studies, with single doses up to 90 mg and multiple doses up to 210 mg per day. The maximum plasma THC concentration (Cmax) appeared to increase in a dose-proportional manner over this dose range. All high-dose THC studies enrolled participants with previous cannabis experience, although current use ranged from nonusers to regular cannabis users. High-dose THC was generally well tolerated with transient mild to moderate AE, including nausea and vomiting, anxiety, paranoia, and sedation. There were occasional participant withdrawals due to AEs, but there were no serious AE. Participants with frequent cannabis use tolerated high-dose THC best. Conclusion: Although based on limited data, THC was generally adequately tolerated with single oral doses of at least 50 mg in a controlled laboratory setting in healthy participants with past cannabis experience.
... Another approach to improving the therapeutic potential of CBD involves exploring different methods of administration. For example, aerosolized CBD has been shown to have a bioavailability of 31%, making it a potentially effective method of delivery (Stott et al., 2013;Chayasirisobhon, 2020). Finally, genetic engineering can be used to create strains of the cannabis plant with high CBD content, which is key to ensuring a consistent supply of CBD for production (Luo et al., 2019). ...
Cannabidiol (CBD) is a naturally occurring non-psychoactive cannabinoid found in Cannabis sativa, commonly known as cannabis or hemp. Although currently available CBD products do not meet the safety standards of most food safety authorities to be approved as a dietary supplement or food additive, CBD has been gaining widespread attention in recent years due to its various potential health benefits. While primarily known for its therapeutic effects in managing epileptic seizures, psychosis, anxiety, (neuropathic) pain, and inflammation, CBD’s influence on brain function has also piqued the interest of researchers and individuals seeking to enhance cognitive performance. The primary objective of this review is to gather, synthesize, and consolidate scientifically proven evidence on the impact of CBD on brain function and its therapeutic significance in treating neurological and mental disorders. First, basic background information on CBD, including its biomolecular properties and mechanisms of action is presented. Next, evidence for CBD effects in the human brain is provided followed by a discussion on the potential implications of CBD as a neurotherapeutic agent. The potential effectiveness of CBD in reducing chronic pain is considered but also in reducing the symptoms of various brain disorders such as epilepsy, Alzheimer’s, Huntington’s and Parkinson’s disease. Additionally, the implications of using CBD to manage psychiatric conditions such as psychosis, anxiety and fear, depression, and substance use disorders are explored. An overview of the beneficial effects of CBD on aspects of human behavior, such as sleep, motor control, cognition and memory, is then provided. As CBD products remain largely unregulated, it is crucial to address the ethical concerns associated with their use, including product quality, consistency, and safety. Therefore, this review discusses the need for responsible research and regulation of CBD to ensure its safety and efficacy as a therapeutic agent for brain disorders or to stimulate behavioral and cognitive abilities of healthy individuals.
... However, CBD shows poor bioavailability and a variable pharmacokinetic profile across individuals. The delivery of CBD can be influenced by numerous factors including route of administration, CBD formulation, food intake, as well as natural inter-and intra-individual variation [7][8][9]. Therefore, quantitation of blood CBD concentrations is paramount to the effective interpretation of CBD administration for both medicinal and research purposes, and is necessary to help establish therapeutic concentration ranges when used as a prescribed drug. The assessment of blood CBD is also important to evaluate abstinence from, or adherence to, prohibited or prescribed treatments in patients and research participants alike. ...
... Participants received the study product in the morning after a standardized high-fat, high-calorie breakfast (e.g., two eggs fried in butter, 4 oz hashbrowns, two strips of bacon, 8 oz whole milk) to improve the bioavailability of the cannabinoid. [26][27][28][29][30] During dosing of active THCV, participants received water in addition to the study product, coadministered with an oral syringe, to create equivalence across doses with respect to volume of liquid administered (5 mL). During dosing of placebo, participants received a mixture of placebo MCT oil and water coadministered with syringes, to closely mimic the ratio of oil and water in the active doses, and thus preserve the blind in phase 2. ...
Introduction: Tetrahydrocannabivarin (THCV) is an understudied cannabinoid that appears to have effects that vary as a function of dose. No human study has evaluated the safety and nature of effects in a wide range of THCV doses.
Methods: This was a two-phase, dose-ranging, placebo-controlled trial of the Δ8 isomer of oral THCV in healthy adults. Phase 1 utilized an unblinded, single-ascending dose design (n=3). Phase 2 used a double-blind, randomized, within-participant crossover design (n=18). Participants received single acute doses of placebo and 12.5, 25, 50, 100, and 200 mg of THCV. Safety measures and subjective and cognitive effects were assessed predose and up to 8 h postdose.
Results: Most adverse events (AEs; 55/60) were mild. Euphoric mood was the most common AE. The 12.5, 25, and 200 mg doses produced significantly lower minimum times to complete the digit vigilance test (ps=0.01). The 25 mg dose showed elevations on mean ratings of “energetic” at 1-, 2-, and 4-h postdose, but the maximum postdose rating for this dose did not achieve statistical significance relative to placebo ([95% confidence interval]=3.2 [−0.5 to 6.9], p=0.116). The 100 and 200 mg doses showed elevations on ratings of “feel a drug effect” and “like the drug effect.” Almost all urine drug screens (78/79) at 8 h postdose in the active THCV conditions tested positive for tetrahydrocannabinol (THC).
Conclusion: All THCV doses displayed a favorable safety profile. Several THCV doses showed a preliminary signal for improved sustained attention, but the effect was not dose dependent. Though mild and not associated with impairment, THC-like effects were observed at higher THCV doses. Oral THCV-containing products could lead to positive urine drug screens for THC. ClinicalTrials.gov ID: NCT05210634.
... Future work should aim to replicate these findings in a larger, more diverse sample. Finally, CBD's bioavailability is impacted by the presence of high-fat foods (e.g., peanut butter, cheese; Stott et al. 2013). Therefore, Content courtesy of Springer Nature, terms of use apply. ...
Rationale
Evidence suggests cannabidiol (CBD) displays broad therapeutic potential in the context of anxiety; however, no study has examined the effects of CBD on worry, a defining, cognitive feature of anxiety. Additionally, no study has examined the effects of an acute, single dose of CBD compared to repeated CBD administration.
Objectives
Within a sample of 63 individuals with elevated trait worry, the current study aimed to assess the effects of an empirically-derived high dose of CBD (i.e., 300mg) compared to a commercially-derived dose of CBD (i.e., 50mg) versus placebo on worry severity and anxiety symptoms after an acute dose and after a 2-week administration period.
Results
Results indicated no effect of acute CBD dosing on worry severity or anxiety symptoms. Repeated CBD administration similarly did not impact worry severity; however, 300mg of CBD reduced anxiety symptoms across the 2-week administration period compared to placebo.
Conclusions
Taken together, these findings suggest 300mg of oral CBD does not attenuate cognitive symptoms of anxiety (i.e., worry), following both acute and repeated administration. Some evidence for repeated administration of 300mg on physical symptoms of anxiety was obtained. Findings from the current study suggest CBD’s modest anxiolytic effects may be specific to the physical aspects of anxious arousal.
... It is also largely unknown if those who use oral cannabis products hold beliefs on how to mitigate unwanted effects and, if so, what advice they received and from where. Finally, while previous studies suggest that product formulation and use-behaviors may influence the acute effects of oral cannabis products (Bergeria et al., 2022;Crockett et al., 2020;Lunn et al., 2019;McClements, 2020;Peng and Shahidi, 2021;Spindle et al., 2020;Stott et al., 2013a;Trevaskis et al., 2009;Zgair et al., 2016), few studies have been conducted to understand if such factors impact perceived effects among oral cannabis product-experienced individuals. Because controlled studies generally utilize methodology that may not reflect how these products are consumed in the natural environment (e.g., providing standardized meals), perceived effects are an important component for further examination. ...
Background:
Cannabis-infused products available for oral consumption include food and drink items (i.e., edibles) (e.g., baked goods, gummy-, chocolate-, and hard-candies, beverages/drinks) as well as non-food formulations (e.g., oils/tinctures, pills/capsules). This study characterized the motives, opinions, and subjective experiences associated with the use of these seven subtypes of oral cannabis products.
Methods:
This web-based survey collected cross-sectional, self-report data from a convenience sample of 370 adults regarding various use-motives, self-reported cannabinoid content, subjective experiences, and opinions related to ingesting oral cannabis products with alcohol and/or food. Advice participants had received about modifying oral cannabis product effects, in general, was also collected.
Results:
Participants reported consuming cannabis baked goods and gummy candies most frequently over the past year (68% and 63%, respectively). Participants were less likely to use oils/tinctures for enjoyment/desire relative to other product types and more likely to use oils/tinctures for therapeutic purposes (e.g., medication-replacement). Self-reported cannabinoid content was highly variable across participants and within product subtype. Participants reported feeling stronger and longer-lasting effects when consuming oral cannabis products on an empty stomach and 43% received advice to "eat a snack or meal" to mitigate effects that are too strong, which contrasts with controlled studies. Finally, 43% of participants reported modifying their experiences with alcohol at least some of time.
Conclusions:
These findings underscore the need to further evaluate use-motives as well as the interaction between dietary factors, cannabinoid pharmacokinetics, and subjective drug effects and the interactive effects of oral cannabis products and alcohol in a controlled laboratory setting.
... In a human study, the administration of CBD with a high-fat meal, resulted in Cmax and AUC over 4 times greater than in fasted condition (25). It is believed that food enhances the absorption of lipophilic drugs by increasing their permanence in the gastrointestinal tract, their solubilization and their lymphatic transport by lymph lipoproteins (26). Deabold et al. (10), suggested that the same phenomena might incur in dogs, where the administration of CBD formulated as soft chew, considered a food matrix, resulted in Cmax and AUC about 3 times greater than that observed in a previous published study performed with CBD oil (4). ...
Introduction
In the last few years, different formulations containing cannabidiol (CBD) were tested with regard to its efficacy on chronic pain, refractory epilepsy, anxiety, aggressive behavior and atopic dermatitis in dogs. CBD is generally administered orally, but its low bioavailability, probably due to a first-pass metabolism, represents a great limitation. The aim of this study was to evaluate if CBD bioavailability increases after oral transmucosal administration (OTM) compared to oral treatment.
Methods
Twelve dogs diagnosed with mild chronic pain were enrolled in the study and treated once orally or OTM (6 dogs/group) with a pure CBD in oil formulation at a dosing rate of 1 mg/kg b.w. At prefixed time points, blood samples were collected to define CBD plasma concentrations vs. time profiles, and the main pharmacokinetics parameters were obtained by non-compartmental model.
Results
CBD Cmax, Tmax, terminal half-life and AUC0 − t were 206.77 ± 167 and 200.33 ± 158.33 ng/mL, 2.17 ± 0.98 and 1.92 ± 1.11 h, 2.67 ± 0.53 and 2.62 ± 0.64 h, 647.51 ± 453.17, and 536.05 ± 370.21 h*ng/mL, following oral and OTM administration, respectively. No significant difference in pharmacokinetic parameters were observed between treatments.
Discussion
The OTM administration did not increase cannabidiol bioavailability compared to oral treatment. The almost perfectly superimposable mean plasma concentrations of cannabidiol following the two treatments suggests that CBD is not able to be adsorbed by the oral mucosa or that its absorption is very scarce, and that CBD is swallowed and absorbed in the gastrointestinal tract.
... Inhaled cannabinoids are rapidly absorbed in the bloodstream. Gastrointestinal absorption is irregular, causing low bioavailability and poor pharmacokinetic profile, although it can be increased with food [137]. This is a limitation for using cannabis in oral formulations [119]. ...
In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented.
... When orally ingested, there are a number of factors that influence the degree to which CBD can pass from the digestive system to the blood. Research suggests eating high fat foods around the time of dosing increases the bioavailability of CBD (Stott, White, Wright, Wilbraham, & Guy, 2013). Standardizing the amount of food and fat content can be an important method for controlling the bioavailability of CBD. ...
Empirical evidence continues to accumulate suggesting cannabidiol (CBD) may have potential as an anxiolytic. Yet, research in the area is insufficient to support strong inferences. Accordingly, there is a need for additional empirical investigation. Research on the effects of CBD and anxiety requires a working knowledge of both. Understanding of contemporary CBD and anxiety research methods is critical to safely and convincingly test predictions regarding potential anxiolytic effects of CBD. The current paper outlines major design, methods, and safety considerations pertinent both to CBD administration and measuring effects on anxiety outcomes in order to facilitate needed research in this domain.
... One of the variability examples includes the food effect for oral administration (Figure 10.3). 75 Best practices in studying clinical pharmacology are highly relevant to cannabis product development and should be applied to produce better outcomes and higher satisfaction for customers using these products. Cannabis sativa is one of the oldest plants known to mankind. ...
The cannabis industry is unique in many facets, most of them products of history. Cannabis has been prevalent in society for millennia, but for the period between 1937 and 1997 prohibition was imposed in the United States stifling research and creating an unregulated market. From 1997 to present, starting with California, there has been a wave of state-by-state legalizations. Each of these states has individual regulations that operators must comply with. For those working with hemp (cannabis containing less than 0.3% THC by dry weight), there is an entirely different framework of federal regulations. As an unfortunate consequence of this history, the science of cannabis along with the safety culture are relatively unevolved compared with other modern industries. In 2015, the Cannabis Chemistry Subdivision (CANN) of the division of Chemical Health and Safety (CHAS) was recognized by the America Chemical Society (ACS). Since its inception, CANN symposia at ACS National Meetings have served as the premiere venue for cannabis chemists and scientists to share their research, much of it related to improving the health and safety culture in the industry. This proceedings publication highlights 16 presentations that were given at CANN symposia during the Fall 2020 ACS National Meeting. Topics covered include analytical testing methods, consumer education and protection, formulation science, intellectual property considerations, best practices for pharmacokinetics and dosing studies, assessment of smoke exposure, and more.
... A potential method to increase oral bioavailability is to administer CBD alongside a highfat/high-calorie meal [16]. This has been demonstrated in healthy subjects with about four-fold increases in bioavailability compared to fasted, and in adult patients with refractory epilepsy with four-and fourteen-fold increases in area under the curve (AUC) and Cmax, respectively, in the fed state compared to fasted [18][19][20]. This is likely due to increased micelle and chylomicron formation making more drugs available for lymphatic transport [21,22]. ...
Cannabidiol (CBD) has substantial therapeutic potential, but its development as an effective drug by the pharmaceutical industry is hindered by intrinsic characteristics such as low bioavailability, low water solubility, and variable pharmacokinetic profiles. Importantly, lack of patentability of the drug substance also limits the likelihood of an expensive, full development programme in anything other than orphan indications. Potential avenues to overcome these issues with CBD include self-emulsifying drug delivery systems, improved crystal formulations and other solid-state delivery formulations, which are mostly in the pre-clinical or early clinical stages of development. This review identifies issues compromising current delivery of solid-state CBD, and how advanced pharmaceutical development strategies can enable CBD to realise the full potential as a successful therapeutic agent.
... The absorption of CBD administered by smoking, vaporization, buccal spray, or oral ingestion is highly variable and results in extremely inconsistent pharmacokinetic profiles when investigated. 21,39,42,44,52 Cannabidiol also shows limited oral bioavailability due to poor aqueous solubility and extensive first-pass metabolism. 22,41,55 Although the current study did not assess pharmacokinetic parameters among canine study participants, the effect of liposomal CBD on LPS-induced TNF-a production in mice provides an objective measure of its pharmacodynamic drug action and suggests a greater Copyright © 2020 by the International Association for the Study of Pain. ...
Over the last two decades, affirmative diagnoses of osteoarthritis in the United States have tripled due to increasing rates of obesity and an aging population. Hemp-derived cannabidiol (CBD) is the major non-THC component of cannabis and has been promoted as a potential treatment for a wide variety of disparate inflammatory conditions. Here we evaluated CBD for its ability to modulate the production of pro-inflammatory cytokines in vitro and in murine models of induced inflammation and further validated the ability of a liposomal formulation to increase bioavailability in mice and in humans. Subsequently, the therapeutic potential of both naked and liposomally-encapsulated CBD was explored in a 4-week, randomized placebo-controlled, double-blinded study in a spontaneous canine model of osteoarthritis. In vitro and in mouse models, CBD significantly attenuated the production of pro-inflammatory cytokines IL-6 and TNF-α while elevating levels of anti-inflammatory IL-10. In the veterinary study, CBD significantly decreased pain and increased mobility in a dose-dependent fashion among animals with an affirmative diagnosis of osteoarthritis. Liposomal CBD (20 mg/day) was as effective as the highest dose of non-liposomal CBD (50 mg/day) in improving clinical outcomes. Hematocrit, comprehensive metabolic profile, and clinical chemistry indicated no significant detrimental impact of CBD administration over the four-week analysis period. This study supports the safety and therapeutic potential of hemp-derived CBD for relieving arthritic pain and suggests follow-up investigations in humans is warranted.
... 11 The high variability in the PK of CBD and its metabolites in this trial is common with other cannabinoids. [11][12][13][14]23,24 During validation of the bioanalytical method to quantify CBD and metabolite plasma concentrations, recovery of CBD was low at 45.4%-48.8%; however, recovery levels were consistent across the assay range and sufficient to achieve adequate method sensitivity. ...
Objective
The pharmacokinetics (PK) and safety of single oral 750‐mg doses of a plant‐derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the USA and Epidyolex in Europe; 100‐mg/mL oral solution) were assessed in healthy adults following a high‐fat/calorie meal (n = 15), a low‐fat/calorie meal (n = 14), whole milk (n = 15), or alcohol (n = 14), relative to the fasted state (n = 29).
Methods
Blood samples were collected until 96 hours postdose in each period and evaluated by liquid chromatography and tandem mass spectrometry. PK parameters (maximum observed plasma concentration [Cmax], area under the plasma concentration‐time curve from time zero to the last observed quantifiable concentration, area under the concentration‐time curve from time zero to infinity [AUC0‐∞], and time to maximum plasma concentration [tmax]) of CBD and its major metabolites were derived using noncompartmental analysis.
Results
CBD exposure increased by 3.8‐fold for AUC0‐∞ and 5.2‐fold for Cmax when CBD was administered with a high‐fat/calorie meal versus fasted. To a lesser extent, a low‐fat/calorie meal enhanced CBD exposure versus fasted with a 2.7‐fold increase in AUC0‐∞ and a 3.8‐fold increase in Cmax. Similarly, when dosed with whole milk, CBD exposure increased versus fasted by 2.4‐fold for AUC0‐∞ and 3.1‐fold for Cmax. Modest elevations in CBD exposure occurred when it was dosed with alcohol: 1.6‐fold for AUC0‐∞ and 1.9‐fold for Cmax. No clinically relevant effect of any test condition on CBD tmax or t½ versus the fasted state was apparent. The same trend was seen for the CBD metabolites, except that 7‐carboxy‐cannabidiol tmax was considerably longer when CBD was administered with alcohol (14 vs 4 hours fasted). Inter‐ and intrasubject variability in PK parameters was moderate to high during the trial.
Significance
CBD and metabolite exposures were most affected by a high‐fat/calorie meal. CBD exposures also increased with a low‐fat/calorie meal, whole milk, or alcohol, but to a lesser extent. CBD was tolerated, and there were no severe or serious adverse events during the trial.
... After reviewing the literature on the topic of pharmacokinetics (PK) of cannabinoids after delivery by Sativex® spray, we encountered an interesting discrepancy. It was clearly shown by Stott et al. [6] (authors affiliated with GW Pharmaceuticals) that PK of cannabinoids delivered by Sativex® is different when administered to fasting subjects compared to ones that were fed. This finding seems rather strange, as food intake before oro-mucosal administration of the medicine should not influence its PK. ...
Introduction: Sativex® spray is clinically utilized to deliver delta9-tetrahydrocannabinol and cannabidiol to oral mucosa for systemic absorption. We challenge the consensus that the mechanism of absorption following the oro-mucosal application occurs via the buccal tissue.
Areas covered: Correctness of the consensus of this absorption pathway arose when reviewing publications regarding the influence fed versus fasting states have on pharmacokinetics of these cannabinoids administered to oral mucosa. This finding is more suitable for per oral administration, where stomach content affects the absorption profile. We hypothesize that these cannabinoids are ingested and absorbed in the gastro-intestinal tract.
Expert opinion: Although clinical importance of Sativex® is not disputed, the wide acceptance of its being a successful example of drug delivery through oral mucosa is questionable. Sativex® acts as example for other drugs delivered to oral mucosa for systemic absorption and unintentionally washed by the saliva flow into the gastro-intestinal tract. Delivery of each medicine through oral mucosa should be validated in-vivo to ensure this route to be the predominant one. Revealing the underlying absorption mechanisms would enable predicting the impact of different physiological parameters such as saliva flow and fed/fasting states on the pharmacokinetics of the delivered medication.
... Interperson variability in oral THC absorption is considerable (8), which also contributes to the unpredictability of drug effects and adverse outcomes. Some of this is due to the fat content of food ingested when THC is consumed. ...
Background
Depression is a prevalent and disabling disorder that poses serious problems in mental health care, and rapid antidepressants are novel treatments for this disorder. Cannabidiol (CBD), a non-intoxicating phytocannabinoid, is thought to have therapeutic potential due to its important neurological and anti-inflammatory properties. Despite major advances in pharmacotherapy in experimental animals, the exact mechanism of antidepressant-like effects remains to be elucidated.
Methods
In this paper, we review the current state of knowledge on the antidepressant properties of CBD in numerous experimental and clinical studies.
Results
Accumulating evidence suggests that CBD has antidepressant properties in humans and animals with few side effects, suggesting that CBD may be a potential antidepressant. Furthermore, we discuss CBD may therefore provide a potential treatment to exert antidepressant-like effects through various molecular targets, reducing inflammation, and enhancing neurogenesis.
Conclusions
Taken together with the growing popularity of CBD as a medicine, these findings extend the limited knowledge on the antidepressant effects of CBD. This potentially opens up new therapeutic means for the patients with depression.
The poor physicochemical properties of cannabidiol (CBD) hamper its clinical development. The aim of this review was to examine the literature to identify novel oral products and delivery strategies for CBD, while assessing their clinical implications and translatability. Evaluation of the published literature revealed that oral CBD strategies are primarily focused on lipid-based and emulsion solutions or encapsulations, which improve the overall pharmacokinetics (PK) of CBD. Some emulsion formulations demonstrate more rapid systemic delivery. Variability in the PK effects of different oral CBD products is apparent across species. Several novel administration routes exist for CBD delivery that may offer promise for specific indications. For example, intranasal administration and inhalation allow quick delivery of CBD to the plasma and the brain, whereas transdermal and transmucosal administration routes deliver CBD systemically more slowly. There are limited but promising data on novel delivery routes such as intramuscular and subcutaneous. Very limited data show that CBD is generally well distributed across tissues and that some CBD products enable increased delivery of CBD to different brain regions. However, evidence is limited regarding whether changes in CBD PK profiles and tissue distribution equate to superior therapeutic efficacy across indications and whether specific CBD products might be suited to particular indications.
Background:
Cannabinoid-containing products are marketed to athletes as promoting recovery, in spite of a lack of data on their safety and effects. This randomized, double-blind, placebo-controlled, repeated-dose pilot study tested the safety, tolerability, and preliminary effects on recovery of a formulation containing cannabidiol (CBD; 35 mg), cannabigerol (CBG; 50 mg), beta caryophyllene (BCP; 25 mg), branched-chain amino acids (BCAAs; 3.8 g), and magnesium citrate (420 mg).
Methods:
Exercise-trained individuals (N = 40) underwent an experimental induction of delayed onset muscle soreness (DOMS) and completed follow-up visits 24-, 48-, and 72-hours post-DOMS. Participants were randomized to active or placebo formulation, and consumed the formulation twice per day for 3.5 days.
Results:
There was one adverse event (AE) in the active group (diarrhea) and two AEs in placebo (dry mouth; eye rash/swollen eye). There was 100% self-reported compliance with formulation consumption across the two groups. For the primary outcome of interest, the estimate of effect for ratings of average soreness/discomfort 72 hours post-DOMS between active and placebo groups was -1.33 (85% confidence interval = -2.55, -0.10), suggesting moderate evidence of a treatment difference. The estimate of effect for the outcome of ratings of interference of soreness, discomfort, or stiffness on daily activities at work or home 48 hours post-DOMS was -1.82 (95% confidence interval = -3.64, -0.01), indicating a treatment difference of potential clinical importance. There was no significant effect between active and placebo groups on objective measures of recovery, sleep quality, or mood disturbance.
Conclusions:
The tested formulation reduced interference of DOMS on daily activities, demonstrating its improvement on a functional aspect of recovery.
Introduction: Cannabidiol (CBD) is a nonintoxicating phytocannabinoid used in clinical treatments and sold widely in consumer products. CBD products may be designed for sublingual or oral delivery, but it is unclear whether either is advantageous for CBD absorption. This study compared CBD pharmacokinetics after providing CBD oil as sublingual drops and within orally ingested gelatin capsules, at a dose relevant to consumer products.
Materials and Methods: Eight males completed three conditions in a participant-blinded, randomized crossover design. Participants received the following combinations of placebo and CBD-containing (69 mg/mL) hemp oil in capsules and as sublingual drops: placebo capsules/placebo drops (Placebo), CBD capsules/placebo drops (CBD-Caps), and placebo capsules/CBD drops (CBD-Drops). Blood samples, blood pressure, and subjective scales were obtained/completed hourly for 6 h and at 24 h.
Discussion: Plasma CBD concentrations were not different between CBD-Caps and CBD-Drops (interaction effect p=0.76). Peak CBD concentration (28.0±15.6 vs. 24.0±22.2 ng/mL), time of peak CBD concentration (4±1 vs. 4±2 h), and area under the concentration curve (45.3±20.3 vs. 41.8±23.3 ng/mL·6 h) were not different between conditions (p≥0.25). Cardiometabolic outcomes (plasma glucose/triacylglycerol, heart rate, blood pressure), liver function (plasma alanine aminotransferase/aspartate aminotransferase), kidney function (plasma creatinine), and subjective feelings/symptoms were not different between conditions (p≥0.07).
Conclusions: Plasma CBD profiles were comparable between CBD-Caps and CBD-Drops, suggesting that there were not meaningful differences in routes of CBD absorption between conditions. This implies that CBD oil delivered sublingually is swallowed before oral mucosal CBD absorption occurs, which may have implications for research design, CBD product design, and consumer product choice.
Background:
Little is known about the distribution of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) to patients participating in state medical cannabis programs. The Minnesota cannabis program requires third-party testing of products with limited formulations of cannabis for distribution to patients.
Objective:
To characterize the distribution of cannabis products, their CBD/THC content, and dosing among patients with qualifying conditions.
Methods:
This is a retrospective analysis of ∼50% of registered users receiving medical cannabis in Minnesota (June 16, 2016, to November 15, 2019). Data included formulation, CBD/THC prescribed doses, and qualifying conditions. The primary end points were calculated using daily dose and duration of use. Comparisons were made for CBD and THC total daily dose dispensed, patient age, and approved product. Nonparametric statistical tests were used (significance was set at p < 0.05).
Results:
A total of 11,520 patients were listed with 1 qualifying condition. The most common condition was intractable pain (60.0%). Median dispensation duration varied from 53 days (cancer) to 322 days (muscle spasms). Most (≥62.8%) patients across all qualifying conditions received both CBD and THC. Median THC dose was lower in older (≥65 years) compared with younger adults with intractable pain (p < 0.0001) and cancer patients (p = 0.0152), and the same pattern was found CBD dose with seizure (p = 0.0498) patients. For commercial products with Food and Drug Administration indications, the median CBD total daily dose was 86.9% lower than the recommended doses for patients with seizures (Epidiolex: Jazz Pharmaceuticals, Palo Alto CA) and median THC total daily dose was 65.3% (Syndros: Benuvia Manufacturing, Round Rock, TX) or 79.3% lower (Marinol: Banner Pharmacaps, Inc., High Point, NC) for cancer patients.
Conclusions:
A majority of patients received products containing both CBD and THC. Dosages varied by age group and were lower than recommended for conditions with Food and Drug Administration-approved products. Complex pharmacokinetics of THC and CBD, possible age-related changes in physiology, unknown efficacy, and potential for drug interactions all increase the need for monitoring of patients receiving cannabis products. (Curr Ther Res Clin Exp. 2023; 84:XXX-XXX).
Background: Detecting the presence of Δ9-THC and CBD is mainly done through venous blood sampling, but other methods are becoming available. Oromucosal administration of Δ9-THC and CBD is less studied than inhalation, but this mode of administration is growing. In this study, we analyze samples obtained through invasive and noninvasive methods in a cohort of patients given oromucosally administered Δ9-THC and CBD to gain understanding in the strengths and weaknesses of the various detection methods. Materials and Methods: Blood, oral fluid (OF), exhaled breath, and urine were collected at several time points from 23 cannabis-naive patients after receiving a single dose of Sativex®; dose ranges: Δ9-THC, 2.7-18.9 mg; CBD 2.5-17.5 mg. Detection of Δ9-THC and CBD was done using liquid chromatography-mass spectrometry methods. Results: Δ9-THC and CBD were present in plasma, OF, and exhaled breath in all 23 patients. The detection time of Δ9-THC and CBD in OF and exhaled breath was longer than in blood. Urine analysis detected the Δ9-THC carboxy metabolite (THC-COOH) up to 7 days after administration, also in a patient who received 8.1/7.5 mg Δ9-THC/CBD. Conclusion: Time to detection of cannabinoids in blood samples was shorter than in exhaled breath and OF. Relative ease of sample collection combined with high sensitivity makes OF and exhaled breath specimens a valuable addition when samples are handled correctly. Δ9-THC metabolites were detected for an unexpected long period of time in urine. EudraCT Number: 2014-005553-39. Date of registration, December 29, 2015.
Objective:
To determine the pharmacokinetics of 8 cannabinoids and 5 metabolites after oral administration of single and multiple doses of a cannabidiol (CBD)-cannabidiolic acid (CBDA)-rich hemp extract to orange-winged Amazon parrots (Amazona amazonica) as well as to evaluate the extract's adverse effects.
Animals:
12 birds.
Procedures:
Based on pilot studies, a single-dose study based on 30/32.5 mg/kg of cannabidiol/cannabidiolic acid of a hemp extract was administered orally to 8 fasted parrots, and 10 blood samples were collected over 24 hours after administration. After a 4-week washout period, the hemp extract was administered orally to 7 birds at the previous dose every 12 hours for 7 days, and blood samples were collected at the previous time points. Cannabidiol, Δ9-tetrahydrocannabinol, cannabinol, cannabichromene, cannabigerol, cannabidiolic acid, cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, and 5 specific metabolites were measured by liquid chromatography-tandem/mass-spectrometry, and pharmacokinetic parameters were calculated. Adverse effects and changes in the plasma biochemistry and lipid panels were evaluated.
Results:
Pharmacokinetic parameters for cannabidiol, cannabidiolic acid, Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabinolic acid, and the metabolite 11-hydroxy-9-tetrahydrocannabinol were established. For the multiple-dose study, cannabidiol/cannabidiolic acid mean Cmax was 337.4/602.1 ng/mL with a tmax of 30 minutes and a terminal half-life of 8.6/6.29 hours, respectively. No adverse effects were detected during the multidose study. The predominant metabolite was 11-hydroxy-9-tetrahydrocannabinol.
Clinical relevance:
Twice daily oral administration of the hemp extract based on 30 mg/kg/32.5 mg/kg of cannabidiol/cannabidiolic acid was well tolerated and maintained plasma concentrations considered to be therapeutic in dogs with osteoarthritis. Findings suggest different cannabinoid metabolism from mammals.
Products containing cannabidiol (CBD) are currently very popular. Besides the use of CBD as a co-medication with clobazam for drug-resistant epilepsy in childhood, there are currently only a few clinical studies on therapeutic uses. CBD interacts with numerous molecular targets whereas its affinity to cannabinoid receptors is negligible. The various delivery forms influence bioavailability as well as the window of detection; however, a sufficient number of pharmacokinetic studies covering major metabolites of CBD is not yet available. The analytical methods for determination of CBD include tetrahydrocannabinol (THC), its major metabolites and other cannabinoids. The in vivo conversion of CBD to THC is still an unresolved problem. There are defined analytical tests for CBD-based medications but the safety of other products regarding the THC content is not ensured. Flowers of CBD as plant components of the species Cannabis are subject to the Controlled Substances Act in Germany. For products containing CBD as an isolated compound, the appropriate regulations apply according to the use stated by the manufacturer.
Cannabis is one of the most widely used illicit drugs during pregnancy and lactation. With the recent legalization of cannabis in many countries, health professionals are increasingly exposed to pregnant and breastfeeding women who are consuming cannabis on a regular basis as a solution for depression, anxiety, nausea, and pain. Cannabis consumption during pregnancy can induce negative birth outcomes such as reduced birth weight and increased risk of prematurity and admission to the neonatal intensive care unit. Yet, limited information is available regarding the pharmacokinetics of cannabis in the fetus and newborn exposed during pregnancy and lactation. Indeed, the official recommendations regarding the use of cannabis during these two critical development periods lack robust pharmacokinetics data and make it difficult for health professionals to guide their patients. Many clinical studies are currently evaluating the effects of cannabis on the brain development and base their groups mostly on questionnaires. These studies should be associated with pharmacokinetics studies to assess correlations between the infant brain development and the exposure to cannabis during pregnancy and breastfeeding. Our project aims to review the available data on the pharmacokinetics of cannabinoids in adults, neonates, and animals. If the available literature is abundant in adult humans and animals, there is still a lack of published data on the exposure of pregnant and lactating women and neonates. However, some of the published information causes concerns on the exposure and the potential effects of cannabis on fetuses and neonates. The safety of cannabis use for non-medical purpose during pregnancy and breastfeeding needs to be further characterized with proper pharmacokinetic studies in humans feasible in regions where cannabis has been legalized. Given the available data, significant transfer occurs to the fetus and the breastfed newborn with a theoretical risk of accumulation of products known to be biologically active.
The use of the intoxicating cannabinoid delta‐8 tetrahydrocannabinol (Δ8‐THC) has grown rapidly over the last several years. There have been dozens of Δ8‐THC studies dating back over many decades, yet no review articles have comprehensively covered these findings. In this review, we summarize the pharmacological studies of Δ8‐THC, including receptor binding, cell signaling, in vivo cannabimimetic activity, clinical activity, and pharmacokinetics. We give special focus to studies that directly compared Δ8‐THC to its more commonly studied isomer, Δ9‐THC. Overall, the pharmacokinetics and pharmacodynamics of Δ8‐THC and Δ9‐THC are very similar. Δ8‐THC is a partial agonist of the cannabinoid CB1 receptor and has cannabimimetic activity in both animals and humans. The reduced potency of Δ8‐THC in clinical studies compared to Δ9‐THC can be explained by weaker cannabinoid CB1 receptor affinity, although there are other plausible mechanisms that may contribute. We highlight the gaps in our knowledge of Δ8‐THC pharmacology where further studies are needed, particularly in humans.
Objective
To determine the plasma pharmacokinetics, short-term safety, and synovial fluid levels of cannabidiol (CBD) following oral administration in horses.
Design
Prospective, randomized, controlled study.
Animals
Twelve institution-leased healthy adult horses.
Procedures
Twelve horses were administered sunflower lecithin oil-based CBD at 1mg/kg (Group 1) or 3mg/kg (Group 2) for a 24-hour pharmacokinetic study. Horses then received 0.5mg/kg (Group 1) or 1.5mg/kg (Group 2) CBD q12 PO for 6 weeks, with steady state and elimination sampling performed up to 96 hours post-final dose. Synovial fluid CBD concentrations were evaluated at 12 and 24 hours, and 5 weeks. Horses were monitored daily and clinicopathologic parameters were evaluated.
Results
Mean ± SD Cmax and tmax were 4.3 ± 2.1 ng/ml and 4.1 ± 4.1 hours, and 19.9 ± 15.6 ng/ml and 5.0 ± 3.7 hours for Groups 1 and 2, respectively. Following the final dose at 6 weeks, one Group 2 horse still had detectable plasma levels at 96 hours. CBD was detectable in synovial fluid in 8/12 horses during steady state. Mild hypocalcemia was seen in all horses and elevated liver enzymes were observed in 8/12 horses, but these changes decreased or normalized within 10 days after the final CBD dose.
Conclusions and Clinical Relevance
CBD has dose-dependent, but variable, oral bioavailability at 1 mg/kg and 3 mg/kg daily dosing. CBD is consistently detectable at steady state in synovial fluid at the higher dose. Further investigation is needed to establish clinically effective doses.
Preclinical studies have demonstrated the analgesic potential of cannabidiol (CBD). Those suggesting an effect on pain-processing receptors have brought CBD back into focus. This study assessed the effect of CBD on acute pain, hyperalgesia, and allodynia compared with placebo. Twenty healthy volunteers were included in this randomized, placebo-controlled, double-blinded, crossover study assessing pain intensities (using numeric rating scale), secondary hyperalgesia (von Frey filament), and allodynia (dry cotton swab) in a well-established acute pain model with intradermal electrical stimulation. The authors compared the effect of 800-mg orally administered CBD on pain compared with placebo. They further examined the effect on hyperalgesia and allodynia. Cannabidiol whole blood levels were also measured. Pain ratings (mean ± SD) did not differ significantly after CBD application compared with placebo (5.2 ± 0.7 vs 5.3 ± 0.7, P-value 0.928), neither did the areas of hyperalgesia and allodynia differ significantly after CBD application compared with placebo (hyperalgesia 23.9 ± 19.2 cm2 vs 27.4 ± 17.0 cm2, P-value 0.597; allodynia 16.6 ± 13.1 cm2 vs 17.3 ± 14.1 cm2, P-value 0.884). The CBD whole blood level (median, first to third quartile) was 2.0 µg/L (1.5-5.1) 60 minutes and 5.0 µg/L (4.0-10.4) 130 minutes after CBD application. Although the oral application of 800-mg CBD failed to show a significant effect, it is important to focus future research on different dosing, routes of administration, and CBD as a part of multimodal treatment strategies before negating its effects on acute pain.
Over the past 5 years, public interest in the potential health benefits of cannabidiol (CBD) has increased exponentially, and a wide range of over-the-counter (OTC) preparations of CBD are now available. A substantial proportion of the population appears to have used these products, yet the extent to which they are effective or safe is unclear. We reviewed the evidence for whether CBD has significant pharmacological and symptomatic effects at the doses typically found in OTC preparations. We found that most of the evidence for beneficial effects is derived from studies of pure, pharmaceutical grade CBD at relatively high doses. Relatively few studies have examined the effect of OTC CBD preparations, or of CBD at low doses. Thus, at present, there is little evidence that OTC CBD products have health benefits, and their safety has not been investigated. Controlled trials of OTC and low-dose CBD preparations are needed to resolve these issues.
Cannabis is the most used illicit drug worldwide and its medicinal use is under discussion, being regulated in several countries. However, the psychotropic effects of Δ⁹-tetrahydrocannabinol (THC), the main psychoactive compound of Cannabis sativa, are of concern. Thus, the interest in the isolated constituents without psychotropic activity, such as cannabidiol (CBD) and cannabidivarin (CBDV) is growing. CBD and CBDV are lipophilic molecules with poor oral bioavailability and are mainly metabolized by cytochrome P450 (CYP450) enzymes. The pharmacodynamics of CBD is the best explored, being able to interact with diverse molecular targets, like cannabinoid receptors, G protein-coupled receptor-55, transient receptor potential vanilloid 1 channel and peroxisome proliferator-activated receptor-γ. Considering the therapeutic potential, several clinical trials are underway to study the efficacy of CBD and CBDV in different pathologies, such as neurodegenerative diseases, epilepsy, autism spectrum disorders and pain conditions. The anti-cancer properties of CBD have also been demonstrated by several pre-clinical studies in different types of tumour cells. Although less studied, CBDV, a structural analogue of CBD, is receiving attention in the last years. CBDV exhibits anticonvulsant properties and, currently, clinical trials are underway for the treatment of autism spectrum disorders. Despite the benefits of these phytocannabinoids, it is important to highlight their potential interference with relevant physiologic mechanisms. In fact, CBD interactions with CYP450 enzymes and with drug efflux transporters may have serious consequences when co-administered with other drugs. This review summarizes the therapeutic advances of CBD and CBDV and explores some aspects of their pharmacokinetics, pharmacodynamics and possible interactions. Moreover, it also highlights the therapeutic potential of CBD and CBDV in several medical conditions and clinical applications.
A cannabis vem sendo utilizada há séculos como terapia médica, em diversas culturas. A planta foi introduzida em larga escala na medicina ocidental século no XIX, por médicos britânicos. Os ingleses acumularam experiência durante os trabalhos nas colônias, indicando o uso como estimulante do apetite, analgésico, relaxante muscular, anticonvulsivante e hipnótico(1,2). As cepas de cannabis são derivadas de duas espécies: a sativa e a indica. As cepas sativa possuem maior concentração de THC (Δ 9 Tetrahidrocanabinol) , portanto tem o potencial de produzir euforia. Por outro lado, as cepas indica apresentam maior teor de canabidiol (CBD), que possui propriedades antieméticas, analgésicas e sedativas-e não produz efeitos psicotrópicos (3,4). As propriedades polifarmacêuticas-inerentes aos produtos botânicos derivados da cannabis-oferecem vantagens distintas sobre o clássico modelo farmacêutico de alvo único. Trata-se de área do conhecimento em contínua evolução. Novas indicações vem sendo estudadas-com metodologia cada vez mais adequada-e as evidências científicas vem ganhando corpo nos últimos anos (1,4,5). O Sistema endocanabinóide A planta cannabis possui mais de 480 substâncias químicas. Cerca de 150 compostos possuem apenas carbono, hidrogênio e oxigênio. São denominados fitocanabinóides. Dentre os fitocanabinóides mais conhecidos e estudados estão o THC (Δ 9 Tetrahidrocanabinol), o CBD (Canabidiol) e o CBG (canabigerol)(1,6). Nas últimas três décadas os receptores de canabinóides (RCs) e os endocanabinóides (EC)-moléculas endógenas capazes de ativar os receptores canabinóides-foram descobertos em diferentes.
Introduction:
There is a large variation in cannabidiol (CBD) pharmacokinetics and little information on its bioavailability. This study aims to establish the CBD dose-exposure relationship and to evaluate the effects of dosage forms, food, and doses on CBD absorption.
Methods:
Single-dose (range: 5-6000 mg) CBD plasma concentration-time profiles administered as oral solution (OS), oral capsule (OC), or oromucosal spray/drop (OM) from healthy volunteers were extracted from 15 published clinical studies. A dose-exposure proportionality assessment was performed, and a population-based meta-analysis of CBD pharmacokinetics and systemic bioavailability was conducted with a nonlinear mixed-effect modeling. A three-compartment model with a Weibull or zero-order absorption model was used to describe CBD disposition and absorption kinetics. Dosage form, food, and dose were assessed for covariation.
Results:
Oral solution CBD exposures increased less than proportionally with doses of 750 mg or greater, and bioavailability (6.5% at 3000 mg) decreased with increasing dose. The bioavailability of OC (5.6%) and fed-state OM (6.2%) were similar, whereas it was lower in fasted-state OM (0.9%). The Weibull absorption model best described OS, OC, and fed-state OM profiles. The slowest absorption rate was observed in OS, resulting in a time of maximum concentration of 4.75 hours, followed by fed-state OM (3.13 hrs) and OC (2.1 hrs). The absorption kinetics of fasted-state OM was best described by a zero-order absorption for the duration of 1.71 hours.
Conclusion:
The effects of doses, dosage forms, and feeding status on CBD pharmacokinetics were quantified and should be taken into consideration for dose optimization.
The legal sale of cannabis-enriched foods and beverages for medical or recreational purposes is increasing in many states and countries, especially in North America and Europe. These food-based cannabis delivery systems vary considerably in their compositions and structures, ranging from low-viscosity watery beverages to solid fatty chocolates. The rate and extent of release of the bioactive components in cannabis within the human gastrointestinal tract (GIT) affect their health and psychoactive effects. Studies with other types of hydrophobic bioactives, such as nutraceuticals and vitamins, have shown that food composition and structure have a major impact on their bioaccessibility, transformation, and absorption within the GIT, thereby influencing their bioavailability and bioactivity. This review outlines how insights on the bioavailability of other lipophilic bioactives can be used to facilitate the design of more efficacious and consistent cannabis-enriched products intended for oral consumption. In particular, the importance of food-matrix composition (such as fat type and level) and structural organization (such as fat domain dimensions) are discussed.
Expected final online publication date for the Annual Review of Food Science and Technology, Volume 11 is March 25, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Cannabis is now emerging from a period of prohibition and being revisited as a potential source of treatments for conditions ill served by synthetic substances. Previous research focussed primarily on effects produced by synthetic cannabinoids such as THC, or cannabis of unknown cannabinoid content. Chemovars of cannabis characterized by high content of specific cannabinoids (primarily, but not only THC and CBD) have been developed. Clinical research using defined extracts from these chemovars is now underway in the UK.Many diseases are multifactorial; a variety of receptors need to be targeted to produce a therapeutic effect. A defined botanical may better achieve this than a single synthetic compound as the components can act synergistically. A new generation of cannabis based medicinal products takes advantage of increasing understanding of the mode of action of cannabinoids, evidence-based research on clinical uses and new technology for realization of products, in anti-diversionary presentations.
This Phase I, open label, four-way crossover study pertains to pharmacokinetic parameters of four cannabis based medicine extracts (CBME). Sublingual, buccal and oro-pharyngeal test treatments (GW-1000-02) consisted of 25 mg cannabidiol (CBD) + 25 mg Δ-tetra-hydrocannabinol (THC) per ml formulated in ethanol (eth):propylene glycol (PG) (50:50), with peppermint flavouring with a 100 μl actuation volume (total dose 10 mg CBD + 10 mg THC in 4 actuations). An oral capsule contained 2.5 mg CBD + 2.5 mg THC sprayed onto granulated lactose and encapsulated in soft gelatin capsules (total dose of 10 mg CBD + 10 mg THC 4 capsules). This study was performed in healthy volunteers in an open label, 4 period, 3-way randomised crossover followed by a nonrandomised oral dose using single doses of 20 mg of CBME (10 mg CBD + 10 mg THC). In Periods 1 to 3, the test treatment was administered as a liquid spray according to the randomisation scheme (i.e., sublingually, buccally, oro-pharyngeally). In Period 4 the test treatment was delivered as an oral capsule. There was a six-day washout between each dose.Primary objectives were to compare the pharmacokinetic profiles of cannabis based medicine extract (CBME) when administered on different areas of the buccal mucosa. Secondary objectives were to investigate the pharmacokinetic profile of CBME when administered as an oral capsule.Concentrations of THC were higher than the corresponding levels of CBD at most time points. Concentrations of 11-hydroxy-THC exceeded the corresponding concentration of THC at most time points. By 720 min (12 h) post-dose, mean concentrations of each cannabinoid were still above the lower limit of quantification (LLOQ). There was a high degree of inter-subject and intra-subject variability in the plasma concentrations achieved.Tmax of CBD and THC occurred earlier following sublingual administration than oro-pharyngeal or buccal although only the difference in Tmax of CBD compared with buccal was statistically significant. Cmax of both CBD and THC was greatest following buccal administration although this was not statistically significant. AUC was greatest following oro-pharyngeal and was statistically significantly greater than buccal. The lower bioavailability, as measured by AUC, following buccal administration when compared to the sublingual and oro-pharyngeal routes may be related to the difficulty of spraying onto the inside of the cheek reported during the study and could be due to some loss of spray. Buccal administration of the pump action sublingual spray (PASS) test treatment resulted in a later Tmax but greater Cmax when compared to the sublingual and oro-pharyngeal routes. Comparison of the sublingual and oro-pharyngeal routes showed no statistically significant difference in THC or CBD pharmacokinetic parameters other than an earlier Tmax following sublingual dosing. The oral capsule appeared to show an early Tmax of both CBD and THC. Mean Cmax of THC and 11-hydroxy-THC were greater, but in contrast the Cmax of CBD was lower, than following the PASS treatments. Relative to THC, the plasma level AUC of 11-hydroxy-THC was proportionally greatest following oral capsules which could be a reflection of greater metabolism by this route. Of the PASS treatments the ratio of 11-hydroxy-THC to THC was greatest following sublingual and least following oro-pharyngeal. There was very wide inter-and to a lesser extent intra-subject variability in pharmacokinetics. Differences in mean values between the routes of administration, even when statistically significant, are small relative to the very wide range of values between subjects. The sublingual and oro-pharyngeal routes of administration appear to have the same pharmacokinetic results. The buccal pharmacokinetic parameters are lower when compared to the sublingual and oro-pharyngeal routes.A total of 146 adverse events (AEs) occurred in 12 subjects. Two events were classified as moderate (flu-like illness and pharyngeal irritation) and the remaining 144 were classified as mild. All routes of administration were well tolerated by all subjects with no serious AEs and no withdrawals due to AEs.The overall results indicate that administration of the liquid spray (GW-1000-02) need not be limited to sublingual administration. The oral capsule, has good bioavailability, and provided, as is the case here the formulation is not oil based, may be a viable formulation when self-titration is not necessary.
Unlabelled:
Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge. Nabiximols (Nabiximols is the U.S. Adopted Name [USAN] for Sativex [GW Pharma Ltd, Wiltshire, U.K.], which does not yet have an INN), a novel cannabinoid formulation, is undergoing investigation as add-on therapy for this population. In a randomized, double-blind, placebo-controlled, graded-dose study, patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose (1-4 sprays/day), medium dose (6-10 sprays/day), or high dose (11-16 sprays/day). Average pain, worst pain and sleep disruption were measured daily during 5 weeks of treatment; other questionnaires measured quality of life and mood. A total of 360 patients were randomized; 263 completed. There were no baseline differences across groups. The 30% responder rate primary analysis was not significant for nabiximols versus placebo (overall P = .59). A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall (P = .035), and specifically in the low-dose (P = .008) and medium-dose (P = .039) groups. In the low-dose group, results were similar for mean average pain (P = .006), mean worst pain (P = .011), and mean sleep disruption (P = .003). Other questionnaires showed no significant group differences. Adverse events were dose-related and only the high-dose group compared unfavorably with placebo. This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials.
Perspective:
Nabiximols, a novel cannabinoid formulation, may be a useful add-on analgesic for patients with opioid-refractory cancer pain. A randomized, double-blind, placebo-controlled, graded-dose study demonstrated efficacy and safety at low and medium doses.
This report describes a method for the quantitative analysis of Δ9-tetrahydrocannabinol and six of its metabolites, 8α-hydroxy-Δ9-tetrahydrocannabinol, 8β-hydroxy-Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol, 8α,11-dihydroxy-Δ9-tetrahydrocannabinol, 8β,11-dihydroxy-Δ9-tetrahydrocannabinol, and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol. In addition, the method was designed to detect cannabidiol and cannabinol, two naturally occurring
cannabinoids. Plasma and urine samples were hydrolyzed with bacterial (Escherichia coli) β-glucuronidase and extracted with hexane-ethyl acetate (7:1). Analysis and quantitation were performed by gas chromatography-mass
spectrometry in the electron ionization mode coupled with selected ion monitoring. The cannabinoids were detected as their
trimethylsilyl derivatives to enhance their chromatographic separation and mass spectral characteristics. The linearity of
the procedure was excellent for all of the compounds within the range tested (0–100 ng/mL). Limits of detection ranged from
0.5 to 1.5 ng/mL in urine and from 0.6 to 2.1 ng/mL in plasma depending on the analyte.
Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.
This book represents another attempt to educate analytical chemists in the use of simple statistics. It is an easy-to-read overview of the topics with which every analytical chemist should be familiar. The early chapter on errors in analysis, significance testing, and quality control are well written. A good introduction to these topics is provided in the first 100 pages. Chapter 6 on nonparametric methods is quite useful; it provides justification and incentive to learn and use these methods. Chapter 7 covers very large and useful topics such as experimental design, optimization, and pattern recognition. Fractional factorial designs and principle component analysis are only mentioned, not discussed in detail. This book can be easily read and can heighten one's awareness of many important topics from statistics to chemometrics. Because it comes complete with a number of good exercises (no programs), the author also recommend it as a textbook for a short course.
Primary objectives of this study were to assess the pharmacokinetic characteristics of CBME when administered sublingually in different ratios, to determine if the pharmacokinetic profiles of THC and its metabolite 11-hydroxy-THC are different when administered sublingually in different formulations, and to characterise the pharmacokinetic profile of CBD when administered with THC in equal amounts. Secondary objectives were to determine if there was a correlation between intoxication levels and plasma concentrations of THC and/or its metabolite 11-hydroxy-THC, and to assess safety and tolerability of CBME when administered sublingually.Methodology employed a double-blind, randomised, three-way crossover study of placebo, High THC and CBD:THC administered sublingually as a liquid spray. Twenty-four subjects were planned, dosed, completed the study and were analysed.Test products were Δ-tetrahydrocannabinol (THC, formulated as 25 mg THC per ml) with or without cannabidiol (CBD) (formulated as 25 mg CBD + 25 mg THC per ml) formulated in ethanol (Eth):propylene glycol (PG) with peppermint (ppmt) flavouring or matching placebo, administered with a 100 μl pump. Each subject received one single dose of 10 mg THC and one single dose of 10 mg CBD + 10 mg THC plus a single dose of placebo in a randomised manner on three separate occasions. The washout period was six days between each dose. Placebo was Eth:PG in a 50:50 ratio with ppmt flavouring, administered with a 100 μl actuator pump.Mean plasma concentrations show that following administration of both High THC and CBD:THC formulations CBD and or THC was detectable in plasma in measurable concentrations 15–30 minutes after dosing, although individual subjects showed quite wide variability, 15 to 135 minutes, to appearance measurable concentrations. At all time points up to 180 minutes after dosing mean concentrations of THC were greater following the High THC formulation than CBD:THC. Concentrations of THC were also greater than corresponding concentrations of CBD following the CBD:THC treatment.There were no statistically significant differences in mean Cmax, t1/2, AUC0-t and AUC0-∞of both THC and 11-hydroxy-THC between the High THC and CBD:THC formulations. THC Tmax was statistically significantly later following CBD:THC than High THC (p = 0.014) and this was the only statistically significant difference in pharmacokinetic parameters between the treatments. The AUC values (AUC0-t and AUC0-∞) for THC show an approximate 8 to 10-fold difference between the lowest and highest subject values while the difference for CBD was approximately 3.5 to 4-fold. Differences in Cmax were 20 to 30 fold for THC and approximately 14-fold for CBD. Intra-subject differences in values for THC between treatments were smaller though differences in Cmax of up to 5-fold and 3-fold in AUC (AUC0-t and AUC0-∞) were observed. Other than a single isolated significant difference in Tmax there were no significant differences in pharmacokinetic parameters between the CBD:THC and High THC formulations. The bioavailability of THC appears to be greater than that of CBD.Mean intoxication scores on both CBME treatments were very low throughout the observation period. The majority of subjects scored zero for the majority of assessment points and there were few scores greater than three on the Box Scale 11 (BS-11). Recorded intoxication scores do not seem to show a direct relationship to plasma concentrations of THC and/or 11-hydroxy-THC either within or between subjects. The time of intoxication scores in individual subjects do not seem to relate consistently with the timing of increases in plasma concentrations or maximal concentrations of THC or 11-hydroxy-THC. Neither is there an apparent relationship between subjects reporting intoxication and those with the highest plasma levels of THC or 11-hydroxy-THC.No subjects withdrew from the study as a result of adverse events and both active and the placebo test treatments were well tolerated. The treatment with the least number of treatment related adverse events was placebo. High THC and CBD:THC had a greater number of subjects who experienced intoxication type adverse events and application site type reactions. The most common overall adverse event experienced was throat irritation, followed by dizziness, somnolence, oral paraesthesia and then headache. All the events were mild and only two events needed any treatment. There were no clinically significant changes from baseline for haematology, biochemistry, vital signs or ECGs.There was wide inter- and intra-subject variability in pharmacokinetic parameters with up to 10-fold differences in THC AUC between subjects and even greater differences in Cmax. Results suggest that there are no overall statistically significant differences between the pharmacokinetic parameters of High THC and CBD:THC other than a delay in Tmax. Considering the wide inter- and intra-subject variability in pharmacokinetic parameters including Tmax this is unlikely to be clinically important in a medication that is self titrated by the patient.
Drugs are absorbed after oral administration as a consequence of a complex array of interactions between the drug, its formulation, and the gastrointestinal (GI) tract. The presence of food within the GI tract impacts significantly on transit profiles, pH, and its solubilization capacity. Consequently, food would be expected to affect the absorption of co-administered drugs when their physicochemical properties are sensitive to these changes. The physicochemical basis by which ingested food/lipids induce changes in the GI tract and influence drug absorption are reviewed. The process of lipid digestion is briefly reviewed and considered in the context of the absorption of poorly water-soluble drugs. The effect of food on GI pH is reviewed in terms of location (stomach, upper and lower small intestine) and the temporal relationship between pH and drug absorption. Case studies are presented in which postprandial changes in bioavailability are rationalized in terms of the sensitivity of the physicochemical properties of the administered drug to the altered GI environment.
1. The relative bioavailability of cyclosporin was studied in 11 healthy volunteers after single oral capsule doses of cyclosporin on three separate occasions; fasting, with breakfast and with breakfast together with bile acid tablets (400 mg of cholic acid and 100 mg of dehydrocholic acid). 2. There was a significant increase in the area under the blood concentration vs time curve (AUC) of cyclosporin when the drug was taken together with breakfast and bile acid tablets (9078 ng ml-1 h) as compared with breakfast alone (7453 ng ml-1 h, P less than 0.05) or fasting conditions (7283 ng ml-1 h, P less than 0.01). 3. A blood drug concentration vs time curve displaying two peaks was present in 9/11 subjects when cyclosporin was taken with breakfast or with breakfast and bile acid tablets, but only one peak was present when cyclosporin was taken during fasting, suggesting an enterohepatic circulation of cyclosporin or a second absorption phase after the meal. 4. In a separate study, 12 h trough blood cyclosporin concentrations were measured before and after 1 week of bile acid treatment in 19 clinically stable, out-patient transplant recipients who were treated with oral cyclosporin solution (mean dose 2.0 mg kg-1 twice daily). The administration of cyclosporin was not standardized with regard to food intake. There was no significant difference in the blood concentrations of cyclosporin before and after bile acid treatment (114 +/- 38 ng ml-1 vs 121 +/- 38 ng ml-1).(ABSTRACT TRUNCATED AT 250 WORDS)
delta 9-Tetrahydrocannabinol and two of its metabolites, 11-hydroxy-delta 9-tetrahydrocannabinol and 11-nor-9-carboxy-delta 9-tetrahydrocannabinol, can be measured in a single 1-ml sample of blood, plasma, or urine by a new assay which combines a relatively rapid extraction procedure with capillary column gas chromatography and negative ion chemical ionization mass spectrometry. Deuterium-labeled analogs of each cannabinoid are added to the physiological specimen as internal standards. Two extracts are obtained from each sample: a neutral fraction containing delta 9-tetrahydrocannabinol and 11-hydroxy-delta 9-tetrahydrocannabinol, and an acid fraction containing 11-nor-9-carboxy-delta 9-tetrahydrocannabinol. The neutral fraction is derivatized by treatment with trifluoroacetic anhydride; the acid fraction is first treated with BF3-methanol followed by reaction with trifluoroacetic anhydride. Under electron-capture chemical ionization conditions the derivatized delta 9-tetrahydrocannabinol and 11-nor-9-carboxy-delta 9-tetrahydrocannabinol give abundant molecular anions ideally suited for selected ion monitoring. The negative ion chemical ionization spectrum of the HO-THC-trifluoroacetate shows no molecular anion. Consequently, quantitation of the hydroxy metabolite is achieved by monitoring a fragment ion formed by loss of CF3CO2 from its molecular anion. The limits of reliable measurement are judged to be 0.1 ng ml-1 for 11-nor-9-carboxy-delta 9-tetrahydrocannabinol, 0.2 ng ml-1 for delta 9-tetrahydrocannabinol and 0.5 ng ml-1 for 11-hydroxy-delta 9-tetrahydrocannabinol. Four examples are given of the application of the assay to the analysis of specimens of medico-legal importance.
A sensitive and reliable method was developed for the identification and quantitation of cannabinoids in blood. Samples were screened by fluorescence polarization immunoassay. Analysis was completed on a benchtop mass selective detector using selected ion monitoring. The limits of detection were 0.2 ng/mL for delta9-tetrahydrocannabinol (THC and 11-hydroxy-THC and 2 ng/mL for 11-nor-9-carboxy-THC. Extensive method validation is presented, including within-run variation, between-run variation, and results from external proficiency testing. Sample stability was studied over a 6-month period. Several derivatives and extraction techniques were evaluated to determine optimum performance. Data from a blind study of 217 samples were used to determine the predictive value of the screening procedure. The procedure is used routinely in the laboratory on samples from drivers issued a citation for impaired driving and also on postmortem blood from death investigations.
Following a high-fat meal, triglyceride-rich lipoproteins (TRL) are assembled in the gut and absorbed via the lymph into the blood circulation, producing a temporal hyperlipidemia. The purpose of this study is to verify the hypothesis that this transient acute postprandial hyperlipidemia affects the pharmacokinetics of lipophilic drugs on both absorption and disposition levels by the same underlying mechanism, namely the association of active lipophilic compounds with TRL in the plasma (disposition) or within the enterocyte (lymphatic transport). This concept was assessed in rats using two model compounds, DDT with high affinity to chylomicrons and diazepam which does not bind to chylomicrons. Oral administration of peanut oil significantly increased the AUC of plasma DDT concentrations following its IV bolus administration in comparison to a water treated group. On the other hand, the AUC of diazepam following IV bolus administration was the same in oil and water treated rats. While DDT is known to have significant lymphatic bioavailability, diazepam has negligible intestinal lymphatic transport (0.014+/-0.004% of a given dose). In conclusion, lipophilic molecules that bind extensively to TRL will be prone to both intestinal lymphatic transport and to post-absorptive changes in disposition (decrease in clearance and volume of distribution) following a high-fat meal.
This review discusses clinical and preclinical evidence that supports the use of cannabinoid receptor agonists for the management of multiple sclerosis. In addition, it considers preclinical findings that suggest that as well as ameliorating signs and symptoms of multiple sclerosis, cannabinoid CB(1) and/or CB(2) receptor activation may suppress some of the pathological changes that give rise to these signs and symptoms. Evidence that the endocannabinoid system plays a protective role in multiple sclerosis is also discussed as are potential pharmacological strategies for enhancing such protection in the clinic.
Food-effect bioavailability and fed bioequivalence studies
- Guidance
- Industry
A randomised controlled trial of Sativex, a cannabis based medicine, in central neuropathic pain due to multiple sclerosis. Program and abstracts of the 2005 Canadian Association of Physical Medicine and Rehabilitation Annual Meeting
- C A Young
- T J Nurmikko
- D J Rog
- N Sanantis