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1.
Pharmaceuticals (Basel) ; 17(2)2024 Feb 13.
Article in English | MEDLINE | ID: mdl-38399459

ABSTRACT

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.

2.
J Cannabis Res ; 5(1): 21, 2023 Jun 13.
Article in English | MEDLINE | ID: mdl-37312194

ABSTRACT

The use of cannabidiol (CBD) for therapeutic purposes is receiving considerable attention, with speculation that CBD can be useful in a wide range of conditions. Only one product, a purified form of plant-derived CBD in solution (Epidiolex), is approved for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Appraisal of the therapeutic evidence base for CBD is complicated by the fact that CBD products sometimes have additional phytochemicals (like tetrahydrocannabinol (THC)) present, which can make the identification of the active pharmaceutical ingredient (API) in positive studies difficult. The aim of the present review is to critically review clinical studies using purified CBD products only, in order to establish the upcoming indications for which purified CBD might be beneficial. The areas in which there is the most clinical evidence to support the use of CBD are in the treatment of anxiety (positive data in 7 uncontrolled studies and 17 randomised controlled trials (RCTs)), psychosis and schizophrenia (positive data in 1 uncontrolled study and 8 RCTs), PTSD (positive data in 2 uncontrolled studies and 4 RCTs) and substance abuse (positive data in 2 uncontrolled studies and 3 RCTs). Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT. Limited evidence supports the use of CBD for the treatment of Parkinson's (3 positive uncontrolled studies and 2 positive RCTs), autism (3 positive RCTs), smoking cessation (2 positive RCTs), graft-versus-host disease and intestinal permeability (1 positive RCT each). Current RCT evidence does not support the use of purified oral CBD in pain (at least as an acute analgesic) or for the treatment of COVID symptoms, cancer, Huntington's or type 2 diabetes. In conclusion, published clinical evidence does support the use of purified CBD in multiple indications beyond epilepsy. However, the evidence base is limited by the number of trials only investigating the acute effects of CBD, testing CBD in healthy volunteers, or in very small patient numbers. Large confirmatory phase 3 trials are required in all indications.

3.
Pharmacol Ther ; 240: 108216, 2022 12.
Article in English | MEDLINE | ID: mdl-35609718

ABSTRACT

Characterised by chronic widespread musculoskeletal pain, generalised hyperalgesia, and psychological distress, fibromyalgia (FM) is a significant unmet clinical need. The endogenous cannabinoid system plays an important role in modulating both pain and the stress response. Here, we appraise the evidence, from preclinical and clinical studies, for a role of the endocannabinoid system in FM and the therapeutic potential of targeting the endocannabinoid system. While many animal models have been used to study FM, the reserpine-induced myalgia model has emerged as perhaps the most translatable to the clinical phenotype. Inhibition of fatty acid amide hydrolase (FAAH) has shown promise in preclinical studies, ameliorating pain- and anxiety-related behaviour . Clinically, there is evidence for alterations in the endocannabinoid system in patients with FM, including single nucleotide polymorphisms and increased levels of circulating endocannabinoids and related N-acylethanolamines. Single entity cannabinoids, cannabis, and cannabis-based medicines in patients with FM show promise therapeutically but limitations in methodology and lack of longitudinal studies to assess efficacy and tolerability preclude the current recommendation for their use in patients with FM. Gaps in the literature that warrant further investigation are discussed, particularly the need for further development of animal models with high validity for the multifaceted nature of FM, balanced studies to eliminate sex-bias in preclinical research, and ultimately, better translation between preclinical and clinical research.


Subject(s)
Cannabinoids , Cannabis , Chronic Pain , Fibromyalgia , Animals , Humans , Endocannabinoids , Cannabinoids/pharmacology , Cannabinoids/therapeutic use , Fibromyalgia/drug therapy , Fibromyalgia/chemically induced , Fibromyalgia/psychology , Chronic Pain/drug therapy
4.
Cannabis Cannabinoid Res ; 7(2): 207-213, 2022 04.
Article in English | MEDLINE | ID: mdl-33998849

ABSTRACT

Introduction: Over-the-counter cannabidiol (CBD) products have seen unprecedented recent growth in the United Kingdom. However, analysis of these predominantly unregulated products from other countries tells us that they are often mislabeled or contain unlabeled and potentially dangerous chemicals. Thus, the aim of the present study was to analyze CBD oils available in the United Kingdom. Materials and Methods: Phytocannabinoids, residual solvent, and heavy metals were measured blinded in 29 widely available CBD products by an independent testing facility using high-performance liquid chromatography with diode-array detection for cannabinoids, Headspace-gas chromatography-flame ionization detector and gas chromatography-mass spectrometry for residual solvents, and inductively coupled plasma-mass spectrometry for heavy metals. Results: The mean advertised CBD content was 4.5%, and the actual mean measured CBD content of products was 3.2% (p=0.053, Mann-Whitney test). Only 11/29 (38%) products were within 10% of the advertised CBD content. Fifty five percent of products had measurable levels of the controlled substances Δ9-tetrahydrocannabinol (mean content 0.04%) or cannabinol (mean content 0.01%), as well as most other phytocannabinoid compounds including cannabidiolic acid (CBDA), cannabidivarin (CBDV), and cannabidivarin acid (CBDVA). Detectable levels of N-pentane, ethanol, isopropanol, heptane, lead, and arsenic were found in many of the CBD products, but these were within acceptable levels. Conclusions: As demonstrated in other countries, the quality of over-the-counter CBD products in the United Kingdom can be substandard, particularly with regard to CBD content, and often contains levels of controlled substances. We recommend that these products be more strictly regulated for consumer welfare.


Subject(s)
Cannabidiol , Cannabis , Cannabidiol/analysis , Cannabis/chemistry , Controlled Substances , Dronabinol/analysis , Gas Chromatography-Mass Spectrometry
5.
Molecules ; 26(20)2021 Oct 13.
Article in English | MEDLINE | ID: mdl-34684760

ABSTRACT

The cannabinoid 1 (CB1) receptor regulates appetite and body weight; however, unwanted central side effects of both agonists (in wasting disorders) or antagonists (in obesity and diabetes) have limited their therapeutic utility. At the peripheral level, CB1 receptor activation impacts the energy balance of mammals in a number of different ways: inhibiting satiety and emesis, increasing food intake, altering adipokine and satiety hormone levels, altering taste sensation, decreasing lipolysis (fat break down), and increasing lipogenesis (fat generation). The CB1 receptor also plays an important role in the gut-brain axis control of appetite and satiety. The combined effect of peripheral CB1 activation is to promote appetite, energy storage, and energy preservation (and the opposite is true for CB1 antagonists). Therefore, the next generation of CB1 receptor medicines (agonists and antagonists, and indirect modulators of the endocannabinoid system) have been peripherally restricted to mitigate these issues, and some of these are already in clinical stage development. These compounds also have demonstrated potential in other conditions such as alcoholic steatohepatitis and diabetic nephropathy (peripherally restricted CB1 antagonists) and pain conditions (peripherally restricted CB1 agonists and FAAH inhibitors). This review will discuss the mechanisms by which peripheral CB1 receptors regulate body weight, and the therapeutic utility of peripherally restricted drugs in the management of body weight and beyond.


Subject(s)
Body Weight/physiology , Receptor, Cannabinoid, CB1/drug effects , Receptor, Cannabinoid, CB1/metabolism , Appetite/physiology , Cannabinoid Receptor Antagonists/therapeutic use , Cannabinoids/therapeutic use , Endocannabinoids/therapeutic use , Humans , Obesity/drug therapy , Receptor, Cannabinoid, CB1/physiology , Receptor, Cannabinoid, CB2/drug effects , Receptor, Cannabinoid, CB2/metabolism , Receptor, Cannabinoid, CB2/physiology , Receptors, Cannabinoid/metabolism , Receptors, Cannabinoid/physiology
6.
Pharmaceuticals (Basel) ; 13(9)2020 Aug 28.
Article in English | MEDLINE | ID: mdl-32872355

ABSTRACT

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.

7.
Drug Discov Today ; 2020 Sep 20.
Article in English | MEDLINE | ID: mdl-32966866

ABSTRACT

Emerging evidence suggests that dysregulated lipid signaling is a key factor in prostate cancer (PC), through fatty acid activation of the nuclear receptors peroxisome proliferator-activated receptors (PPARs), leading to the upregulation of protumoral genes. Fatty acid-binding proteins (FABPs) are intracellular lipid-binding proteins that transport fatty acid to PPARs, facilitating their activation. FABP5 is overexpressed in PC, and correlates with poor patient prognosis and survival. Genetic knockdown or silencing of FABP5 decreases the proliferation and invasiveness of PC cells in vitro, and reduces tumor growth and metastasis in vivo. Pharmacological FABP5-specific inhibitors also reduce tumor growth and metastases, and produce synergistic effects with taxanes. In this review, we present current data supporting FABP5 as a novel molecular target for PC.

8.
Br J Pharmacol ; 173(12): 1899-910, 2016 06.
Article in English | MEDLINE | ID: mdl-27077495

ABSTRACT

Some cannabinoids activate the different isoforms of PPARs (α, ß and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation.


Subject(s)
Cannabinoids/pharmacology , Peroxisome Proliferator-Activated Receptors/agonists , Peroxisome Proliferator-Activated Receptors/metabolism , Animals , Humans , Structure-Activity Relationship
9.
PLoS One ; 10(9): e0136546, 2015.
Article in English | MEDLINE | ID: mdl-26414859

ABSTRACT

The endocannabinoid system is expressed in bone, although its role in the regulation of bone growth is controversial. Many studies have examined the effect of endocannabinoids directly on osteoclast function, but few have examined their role in human osteoblast function, which was the aim of the present study. Human osteoblasts were treated from seeding with increasing concentrations of anandamide or 2-arachidonoylglycerol for between 1 and 21 days. Cell proliferation (DNA content) and differentiation (alkaline phosphatase (ALP), collagen and osteocalcin secretion and calcium deposition) were measured. Anandamide and 2-arachidonoylglycerol significantly decreased osteoblast proliferation after 4 days, associated with a concentration-dependent increase in ALP. Inhibition of endocannabinoid degradation enzymes to increase endocannabinoid tone resulted in similar increases in ALP production. 2-arachidonoylglycerol also decreased osteocalcin secretion. After prolonged (21 day) treatment with 2-arachidonoylglycerol, there was a decrease in collagen content, but no change in calcium deposition. Anandamide did not affect collagen or osteocalcin, but reduced calcium deposition. Anandamide increased levels of phosphorylated CREB, ERK 1/2 and JNK, while 2-arachidonoylglycerol increased phosphorylated CREB and Akt. RT-PCR demonstrated the expression of CB2 and TRPV1, but not CB1 in HOBs. Anandamide-induced changes in HOB differentiation were CB1 and CB2-independent and partially reduced by TRPV1 antagonism, and reduced by inhibition of ERK 1/2 and JNK. Our results have demonstrated a clear involvement of anandamide and 2-arachidonoylglycerol in modulating the activity of human osteoblasts, with anandamide increasing early cell differentiation and 2-AG increasing early, but decreasing late osteoblast-specific markers of differentiation.


Subject(s)
Arachidonic Acids/pharmacology , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Endocannabinoids/pharmacology , Glycerides/pharmacology , Osteoblasts/metabolism , Polyunsaturated Alkamides/pharmacology , Antigens, Differentiation/metabolism , Cells, Cultured , Cyclic AMP Response Element-Binding Protein/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Osteoblasts/cytology , Phosphorylation/drug effects , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , TRPV Cation Channels/metabolism
10.
Handb Exp Pharmacol ; 231: 393-422, 2015.
Article in English | MEDLINE | ID: mdl-26408169

ABSTRACT

The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.


Subject(s)
Cardiovascular Diseases/metabolism , Cardiovascular System/metabolism , Endocannabinoids/metabolism , Animals , Cannabinoid Receptor Agonists/therapeutic use , Cannabinoid Receptor Antagonists/therapeutic use , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/physiopathology , Cardiovascular System/drug effects , Cardiovascular System/physiopathology , Endocannabinoids/therapeutic use , Hemodynamics , Humans , Receptor, Cannabinoid, CB1/drug effects , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/drug effects , Receptor, Cannabinoid, CB2/metabolism , Signal Transduction
11.
J Pharmacol Exp Ther ; 351(2): 457-66, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25212218

ABSTRACT

Cannabidiol (CBD) decreases insulitis, inflammation, neuropathic pain, and myocardial dysfunction in preclinical models of diabetes. We recently showed that CBD also improves vasorelaxation in the Zucker diabetic fatty (ZDF) rat, and the objective of the present study was to establish the mechanisms underlying this effect. Femoral arteries from ZDF rats and ZDF lean controls were isolated, mounted on a myograph, and incubated with CBD (10 µM) or vehicle for 2 hours. Subsequent vasorelaxant responses were measured in combination with various interventions. Prostaglandin metabolites were detected using enzyme immunoassay. Direct effects of CBD on cyclooxygenase (COX) enzyme activity were measured by oxygraph assay. CBD enhanced the maximum vasorelaxation to acetylcholine (ACh) in femoral arteries from ZDF lean rats (P < 0.01) and especially ZDF rats (P < 0.0001). In ZDF arteries, this enhancement persisted after cannabinoid receptor (CB) type 1, endothelial CB, or peroxisome proliferator-activated receptor-γ antagonism but was inhibited by CB2 receptor antagonism. CBD also uncovered a vasorelaxant response to a CB2 agonist not previously observed. The CBD-enhanced ACh response was endothelium-, nitric oxide-, and hydrogen peroxide-independent. It was, however, COX-1/2- and superoxide dismutase-dependent, and CBD enhanced the activity of both purified COX-1 and COX-2. The CBD-enhanced ACh response in the arteries was inhibited by a prostanoid EP4 receptor antagonist. Prostaglandin E2 metabolite levels were below the limits of detection, but 6-keto prostaglandin F1 α was decreased after CBD incubation. These data show that CBD exposure enhances the ability of arteries to relax via enhanced production of vasodilator COX-1/2-derived products acting at EP4 receptors.


Subject(s)
Cannabidiol/pharmacology , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Acetylcholine/pharmacology , Animals , Diabetes Mellitus, Type 2/metabolism , Dinoprostone/metabolism , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Femoral Artery/drug effects , Femoral Artery/metabolism , Hydrogen Peroxide/metabolism , Male , Nitric Oxide/metabolism , PPAR gamma/antagonists & inhibitors , PPAR gamma/metabolism , Rats , Rats, Zucker , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Receptor, Cannabinoid, CB2/metabolism , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Superoxide Dismutase/metabolism
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