Synthetic Cannabidiol Research Articles

The Pharmacological Effects of Plant-Derived versus Synthetic Cannabidiol in Human Cell Lines

Introduction: Cannabidiol (CBD) can be isolated from Cannabis sativa L. or synthetically produced. The aim of this study was to compare the in vitro effects of purified natural and synthetic CBD to establish any pharmacological differences or superiority between sources. Methods: Six purified samples of CBD were obtained, 4 of these were natural and 2 synthetic. The anticancer effects of CBD were assessed in a human ovarian cancer cell line (SKOV-3 cells). The neuroprotective effects of CBD were assessed in human pericytes in a model of stroke (oxygen glucose deprivation [OGD]). The ability of CBD to restore inflammation-induced intestinal permeability was assessed in differentiated human Caco-2 cells (a model of enterocytes). Results: (1) In proliferating and confluent SKOV-3 cells, all CBD samples similarly reduced resazurin metabolism as a marker of cell viability in a concentration-dependent manner (p < 0.001). (2) In pericytes exposed to OGD, all CBD samples similarly reduced cellular damage (measured by lactate dehydrogenase) at 24 h by 31–48% and reduced inflammation (measured by IL-6 secretion) by 30–53%. Attenuation of IL-6 was inhibited by 5HT_1A receptor antagonism for all CBD sources. (3) In differentiated Caco-2 cells exposed to inflammation (TNFα and IFNγ, 10 ng/mL for 24 h), each CBD sample increased the speed of recovery of epithelial permeability compared to control (p < 0.05–0.001), which was inhibited by a CB₁ receptor antagonist. Conclusion: Our results suggest that there is no pharmacological difference in vitro in the antiproliferative, anti-inflammatory, or permeability effects of purified natural versus synthetic CBD. The purity and reliability of CBD samples, as well as the ultimate pharmaceutical preparation, should all be considered above the starting source of CBD in the development of new CBD medicines.

Synthetic and Natural Derivatives of Cannabidiol.

The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical phases, its use in sleep-wake pathological alterations has been widely demonstrated.Despite the outstanding current knowledge on CBD therapeutic effects in numerous in vitro and in vivo disease models, diverse questions still arise from its molecular pharmacology. CBD has been shown to modulate a wide variety of targets including the cannabinoid receptors, orphan GPCRs such as GPR55 and GPR18, serotonin, adenosine, and opioid receptors as well as ligand-gated ion channels among others. Its pharmacology israther puzzling and needs to be further explored in the disease context.Also, the metabolism and interactions of this phytocannabinoid with other commercialized drugs need to be further considered to elucidate its clinical potential for the treatment of specific pathologies.Besides CBD, natural and synthetic derivatives of this chemotype have also been reported exhibiting diverse functional profiles and providing a deeper understanding of the potential of this scaffold.In this chapter, we analyze the knowledge gained so far on CBD and its analogs specially focusing on its molecular targets and metabolic implications. Phytogenic and synthetic CBD derivatives may provide novel approaches to improve the therapeutic prospects offered by this promising chemotype.

Chronic administration of synthetic cannabidiol induces antidepressant effects involving modulation of serotonin and noradrenaline levels in the hippocampus

Cannabidiol (CBD) is a non-psychotomimetic compound derived from Cannabis sativa. Preclinical and clinical studies have shown therapeutic potential of CBD in a variety of disorders. Despite several research efforts on CBD, its antidepressant activity has been poorly investigated and the exact mechanism of action remains unclear. Thus, this study aimed to further explore the mechanism of CBD after chronic administration (7 days). First, the dose level of CBD that is enough to produce antidepressant effects after chronic administration was explored. Second, the changes in key proteins and neurotransmitters through such methods as real-time polymerase chain reaction (RT-PCR), western blotting, and high-performance liquid chromatography-electrochemical detection (HPLC-ECD) were critically studied. Furthermore, correlation between behavioral phenotypes with protein and neurotransmitters was established and the possible mechanism was herein postulated. The results showed that only the high dose CBD 100 mg/kg chronic administration induced antidepressant-like effects in mice subjected to forced swim test. Chronic CBD 100 mg/kg administration resulted in significant increases in serotonin (5-HT) and noradrenaline (NA) levels in the hippocampus (HPC). Similarly, the chronic administration of CBD 30 mg/kg and CBD 100 mg/kg significantly decreased nuclear factor kappa B (NF-κB) expression in the HPC. Moreover, none of the treatments were observed to induce locomotor effects. Thus, we concluded that chronic administration of CBD (100 mg/kg) induced antidepressant-like effects by increasing 5-HT and NA levels in the HPC. These results shed new light on further discovery of the antidepressant effect of CBD.

Report of Objective Responses of Prostate Cancer Patients to Pharmaceutical Grade Synthetic Cannabidiol

This is an observational study of objective responses of Prostate Cancer patients to Pharmaceutical Grade Synthetic Cannabidiol. The total number of patients in the study was 12, 11 had a response of one kind or another.

Report of Objective Responses of Breast Cancer Patients to Pharmaceutical Grade Synthetic Cannabidiol

This report is an observational study of objective responses of Breast Cancer patients to Pharmaceutical Grade Synthetic Cannabidiol. There were 29 total cases out of which 27 showed a clinical response.

Report of Objective Responses of Glioma Patients to Pharmaceutical Grade Synthetic Cannabidiol

This is an observational study of objective responses of Glioma patients to Pharmaceutical Grade Synthetic Cannabidiol. 14 assessable cases were identified, 9 showed a clinical response, 5 showed no effect.

Pharmacokinetic investigation of synthetic cannabidiol oral formulations in healthy volunteers

Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of scientific research. The reasons behind this popularity is the compound’s therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration.The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers.The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS).Administration of CBD in lipid-based vehicles resulted in a significant increase in Cmax and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile.Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid pharmacokinetics.

Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis

Multiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/Cannabinoid receptor type 2 (PPARγ/CB2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) pathway. EHP-101 is an oral lipidic formulation of VCE-004.8 that has shown efficacy in several preclinical models of autoimmune, inflammatory, fibrotic, and neurodegenerative diseases. EHP-101 alleviated clinical symptomatology in EAE and transcriptomic analysis demonstrated that EHP-101 prevented the expression of many inflammatory genes closely associated with MS pathophysiology in the spinal cord. EHP-101 normalized the expression of several genes associated with oligodendrocyte function such as Teneurin 4 (Tenm4) and Gap junction gamma-3 (Gjc3) that were downregulated in EAE. EHP-101 treatment prevented microglia activation and demyelination in both the spinal cord and the brain. Moreover, EAE was associated with a loss in the expression of Oligodendrocyte transcription factor 2 (Olig2) in the corpus callosum, a marker for oligodendrocyte differentiation, which was restored by EHP-101 treatment. In addition, EHP-101 enhanced the expression of glutathione S-transferase pi (GSTpi), a marker for mature oligodendrocytes in the brain. We also found that a diet containing 0.2% cuprizone for six weeks induced a clear loss of myelin in the brain measured by Cryomyelin staining and Myelin basic protein (MBP) expression. Moreover, EHP-101 also prevented cuprizone-induced microglial activation, astrogliosis and reduced axonal damage. Our results provide evidence that EHP-101 showed potent anti-inflammatory activity, prevented demyelination, and enhanced remyelination. Therefore, EHP-101 represents a promising drug candidate for the potential treatment of different forms of MS.

Symrise makes synthetic CBD

The flavor and fragrance maker Symrise has developed a method to produce cannabidiol (CBD) from the citrus extract d-limonene. CBD, which is found naturally in cannabis plants but doesn’t produce a...

Plant derived versus synthetic cannabidiol: Wishes and commitment of epilepsy patients

PurposeA special component of cannabis, cannabidiol (CBD), is currently in the focus of epilepsy treatment and research. In this context, we investigated patients’ expectations and preferences pertaining to plant-derived versus synthetic formulation of cannabidiol, as well as their willingness to get this treatment. MethodsOne hundred and four of 153 patients with different forms of epilepsy (54 % female, mean age 40 ± 16 yrs.) responded to the survey. The survey consisted of 8 questions addressing expectations of and concerns towards CBD treatment, preferences of plant-derived versus synthetic CBD, estimated monthly costs, and willingness to buy CBD at one’s own expense. ResultsThe majority (73 %) of the responding epilepsy patients wished to receive plant-derived CBD; 5 % preferred synthetic CBD. Reasons for this choice were botanic origin, lack of chemistry, and the assumption of fewer and less dangerous side effects. Eighty-two percent of the patients estimated the monthly costs of CBD treatment to be below €500. Using the willingness-to-pay approach to assess the commitment of patients, 68 % could imagine buying the drug themselves. Fifty-three percent of these would be willing to pay up to €100, 40 % €100 to €200, and another 7 % €200 to €500 per month. ConclusionThere is an overwhelming preference towards plant-derived cannabidiol in epilepsy patients, driven by the idea of organic substances being safer and better tolerated than synthetic. The willingness-to-pay approach reflects the high burden and pressure of uncontrolled epilepsy and the expectation of relief. Non-realistic ideas of pricing as well as what patients would be willing and able to pay confirm this perception.

Is cannabidiol a scheduled controlled substance? Origin makes the difference

Cannabidiol (CBD) is the main cannabinoid naturally occurring in hemp. It has recently attracted the attention of the scientific community because of its numerous pharmacological activities. However, its legal status changes depending on whether it is chemically synthesized or extracted from the plant: extracted CBD is a scheduled controlled substance, whereas synthetic CBD is not under control. In Europe, extracted CBD is excluded from the cosmetic ingredients of the CosIng database. Given the confusion surrounding these different forms of CBD, there is an urgent need for clarity to shed light from both a regulatory and a chemical point of view. The impurity profiles of synthetic and natural CBD are different and could currently represent the only means to distinguish the origin of this substance.

Efficacy and Tolerance of Synthetic Cannabidiol for Treatment of Drug Resistant Epilepsy.

Objective: Controlled and open label trials have demonstrated efficacy of cannabidiol for certain epileptic encephalopathies. However, plant derived cannabidiol products have been used almost exclusively. Efficacy of synthetically derived cannabidiol has not been studied before. The objective of this study was to evaluate tolerability and efficacy of synthetic cannabidiol in patients with pharmacoresistant epilepsy.Methods: In this prospective, open-label study (DRKS00013177), patients with pharmacoresistant epilepsy received synthetic cannabidiol in addition to their previously stable anticonvulsive treatment. Starting dose was 5 mg/kg/day, up-titrated to a maximum of 50 mg/kg/day. Primary efficacy endpoint was monthly frequency of motor seizures at 3 months.Results: Between April 2017 and May 2019, 35 patients were enrolled in the study. Mean age was 19.7 years (SD 14.6). Median motor seizure frequency decreased from 21.8 (IQR 7.5–52.5) seizures per month at baseline to 8.5 (IQR 3.7–28.3, p < 0.001) at 3 months, effect not influenced by AED changes and drop-outs. Adjusted percentage reduction was 40.0% (IQR 18.2–58.5). Adverse events (AE) were reported in 25 patients (71.4%), most frequently somnolence (40%), diarrhea (34.3), and loss of appetite (20%). Two patients (5.7%) discontinued treatment due to AE. Median (range) of treatment duration was 321 days (range 36–824). With ongoing treatment up to date in 21 patients (60%).Conclusion: Efficacy and tolerance in our study of synthetic CBD treatment in pharmacoresistant epilepsy is similar to open label studies using plant derived CBD. Regarding economic and ecological aspects, synthetic cannabidiol might be a reasonable alternative to plant derived cannabidiol.

Synthetic pharmaceutical grade cannabidiol for treatment of refractory infantile spasms: A multicenter phase-2 study

PurposeLimited data suggest that cannabidiol (CBD) may be effective for treatment of refractory infantile spasms (IS). This study was designed to more rigorously evaluate the efficacy and safety of synthetic CBD in the treatment of IS. MethodsChildren six to 36 months of age with IS that failed treatment with both adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) were eligible for enrollment. Children receiving clobazam were excluded. After baseline overnight video-electroencephalography (vEEG) to confirm diagnosis and ascertain hypsarrhythmia, patients were treated with synthetic CBD oral solution (20 mg/kg/day). Overnight video-EEG was repeated after 14 days, and both baseline and repeat video-EEGs were completely de-identified and reviewed in a pairwise fashion by an independent, blinded pediatric electroencephalographer. The primary efficacy endpoint was freedom from spasms and hypsarrhythmia on day 14. ResultsNine patients were enrolled, comprising an older (median age = 23 months) cohort with long-standing IS (median duration = 13 months) and numerous prior treatment failures (median = 6). One patient responded to therapy and eight patients exhibited neither clinical nor electrographic response. ConclusionsThe immediate but temporary response in a single patient suggests that CBD oral solution is not particularly effective in highly refractory cases, but may, nevertheless, be effective in younger patients with shorter durations of IS. Further study, examining both short- and long-term outcomes, is warranted to further evaluate the efficacy and safety of CBD oral solution in the treatment of IS.

BioVectra ramps up cannabidiol output

The drug-service firm BioVectra will produce fully synthetic cannabidiol as an active pharmaceutical ingredient at its plant in Charlottetown, Prince Edward Island. The firm says its work with cannabinoids dates back to the early 2000s when it developed a supply of tetrahydrocannabinol. Meanwhile, BioVectra has launched a $1.5 million project to replace large-scale synthetic reactors and upgrade analytical services in Charlottetown.

Report of Objective Clinical Responses in Patients with Brain Cancer to Pharmaceutical-Grade Synthetic Cannabidiol

Report of Objective Clinical Responses in Patients with Brain Cancer to Pharmaceutical-Grade Synthetic Cannabidiol

Case Report: Report of Objective Clinical Responses in Patients with Brain Cancer to Pharmaceutical-Grade Synthetic Cannabidiol

Background/Aim: Cannabinoids are widely used in the management of pain, nausea and cachexia in cancer patients. However, there has been no objective clinical evidence of any anticancer activity yet. The aim of this study was to assess the effects of Pharmaceutical-Grade Synthetic Cannabidiol on a range of Brain Tumours Patients and Methods: We analysed the data routinely collected as part of our treatment program in 11 Brain Cancer patients over a four- year period. Results: Clinical responses were seen in all of these 11 patients, including a reduction in tumour size, as shown by repeat scans. There were no side effects of any kind observed when using Pharmaceutical-Grade Synthetic Cannabidiol. Pharmaceutical-Grade Synthetic Cannabidiol was supplied by STI Pharmaceuticals. Conclusion: Pharmaceutical-Grade Synthetic Cannabidiol is a candidate for treating glioma patients.

Report of Objective Clinical Responses of Cancer Patients to Pharmaceutical-grade Synthetic Cannabidiol

Cannabinoids are widely used in the management of pain, nausea and cachexia in cancer patients. However, there has been no objective clinical evidence of any anticancer activity yet. The aim of this study was to assess the effects of pharmaceutical-grade synthetic cannabidiol on a range of cancer patients. We analysed the data routinely collected, as part of our treatment program, in 119 cancer patients over a four-year period. Clinical responses were seen in 92% of the 119 cases with solid tumours including a reduction in circulating tumour cells in many cases and in other cases, a reduction in tumour size, as shown by repeat scans. No side-effects of any kind were observed when using pharmaceutical grade synthetic cannabidiol. Pharmaceutical-grade synthetic cannabidiol is a candidate for treating breast cancer and glioma patients.

GPR55: A therapeutic target for Parkinson's disease?

The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD.

An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol.

Cannabidiol (CBD) has been traditionally used in Cannabis-based preparation, however historically, it has received far less interest as a single drug than the other components of Cannabis. Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging.

The use of cannabis in supportive care and treatment of brain tumor.

Cannabinoids are multitarget substances. Currently available are dronabinol (synthetic delta-9-tetrahydrocannabinol, THC), synthetic cannabidiol (CBD) the respective substances isolated and purified from cannabis, a refined extract, nabiximols (THC:CBD = 1.08:1.00); and nabilone, which is also synthetic and has properties that are very similar to those of THC. Cannabinoids have a role in the treatment of cancer as palliative interventions against nausea, vomiting, pain, anxiety, and sleep disturbances. THC and nabilone are also used for anorexia and weight loss, whereas CBD has no orexigenic effect. The psychotropic effects of THC and nabilone, although often undesirable, can improve mood when administered in low doses. CBD has no psychotropic effects; it is anxiolytic and antidepressive. Of particular interest are glioma studies in animals where relatively high doses of CBD and THC demonstrated significant regression of tumor volumes (approximately 50% to 95% and even complete eradication in rare cases). Concomitant treatment with X-rays or temozolomide enhanced activity further. Similarly, a combination of THC with CBD showed synergistic effects. Although many questions, such as on optimized treatment schedules, are still unresolved, today's scientific results suggest that cannabinoids could play an important role in palliative care of brain tumor patients.