Cannabidiol Concentration Research Articles

Changes in the composition of cannabis from 2000-2017 in Denmark: Analysis of confiscated samples of cannabis resin.

Globally, recent studies report increases in Δ-9-tetrahydrocannabinol (THC) concentration in seized samples of cannabis for human consumption. This is important, because use of cannabis with a high concentration of THC has been linked to a number of adverse health outcomes. The objective of this study was to assess recent changes in the composition of seized cannabis resin in Denmark by (a) examining THC concentration in samples from Danish forensic laboratories from 2000 to 2017 (N = 430) and (b) examining cannabidiol (CBD) concentration and the THC:CBD concentration ratio in samples from the forensic laboratory in Western Denmark from 2008 to 2017 (N = 147). Cannabis resin samples were analyzed using a gas chromatographic analysis with flame ionization detection quantifying the total THC and CBD concentration. Results showed that the THC concentration increased 3-fold from 2000 (mean: 8.3%) to 2017 (mean: 25.3%). Significant increases occurred in all areas of Denmark. After 2011, we found a dramatic increase in cannabis resin samples with high THC concentration and the near disappearance of cannabis resin samples with medium- and low THC concentration. Furthermore, the THC:CBD concentration ratio increased significantly from 1.4 in 2008 to 4.4 in 2017. Whereas THC concentration increased, CBD concentration remained stable at ∼6%. In conclusion, the THC concentration of cannabis resin, and THC:CBD concentration ratio, have increased dramatically in Denmark, potentially leading to higher risk of harm to users. Policymakers, treatment professionals, and educators should be aware of this change. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: Pharmacodynamic and pharmacokinetic studies

Cannabidiol and cannabidiol-enriched products have recently attracted much attention as an add-on therapy for epilepsy, especially drug-resistant seizures. It should be, however, remembered that concomitant use of cannabidiol and antiepileptic drugs may pose a risk of interactions between them. For this reason, the aim of our study was to assess the effect of cannabidiol on the activity of selected new antiepileptic drugs in the electrically-induced seizure models in mice. We studied the effect of cannabidiol on the anticonvulsant action of topiramate, oxcarbazepine, lamotrigine, and pregabalin in the maximal electroshock-induced seizure test as well as on the activity of levetiracetam, tiagabine, lacosamide, and gabapentin in the 6 Hz seizure test in mice. We showed that cannabidiol increased the activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin. It did not affect the anticonvulsant effect of lamotrigine and lacosamide. Interestingly, cannabidiol attenuated the anticonvulsant activity of levetiracetam. Co-administration of antiepileptic drugs with cannabidiol did not cause adverse effects such as impairment of motor coordination, changes in neuromuscular strength or potentiation of the cannabidiol-induced hypolocomotion. Serum and brain levels of antiepileptic drugs and cannabidiol were determined by using HPLC in order to ascertain any pharmacokinetic contribution to the observed behavioral effects. Only interaction with levetiracetam was purely pharmacodynamic in nature because no changes in serum and brain concentration of either levetiracetam or cannabidiol were observed. Increased anticonvulsant activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin could be, at least in part, related to pharmacokinetic interactions with cannabidiol because there were changes in serum and/or brain concentrations of antiepileptic drugs and/or cannabidiol. Pharmacokinetic interactions cannot be also excluded between lacosamide and cannabidiol because cannabidiol increased brain concentration of lacosamide and lacosamide increased brain concentration of cannabidiol. Further pharmacokinetic studies are required to evaluate the type of interactions between cannabidiol and novel antiepileptic drugs.

Development of Standard Operating Protocols for the Optimization of Cannabis-Based Formulations for Medical Purposes.

Under current legislation in Italy, Cannabis for medical purposes may be administered orally in the form of decoction or Cannabis oil extract. The scientific literature reports a number of preparation methods, mainly for oils, but no study is available that compares thoroughly, from a technological viewpoint, the Cannabis-based formulations currently administered to patients. With this in mind, this research work aimed to carry out specific formulation studies to design standard operating procedures for the preparation and optimization of Cannabis-based galenic formulations. Both decoctions and oils were prepared under different operating conditions to identify the most efficient process for the production of formulations with a high concentration of decarboxylated delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Regarding Cannabis oil, a new procedure has been developed that allows significantly higher recovery rates for THC and CBD compared with those for water-based extraction methods (decoction) and those for oil-based methods currently in use. Moreover, based on the results, it is possible to affirm that the prescription of Cannabis-based decoctions should not be the recommended first-choice solution for therapy, considering the low concentration of THC and CBD and, consequently, the high volume of decoction that the patient would have to ingest.

Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy.

To assess the effect of oral cannabidiol (CBD) administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with idiopathic epilepsy. Randomized blinded controlled clinical trial. 26 client-owned dogs with intractable idiopathic epilepsy. Dogs were randomly assigned to a CBD (n = 12) or placebo (14) group. The CBD group received CBD-infused oil (2.5 mg/kg [1.1 mg/lb], PO) twice daily for 12 weeks in addition to existing antiepileptic treatments, and the placebo group received noninfused oil under the same conditions. Seizure activity, adverse effects, and plasma CBD concentrations were compared between groups. 2 dogs in the CBD group developed ataxia and were withdrawn from the study. After other exclusions, 9 dogs in the CBD group and 7 in the placebo group were included in the analysis. Dogs in the CBD group had a significant (median change, 33%) reduction in seizure frequency, compared with the placebo group. However, the proportion of dogs considered responders to treatment (≥ 50% decrease in seizure activity) was similar between groups. Plasma CBD concentrations were correlated with reduction in seizure frequency. Dogs in the CBD group had a significant increase in serum alkaline phosphatase activity. No adverse behavioral effects were reported by owners. Although a significant reduction in seizure frequency was achieved for dogs in the CBD group, the proportion of responders was similar between groups. Given the correlation between plasma CBD concentration and seizure frequency, additional research is warranted to determine whether a higher dosage of CBD would be effective in reducing seizure activity by ≥ 50%.

Therapeutic potential of commercially‐available cannabidiol oil for Alzheimer's disease using Caenorhabditis elegans as a model

Alzheimer's disease (AD) is a neurodegenerative disease linked to loss of cognitive and motor abilities. The neurodegeneration is thought to be caused, in part, by the accumulation of Aβ peptides in the brain. Currently, there is no cure for AD, and the available treatments are rather limited in scope. Most of them are aimed at treating the symptoms, not preventing or reversing the progression of the disease. Recent studies have suggested a therapeutic potential for cannabidiol (CBD), a component of the Cannabis sativa plant. Both, in vitro and in vivo studies have shown improvement in some of the physiological and cognitive signs of the disease, suggesting it may be a better therapeutic strategy compared to current treatments. Given CBD's therapeutic potential and the increase in availability of commercial over‐the‐counter CBD‐based oils, this study is aimed at assessing the therapeutic potential of these products using an invertebrate model of AD. To achieve our aim, we decided to use a transgenic Caenorhabditis elegans worm strain that expresses human Aβ in neurons (CL2355). This is an inducible strain that shows behavioral deficits that make it a suitable model for AD. Prior to treating the animals, a toxicity assay was performed with several concentrations of a commercially available CBD oil. Although more animals need to be tested, preliminary results showed no significant effect of the CBD oil on the worms' mortality. Once we determine the optimal concentration of CBD, Aβ expression will be induced in synchronized animals from the CL2355 strain by a temperature upshift. This will be followed by a 24‐hour exposure to the CBD oil or the vehicle. By the time the CBD exposure ends, the animals will be adults, and behavioral testing will be performed. Specifically, we will perform a thrashing and a short‐term associative learning assay to test for locomotor and memory deficits respectively. Results from this study will allow us to determine whether commercially‐available CBD oils can either prevent or alleviate some of the deficits associated with AD and will support the use of invertebrate models to further explore new possibilities for the development of therapeutic strategies for AD and other neurodegenerative disorders.Support or Funding InformationPUCPR‐PR Louis Stokes Alliances for Minority ParticipationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Determination of cannabinoids in oral fluid and urine of "light cannabis" consumers: a pilot study.

Background In those countries where cannabis use is still illegal, some manufacturers started producing and selling "light cannabis": dried flowering tops containing the psychoactive principle Δ-9-tetrahydrocannabinol (THC) at concentrations lower than 0.2% together with variable concentration of cannabidiol (CBD). We here report a pilot study on the determination of cannabinoids in the oral fluid and urine of six individuals after smoking 1 g of "light cannabis". Methods On site screening for oral fluid samples was performed, as a laboratory immunoassay test for urine samples. A validated gas chromatography-mass spectrometry (GC-MS) method was then applied to quantify THC and CBD, independently from results of screening tests. Results On site screening for oral fluid samples, with a THC cut-off of 25 ng/mL gave negative results for all the individuals at different times after smoking. Similarly, negative results for urine samples screening from all the individuals were obtained. Confirmation analyses showed that oral fluid THC was in the concentration range from 2.5 to 21.5 ng/mL in the first 30 min after smoking and then values slowly decreased. CBD values were usually one order of magnitude higher than those of THC. THC-COOH, the principal urinary THC metabolite, presented the maximum urinary value of 1.8 ng/mL, while urinary CBD had a value of 15.1 ng/mL. Conclusions Consumers of a single 1 g dose of "light cannabis" did not result as positive in urine screening, assessing recent consumption, so that confirmation would not be required. Conversely, they might result as positive to oral fluid testing with some on-site kits, with THC cut-off lower than 25 ng/mL, at least in the first hour after smoking and hence confirmation analysis can be then required. No conclusions can be drawn of eventual chronic users.

Marijuana Use by Breastfeeding Mothers and Cannabinoid Concentrations in Breast Milk.

Between 2014 and 2017, 50 breastfeeding women who reported marijuana use provided 54 breast milk samples to a research repository, Mommy's Milk. Concentrations of Δ-9-tetrahydrocannabinol (∆9-THC), 11-hydroxy-Δ-9-tetrahydrocannabinol, cannabidiol, and cannabinol were measured by using liquid chromatography mass spectrometry electrospray ionization. ∆9-THC was detectable in 34 (63%) of the 54 samples up to ∼6 days after last reported use; the median concentration of ∆9-THC was 9.47 ng/mL (range: 1.01-323.00). Five samples had detectable levels of 11-hydroxy-Δ-9-tetrahydrocannabinol (range: 1.33-12.80 ng/mL) or cannabidiol (range: 1.32-8.56 ng/mL). The sample with the highest concentration of cannabidiol (8.56 ng/mL) did not have measurable ∆9-THC. Cannabinol was not detected in any samples. The number of hours since last use was a significant predictor of log ∆9-THC concentrations (-0.03; 95% confidence interval [CI] -0.04 to -0.01; P = .005). Adjusted for time since last use, the number of daily uses and time from sample collection to analysis were also significant predictors of log ∆9-THC concentrations (0.51; 95% CI 0.03 to 0.99; P = .039; 0.08; 95% CI 0.00 to 0.15; P = .038, respectively). ∆9-THC was measurable in a majority of breast milk samples up to ∼6 days after maternal marijuana use.

Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users.

Introduction: Chronic cannabis use is associated with neuroanatomical alterations in the hippocampus. While adverse impacts of cannabis use are generally attributed to Δ9-tetrahydrocannabinol, emerging naturalistic evidence suggests cannabidiol (CBD) is neuroprotective and may ameliorate brain harms associated with cannabis use, including protection from hippocampal volume loss. This study examined whether prolonged administration of CBD to regular cannabis users within the community could reverse or reduce the characteristic hippocampal harms associated with chronic cannabis use.Materials and Methods: Eighteen regular cannabis users participated in an ∼10-week open-label pragmatic trial involving daily oral administration of 200 mg CBD, with no change to their ongoing cannabis use requested. Participants were assessed at baseline and post-CBD treatment using structural magnetic resonance imaging. Automated longitudinal hippocampal segmentation was performed to assess volumetric change over the whole hippocampus and within 12 subfields.Results: No change was observed in left or right hippocampus as a whole. However, left subicular complex (parasubiculum, presubiculum, and subiculum) volume significantly increased from baseline to post-treatment (p=0.017 uncorrected) by 1.58% (Cohen's d=0.63; 2.83% in parasubiculum). Heavy cannabis users demonstrated marked growth in the left subicular complex, predominantly within the presubiculum, and right cornu ammonis (CA)1 compared to lighter users. Associations between greater right subicular complex and total hippocampal volume and higher plasma CBD concentration were evident, particularly in heavy users.Conclusions: Our findings suggest a restorative effect of CBD on the subicular and CA1 subfields in current cannabis users, especially those with greater lifetime exposure to cannabis. While replication is required in a larger, placebo-controlled trial, these findings support a protective role of CBD against brain structural harms conferred by chronic cannabis use. Furthermore, these outcomes suggest that CBD may be a useful adjunct in treatments for cannabis dependence and may be therapeutic for a range of clinical disorders characterized by hippocampal pathology (e.g., schizophrenia, Alzheimer's disease, and major depressive disorder).

High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets

Background: Cannabidiol (CBD) is considered a promising neuroprotectant after perinatal hypoxia-ischemia (HI). We have previously studied the effects of CBD 1 mg/kg in the early phase after global HI in piglets. In contrast to prior studies, we found no evidence of neuroprotection and hypothesized that higher doses might be required to demonstrate efficacy in this animal model. Objective: To assess the safety and potential neuroprotective effects of high-dose CBD. Methods: Anesthetized newborn piglets underwent global HI by ventilation with 8% O₂ until the point of severe metabolic acidosis (base excess -20 mmol/L) and/or hypotension (mean arterial blood pressure ≤20 mm Hg). Piglets were randomized to intravenous treatment with vehicle (n = 9) or CBD (n = 13). The starting dose, CBD 50 mg/kg, was reduced if adverse effects occurred. The piglets were euthanized 9.5 h after HI and tissue was collected for analysis. Results: CBD 50 mg/kg (n = 4) induced significant hypotension in 2 out of 4 piglets, and 1 out of 4 piglets suffered a fatal cardiac arrest. CBD 25 mg/kg (n = 4) induced significant hypotension in 1 out of 4 piglets, while 10 mg/kg (n = 5) was well tolerated. A significant negative correlation between the plasma concentration of CBD and hypotension during drug infusion was observed (p < 0.005). Neuroprotective effects were evaluated in piglets that did not display significant hypotension (n = 9) and CBD did not alter the degree of neuronal damage as measured by a neuropathology score, levels of the astrocytic marker S100B in CSF, magnetic resonance spectroscopy markers (Lac/NAA and Glu/NAA ratios), or plasma troponin T. Conclusions: High-dose CBD can induce severe hypotension and did not offer neuroprotection in the early phase after global HI in piglets.

Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts.

Introduction: Inflammatory bowel diseases (IBDs) include Crohn's disease, and ulcerative colitis. Cannabis sativa preparations have beneficial effects for IBD patients. However, C. sativa extracts contain hundreds of compounds. Although there is much knowledge of the activity of different cannabinoids and their receptor agonists or antagonists, the cytotoxic and anti-inflammatory activity of whole C. sativa extracts has never been characterized in detail with in vitro and ex vivo colon models.Material and Methods: The anti-inflammatory activity of C. sativa extracts was studied on three lines of epithelial cells and on colon tissue. C. sativa flowers were extracted with ethanol, enzyme-linked immunosorbent assay was used to determine the level of interleukin-8 in colon cells and tissue biopsies, chemical analysis was performed using high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance and gene expression was determined by quantitative real-time PCR.Results: The anti-inflammatory activity of Cannabis extracts derives from D9-tetrahydrocannabinolic acid (THCA) present in fraction 7 (F7) of the extract. However, all fractions of C. sativa at a certain combination of concentrations have a significant increased cytotoxic activity. GPR55 receptor antagonist significantly reduces the anti-inflammatory activity of F7, whereas cannabinoid type 2 receptor antagonist significantly increases HCT116 cell proliferation. Also, cannabidiol (CBD) shows dose dependent cytotoxic activity, whereas anti-inflammatory activity was found only for the low concentration of CBD, and in a bell-shaped rather than dose-dependent manner. Activity of the extract and active fraction was verified on colon tissues taken from IBD patients, and was shown to suppress cyclooxygenase-2 (COX2) and metalloproteinase-9 (MMP9) gene expression in both cell culture and colon tissue.Conclusions: It is suggested that the anti-inflammatory activity of Cannabis extracts on colon epithelial cells derives from a fraction of the extract that contains THCA, and is mediated, at least partially, via GPR55 receptor. The cytotoxic activity of the C. sativa extract was increased by combining all fractions at a certain combination of concentrations and was partially affected by CB2 receptor antagonist that increased cell proliferation. It is suggested that in a nonpsychoactive treatment for IBD, THCA should be used rather than CBD.

ATPS-15CANNABIDIOL REDUCES GLIOMA CELLS PROLIFERATION AND VIABILITY

Phytocannabinoids exert antineoplastic activities in several types of cancers, including gliomas. However, psychotropic effects, such as dizziness and physical dependence produced by the major active ingredient of cannabis Δ9-tetrahydrocannabinol, limit their clinical application. Emerging evidence suggests that cannabidiol (CBD), a non-psychoactive component of plant cannabis, also reduces tumor growth in several glioma models; however, the molecular and cellular mechanisms by which CBD produces antitumor activities are yet to be further explored. To better understand how CBD produces antitumor actions, we studied its effects on the viability and proliferation of human GBM cell line T98G cells using cell proliferation reagents WST-1 and [3H]-thymidine incorporation assay, respectively. Multiple doses and time points were used to assess the dose response and time course of the antitumor actions produced by CBD and the DNA alkylating agent carmustine (BCNU) as comparator. Both CBD and BCNU produced a dose-dependent suppression on the viability of T98G cells. Specifically, the half maximal inhibitory concentration of CBD (IC50 = 1.55 µM) is approximately 30 times lower than BCNU (IC50 = 47.17 µM) at 72hr time point, indicating that CBD is more potent than BCNU in reducing cell viability. Both CBD and BCNU at their maximal effective dose suppressed proliferation of T98G cells in a time-dependent manner. Specifically, the inhibitory effects of CBD (1 µM) on cell viability and proliferation started at 24hr, whereas the inhibitory effects of BCNU (1mM) on cell viability and proliferation started at 4hr. The differences between the two compounds on viability and proliferation are consistent with the notion that they act through distinct mechanism of action. The strong sensitivity of T98G cells to both CBD and BCNU suggest that it is a suitable model system for the study of the molecular and cellular mechanisms of action and potential interaction of these compounds. Supported by {type:entrez-nucleotide,attrs:{text:DA026430,term_id:78765130,term_text:DA026430}}DA026430 (NS).

Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis.

Current arthritis treatments often have side-effects attributable to active compounds as well as route of administration. Cannabidiol (CBD) attenuates inflammation and pain without side-effects, but CBD is hydrophobic and has poor oral bioavailability. Topical drug application avoids gastrointestinal administration, first pass metabolism, providing more constant plasma levels. This study examined efficacy of transdermal CBD for reduction in inflammation and pain, assessing any adverse effects in a rat complete Freund's adjuvant-induced monoarthritic knee joint model. CBD gels (0.6, 3.1, 6.2 or 62.3mg/day) were applied for 4 consecutive days after arthritis induction. Joint circumference and immune cell invasion in histological sections were measured to indicate level of inflammation. Paw withdrawal latency (PWL) in response to noxious heat stimulation determined nociceptive sensitization, and exploratory behaviour ascertained animal's activity level. Measurement of plasma CBD concentration provided by transdermal absorption revealed linearity with 0.6-6.2mg/day doses. Transdermal CBD gel significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner. PWL recovered to near baseline level. Immunohistochemical analysis of spinal cord (CGRP, OX42) and dorsal root ganglia (TNFα) revealed dose-dependent reductions of pro-inflammatory biomarkers. Results showed 6.2 and 62mg/day were effective doses. Exploratory behaviour was not altered by CBD indicating limited effect on higher brain function. These data indicate that topical CBD application has therapeutic potential for relief of arthritis pain-related behaviours and inflammation without evident side-effects.

Cannabis, a Plant and Its Secret: Cannabidiol

Introduction The association between cannabis and psychotic outcomes is systematically reported. Δ9-tetrahydrocannabinol (THC) is the main psychoactive component of cannabis products and studies emphasize the concentration of THC as the main measure of cannabis potency. Cannabidiol (CBD) is another component of cannabis and studies have suggested that CBD might have antipsychotic properties and could therefore modify the paradigm of pharmacologic treatment in psychotic disorders. Objectives This work aims to describe the latest knowledge about CBD, its molecular targets and possible therapeutic use in psychiatric disorders. Methods This revision was based in articles published in PubMed/MEDLINE, using the following terms 'cannabidiol” 'cannabis”, 'psychotic symptoms”, 'molecular targets” and 'treatment”. Results CBD has multiple molecular targets (CB1 receptors, vaniloid system, hydrolysis of anandamide, agonist in 5HT-1A receptors, nuclear receptors of PPAR family and other ion channels), but a full comprehension about them is lacking. Like other cannabinoid compounds, CBD has a biphasic effect in anxiety (lower doses tend to produce anxiolytic-like effect and higher doses produce an anxiogenic-like effect), though the mechanism is not completely understood. The use of high cannabidiol content cannabis and its association with significantly lower degrees of psychotic symptoms have been reported, nevertheless CBD’s antipsychotic properties are still controversial. Conclusions The higher concentration of CBD in cannabis preparations has been related with fewer psychotic symptoms, compared with a higher THC/CBD ratio plants. Further studies must be held to conclude about CBD’s antipsychotic properties, but its effects in anxiety disorders seems to be promising.

Impact of enzymatic and alkaline hydrolysis on CBD concentration in urine

A sensitive and specific analytical method for cannabidiol (CBD) in urine was needed to define urinary CBD pharmacokinetics after controlled CBD administration, and to confirm compliance with CBD medications including Sativex-a cannabis plant extract containing 1:1 ∆(9)-tetrahydrocannabinol (THC) and CBD. Non-psychoactive CBD has a wide range of therapeutic applications and may also influence psychotropic smoked cannabis effects. Few methods exist for the quantification of CBD excretion in urine, and no data are available for phase II metabolism of CBD to CBD-glucuronide or CBD-sulfate. We optimized the hydrolysis of CBD-glucuronide and/or -sulfate, and developed and validated a GC-MS method for urinary CBD quantification. Solid-phase extraction isolated and concentrated analytes prior to GC-MS. Method validation included overnight hydrolysis (16 h) at 37 °C with 2,500 units β-glucuronidase from Red Abalone. Calibration curves were fit by linear least squares regression with 1/x (2) weighting with linear ranges (r(2) > 0.990) of 2.5-100 ng/mL for non-hydrolyzed CBD and 2.5-500 ng/mL for enzyme-hydrolyzed CBD. Bias was 88.7-105.3 %, imprecision 1.4-6.4 % CV and extraction efficiency 82.5-92.7 % (no hydrolysis) and 34.3-47.0 % (enzyme hydrolysis). Enzyme-hydrolyzed urine specimens exhibited more than a 250-fold CBD concentration increase compared to alkaline and non-hydrolyzed specimens. This method can be applied for urinary CBD quantification and further pharmacokinetics characterization following controlled CBD administration.

Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers

Context: The nonpsychoactive cannabinoid, cannabidiol (CBD), has great potential for the treatment of chronic and ‘breakthrough’ pain that may occur in certain conditions like cancer. To fulfill this goal, suitable noninvasive drug delivery systems need to be developed for CBD. Chronic pain relief can be best achieved through the transdermal route, whereas ‘breakthrough’ pain can be best alleviated with intranasal (IN) delivery. Combining IN and transdermal delivery for CBD may serve to provide patient needs-driven treatment in the form of a nonaddictive nonopioid therapy. Objective: Herein we have evaluated the IN and transdermal delivery of CBD with and without permeation enhancers. Materials and Methods: In vivo studies in rats and guinea pigs were carried out to assess nasal and transdermal permeation, respectively. Results: CBD was absorbed intranasally within 10 minutes with a bioavailability of 34–46%, except with 100% polyethylene glycol formulation in rats. Bioavailability did not improve with enhancers. The steady-state plasma concentration of CBD in guinea pigs after transdermal gel application was 6.3 ± 2.1 ng/mL, which was attained at 15.5 ± 11.7 hours. The achievement of a significant steady-state plasma concentration indicates that CBD is useful for chronic pain treatment through this route of administration. The steady-state concentration increased by 3.7-fold in the presence of enhancer. A good in vitro and in vivo correlation existed for transdermal studies. Conclusion: The results of this study indicated that CBD could be successfully delivered through the IN and transdermal routes.

Inhibitory Effect of Cannabidiol Hydroxy-quinone, an Oxidative Product of Cannabidiol, on the Hepatic Microsomal Drug-Metabolizing Enzymes of Mice.

Cannabidiol hydroxy-quinone (CBDHQ) was identified as an air oxidation product of cannabidiol (CBD). The in vitro incubation of mouse hepatic microsomes with CBDHQ resulted in a decrease of cytochrome P-450 content. CBDHQ inhibited the hepatic microsomal drug-metabolizing enzymes of mice. This inhibitory effect was stronger than that of CBD. CBDHQ (150 microM) inhibited aniline hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase in the microsomes by 70, 52 and 77%, respectively, whereas the same concentration of CBD caused the inhibition by 39, 30 and 26%, respectively. CBDHQ (91.5 microM) significantly decreased total heme content by 21% and free SH groups by 11% in the microsomes. The results indicate that CBDHQ, which is an oxidation product of CBD, inhibits the hepatic microsomal drug-metabolizing enzymes through the decrease of cytochrome P-450 content.

Responses of Greenhouse‐grown Cannabis sativa L. to Nitrogen, Phosphorus, and Potassium1

AbstractGrowers of illegal Cannabis sativa L. use various cultural practices to maximize crop production. The objective of this study was to evaluate the morphological and biochemical responses of greenhouse grown C. sativa to soil incorporated N, P, and K as they reflect the geographical origin of Cannabis derivatives. Fertilizers were blended with Ap horizon soil from a Gilpin silt loam before placement in 12‐cm pots. NH4NO3‐N was applied at 0, 25, and 125 ppm. Phosphorus and K from super‐phosphate and KCI, respectively, were applied at 0, 50, and 150 ppm. Forty‐five‐day‐old anthesic Cannabis plants were harvested and combined leaf and flower tissues were analyzed for cannabidiol (CBD) and Δ9‐tetrahydrocanna‐binol (Δ9THC). Nine essential elements were also measured in plant tissue. Plant growth, tissue yield, and concentration of CBD and Δ9THC were positively correlated with extractable P2O5 (p &lt; 0.01). Phosphorus concentrations in tissue were similarly related to yield of dry matter and cannabinoid concentrations. Uptake of K was positively correlated with extractable K2O across all treatment levels (r=0.40**), but was negatively correlated with tissue yield (r=‐‐0.36**). Growth and tissue yields were negatively related to total plant N (p&lt; 0.01). Levels of extractable P2O5, Mn, B, and Mg were associated with specific concentration ranges for several plant elements plus Δ9THC. Thus, it was possible to partially characterize a soil by tissue analysis. For example, all of the plants grown on soil with less than 100 ppm of extractable P2O5 contained less than 8,000 ppm Δ9THC. Usefulness of such relationships will be dependent upon extensive evaluation of Cannabis on different soils under various cultural conditions. At this time, the reliability required for determination of origin of Canabis derivatives via chemical analysis does not exist when only essential elements and cannabinoids are considered.

Cannabinoid Profile and Elemental Uptake of Cannabis sativa L. as Influenced by Soil Characteristics1

AbstractThe consumption of Cannabis products (marihuana) derived from domestic and foreign sources persists in the United States despite its illegality and health hazards. The objectives of this investigation were: 1) to evaluate relationships between soil and plant elements, cannabinoids, and growth of Cannabis sativa L., and 2) to evaluate the practicality of using chemical analysis of Cannabis products to determine their geographic origin. Knowledge of geographic origin is useful to governmental agencies investigating illicit narcotic traffic.Cannabis sativa L. was grown on 11 different soils for 45 days in the greenhouse. Soils differed significantly in 15 measured elements and pH. Plants were grown from seed of Afghan origin. The following cannabinoids were extracted and measured from leaf tissue: cannabicyclol (CCC), cannabidiol (CBD), Δ9‐Tetrahydrocannabinol (Δ9THC), and cannabinol (CBN). Fifteen elements measured in leaf tissue and correlated with soil and cannabinoid measurements. Soil pH was negatively correlated with leaf concentrations of Mn, Fe, Zn, and S. Extractable soil Mg was negatively correlated with N, Δ9THC and CBD concentrations in leaf tissue (p &lt; 0.05). Plant height was negatively correlated with Δ9THC concentration, suggesting enhancement of the narcotic principle of marihuana when grown under stress. Extractable soil P2O5 was negatively correlated with CBD concentration while extractable soil Zn was positively correlated with CCC concentration. Several correlations between soil and plant characteristics having potential value for determination of geographic origin of marihuana were elucidated. However, environmental, harvesting, and analytical procedures used by different workers which do not conform to one another could result in changes in the soil‐plant correlations reported herein. Thus, additional studies are required before determination of the geographic origin of Cannabis products by foliar analysis becomes feasible.