Cannabis-based Medicinal Extracts Research Articles

Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial

IntroductionAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3–5 years post diagnosis. The use of complementary medicine such as...

Medicinal cannabis: Principal cannabinoids concentration and their stability evaluated by a high performance liquid chromatography coupled to diode array and quadrupole time of flight mass spectrometry method

In the last few years, there has been a boost in the use of cannabis-based extracts for medicinal purposes, although their preparation procedure has not been standardized but rather decided by the individual pharmacists. The present work describes the development of a simple and rapid high performance liquid chromatography method with UV detection (HPLC-UV) for the qualitative and quantitative determination of the principal cannabinoids (CBD-A, CBD, CBN, THC and THC-A) that could be applied to all cannabis-based medicinal extracts (CMEs) and easily performed by a pharmacist. In order to evaluate the identity and purity of the analytes, a high-resolution mass spectrometry (HPLC-ESI-QTOF) analysis was also carried out. Full method validation has been performed in terms of specificity, selectivity, linearity, recovery, dilution integrity and thermal stability. Moreover, the influence of the solvent (ethyl alcohol and olive oil) was evaluated on cannabinoids degradation rate. An alternative extraction method has then been proposed in order to preserve cannabis monoterpene component in final CMEs.

The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review.

To carry out a systematic review to assess the effectiveness of cannabis extracts and cannabinoids in the management of chronic nonmalignant neuropathic pain. Electronic database searches were performed using Medline, PubMed, Embase, all evidence-based medicine reviews, and Web of Science, through communication with the Canadian Consortium for the Investigation of Cannabinoids (CCIC), and by searching printed indices from 1950. Terms used were marijuana, marihuana, cannabis, cannabinoids, nabilone, delta- 9-tetrahydrocannabinol, cannabidiol, ajulemic acid, dronabinol, pain, chronic, disease, and neuropathic. Randomized placebo-controlled trials (RCTs) involving cannabis and cannabinoids for the treatment of chronic nonmalignant pain were selected. Outcomes considered were reduction in pain intensity and adverse events. Of the 24 studies that examined chronic neuropathic pain, 11 studies were excluded. The 13 included studies were rated using the Jadad Scale to measure bias in pain research. Evaluation of these studies suggested that cannabinoids may provide effective analgesia in chronic neuropathic pain conditions that are refractory to other treatments. Cannabis-based medicinal extracts used in different populations of chronic nonmalignant neuropathic pain patients may provide effective analgesia in conditions that are refractory to other treatments. Further high-quality studies are needed to assess the impact of the duration of the treatment as well as the best form of drug delivery.

Nabiximols in the treatment of spasticity, pain and urinary symptoms due to multiple sclerosis

Introduction: Over the last two decades, experimental and clinical data suggest a therapeutic benefit of cannabis-based medicines for a variety of multiple sclerosis (MS) symptoms. Clinical trials, both with synthetic or plant-derived cannabinoids, have demonstrated clinical efficacy of cannabinoids for the treatment of spasticity, neuropathic pain and bladder dysfunction. Nabiximols, a 1:1 mix of delta-9-tetrahydrocanabinol and cannabidiol extract from cloned chemovars, was licensed in the UK in 2010 and has also been approved in other European countries and Canada. The European Federation of Neurological Societies recommends that cannabis should be used only as a second or third line treatment in central neuropathic pain.Areas covered: After a brief discussion of the endocannabinoid system, this review focuses on the use of cannabis to improve MS symptoms. More specifically, the authors have analyzed clinical studies on cannabis-based medicine extract (CBME), in particular nabiximols, in spasticity, as well as pain, and bladder dysfunction in MS. The authors have considered the large randomized controlled trials examining the psychological effects associated with cannabinoids use as well as long-term follow-up studies.Expert opinion: Despite a number of trials with very promising results, there are still concerns related to relative paucity of data on long-term safety. Also, the long-term efficacy information in terms of the control of symptoms of a disease in which the natural history is progression is sparse. Therefore, further studies are required to improve the current knowledge of nabiximols.

Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects

Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL(-1) . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. http://dx.doi.org/10.1111/bph.2011.163.issue-7.

New approaches in the management of spasticity in multiple sclerosis patients: role of cannabinoids.

Cannabinoids such as Cannabis-based medicinal extracts (CBMEs) are increasingly being used in the treatment of spasticity associated with multiple sclerosis (MS). They have been shown to have a beneficial effect on spasticity; however, this evidence is largely based on subjective rating scales. Objective measurements using the Ashworth scale have tended to show no significant effect; however, the validity of this scale has been questioned. The available clinical trial data suggest that the adverse side effects associated with using CBMEs are generally mild, such as dry mouth, dizziness, somnolence, nausea and intoxication. However, most of these trials were run over a period of months and it is possible that other adverse side effects could develop with long-term use. There may be reason to be concerned about the use of therapeutic cannabinoids by adolescents, people predisposed to psychosis and pregnant women.

MULTIPLE SCLEROSIS AND CANNABIS: A COGNITIVE AND PSYCHIATRIC STUDY

Drs. Ghaffar and Feinstein1 report important new data associating regular smoking of street cannabis in patients with multiple sclerosis (MS) with more extensive cognitive abnormalities compared to patients with MS who do not use cannabis. In 2006 we reported subtle deficits in specific neuropsychological domains in heavy, long-term cannabis users that were in the unintoxicated state.2 The Ghaffar and Feinstein report provides evidence that patients with MS might suffer additional cognitive decline when smoking cannabis regularly.1 However, cognitive deficits that have been attributed to regular recreational use of cannabis are not necessarily extended to controlled pharmaceutical use of cannabis-based medicinal extracts (CBMEs). However, the findings of Ghaffar and Feinsten form the basis on which to raise concern regarding potential cognitive adverse effects of long-term regular cannabis use in MS. We recently reviewed MS clinical trial data of CBMEs and specifically focused on parallel assessments of cognitive status in order to establish whether any disruptive effects on cognition had been documented in these trials.3 Available data indicated that no significant cognitive decline occurs after relatively short-term administration of CBMEs. …

Multiple Sclerosis, Cannabinoids, and Cognition

Multiple Sclerosis, Cannabinoids, and Cognition

Multiple Sclerosis, Cannabinoids, and Cognition

There is increasing interest in the therapeutic potential of cannabis-based medicinal extracts in multiple sclerosis. Cognitive deficits that have been attributed to long-term heavy recreational use of cannabis are not necessarily extended to controlled pharmaceutical use of cannabis-based medicinal extracts. Available data indicate that after relatively short-term administration of cannabis-based medicinal extracts no significant cognitive decline occurs. Due to the absence of large scale long-term systematic clinical trials of cannabis-based medicinal extracts in multiple sclerosis therapeutics, however, many issues remain unresolved, including the possible adverse effects of cannabis-based medicinal extracts on cognition. This article critically reviews the current literature and considers the potential for cognitive adverse effects of long-term cannabinoid use in multiple sclerosis therapeutics.

Randomized, Double-Blind, Placebo-Controlled Study About the Effects of Cannabidiol (CBD) on the Pharmacokinetics of ??9-Tetrahydrocannabinol (THC) After Oral Application of THC Verses Standardized Cannabis Extract

Cannabidiol (CBD) is known to modify the effects of Delta-tetrahydrocannabinol (THC) by decreasing anxiety and antagonizing other THC-effects. As a reason, pharmacodynamic as well as pharmacokinetic mechanisms were suggested. In context of the use of cannabis-based medicine extracts for therapeutic purposes, a study was performed in a double-blind and placebo-controlled cross-over design in which each of 24 volunteers (12 male and 12 female, age 18-45 years) obtained soft-gelatin capsules with 10 mg THC (THC-set), cannabis extract containing 10 mg THC +5.4 mg CBD (CAN-set) or placebo in weekly intervals. Blood samples were taken 30 minutes before and 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours and 24 hours after the intake. The concentrations of THC, of its metabolites 11-OH-THC, THC-COOH and of CBD in the plasma samples were determined by automatic solid phase extraction, derivatization with N,O-bis(trimethylsilyl)triflouroacetamide and gas chromatography-mass spectrometry. The concentration versus time curves (maximum concentrations Cmax, corresponding time tmax and areas under the curves AUC) were evaluated by statistical methods with respect to equivalence or differences between the CAN-set and the THC-set. Furthermore, the intra-individual ratios of Cmax and AUC for 11-OH-THC/THC, THC-COOH/THC and THC-COOH/11-OH-THC were compared between the THC-set and the CAN-set. Despite the large variation of the data, evidence emerged from the total of the results that CBD partially inhibits the CYP 2C catalyzed hydroxylation of THC to 11-OH-THC. The probability for this inhibition is particularly high for oral intake because THC and CBD attain relatively high concentrations in the liver and because of the high first-pass metabolism of THC. However, the effect of CBD is small in comparison to the variability caused by other factors. Therefore, a pharmacokinetic reason for the differences determined between pure THC and cannabis extract is improbable at the doses chosen in this study. Significantly higher AUC and Cmax and shorter tmax were found for females as compared with males.

Simultaneous and Sensitive Analysis of THC, 11-OH-THC, THC-COOH, CBD, and CBN by GC-MS in Plasma after Oral Application of Small Doses of THC and Cannabis Extract

Besides the psychoactive Delta(9)-tetrahydrocannabinol (THC), hashish and marijuana as well as cannabis-based medicine extracts contain varying amounts of cannabidiol (CBD) and of the degradation product cannabinol (CBN). The additional determination of these compounds is interesting from forensic and medical points of view because it can be used for further proof of cannabis exposure and because CBD is known to modify the effects of THC. Therefore, a method for the simultaneous quantitative determination of THC, its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH), CBD and CBN from plasma was developed. The method was based on automatic solid-phase extraction with C(18) ec columns, derivatization with N,O-bistrimethylsilyltrifluoroacetamide (BSTFA), and gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS) with deuterated standards. The limits of detection were between 0.15 and 0.29 ng/mL for THC, 11-OH-THC, THC-COOH, and CBD and 1.1 ng/mL for CBN. The method was applied in a prospective pharmacokinetic study after single oral administration of 10 mg THC alone or together with 5.4 mg CBD in cannabis extract. The maximum plasma concentrations after cannabis extract administration ranged between 1.2 and 10.3 ng/mL (mean 4.05 ng/mL) for THC, 1.8 and 12.3 ng/mL (mean 4.9 ng/mL) for 11-OH-THC, 19 and 71 ng/mL (mean 35 ng/mL) for THC-COOH, and 0.2 and 2.6 ng/mL (mean 0.95 ng/mg) for CBD. The peak concentrations (mean values) of THC, 11-OH-THC, THC-COOH, and CBD were observed at 56, 82, 115, and 60 min, respectively, after intake. CBN was not detected. Caused by the strong first-pass metabolism, the concentrations of the metabolites were increased during the first hours after drug administration when compared to literature data for smoking. Therefore, the concentration ratio 11-OH-THC/THC was discussed as a criterion for distinguishing oral from inhalative cannabis consumption.

The safety of cannabinoids for the treatment of multiple sclerosis

The evidence for the therapeutic efficacy of cannabinoids in the treatment of multiple sclerosis (MS) is increasing but is not as yet convincing. Although several trials have reported no significant effect, the majority of the evidence which supports a beneficial effect on spasticity and pain is based on subjective measurements in trials where unblinding was likely to be a problem. The available clinical trial data suggest that the adverse side effects associated with using cannabis-based medicinal extracts (CBMEs) are generally mild, such as dry mouth, dizziness, somnolence, nausea and intoxication, and in no case did toxicity develop. However, most of these trials were run over a period of months and it is possible that other adverse side effects, not seen in these short-term studies, could develop with long-term use. Despite the evidence that cannabinoids can disrupt cognitive function and promote depression, on the basis of current data, such adverse effects seem unlikely to be associated with the use of CBMEs. Likewise, there is no evidence to suggest that their effects on balance and motor control, or immune function, may be clinically significant. There is, however, reason to be concerned about the use of therapeutic cannabinoids by people predisposed to psychosis and by pregnant women, given the increasing evidence of their adverse effects on the fetus. In conclusion, given the modest therapeutic effects of cannabinoids demonstrated so far, and the risk of long-term adverse side effects, there is reason to be cautious about their use in the treatment of MS.

An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis.

The majority of patients with multiple sclerosis (MS) develop troublesome lower urinary tract symptoms (LUTS). Anecdotal reports suggest that cannabis may alleviate LUTS, and cannabinoid receptors in the bladder and nervous system are potential pharmacological targets. In an open trial we evaluated the safety, tolerability, dose range, and efficacy of two whole-plant extracts of Cannabis sativa in patients with advanced MS and refractory LUTS. Patients took extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD; 2.5 mg of each per spray) for eight weeks followed by THC-only (2.5 mg THC per spray) for a further eight weeks, and then into a long-term extension. Assessments included urinary frequency and volume charts, incontinence pad weights, cystometry and visual analogue scales for secondary troublesome symptoms. Twenty-one patients were recruited and data from 15 were evaluated. Urinary urgency, the number and volume of incontinence episodes, frequency and nocturia all decreased significantly following treatment (P <0.05, Wilcoxon's signed rank test). However, daily total voided, catheterized and urinary incontinence pad weights also decreased significantly on both extracts. Patient self-assessment of pain, spasticity and quality of sleep improved significantly (P <0.05, Wilcoxon's signed rank test) with pain improvement continuing up to median of 35 weeks. There were few troublesome side effects, suggesting that cannabis-based medicinal extracts are a safe and effective treatment for urinary and other problems in patients with advanced MS.

Cannabis and Cannabis Based Medicine Extracts: Additional Results

SUMMARY This study reviews results in recent human clinical trials with cannabis based medicine extract (CBME), THC or cannabis. In a study performed at Queen's Square, London, both High THC and THC:CBD fixed ratio sublingual CBME demonstrated significant benefits on mean maximum cystometric capacity, mean daytime frequency of urination, frequency of nocturia, and mean daily episodes of incontinence in 11 multiple sclerosis patients with intractable lower urinary tract symptoms. A Phase II clinical study in Oxford, England with 24 MS and intractable pain patients was performed as a consecutive series of double-blind, randomized, placebo-controlled single patient cross-over trials with sublingual CBME. Pain scores on visual analogue scales were significantly improved over placebo with both High THC and High CBD CBME. Subjectively, spasm was significantly improved with High THC and THC:CBD fixed ratio extracts. Spasticity was also subjectively improved with the High THC CBME. All three extracts significantl...

A Phase I, Open Label, Four-Way Crossover Study to Compare the Pharmacokinetic Profiles of a Single Dose of 20 mg of a Cannabis Based Medicine Extract (CBME) Administered on 3 Different Areas of the Buccal Mucosa and to Investigate the Pharmacokinetics of CBMEper Oralin Healthy Male and Female Volunteers (GWPK0112)

SUMMARY 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 Δ9-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 te...

A Phase I, Double Blind, Three-Way Crossover Study to Assess the Pharmacokinetic Profile of Cannabis Based Medicine Extract (CBME) Administered Sublingually in Variant Cannabinoid Ratios in Normal Healthy Male Volunteers (GWPK0215)

SUMMARY 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 Δ9-tetrahydrocannabinol (THC, formulated as 25 mg THC per ml) with or without cannabidiol (CBD) (formulated as 25 ...

Future of Cannabis and Cannabinoids in Therapeutics

SUMMARY This study reviews human clinical experience to date with several synthetic cannabinoids, including nabilone, levonantradol, ajulemic acid (CT3), dexanabinol (HU-211), HU-308, and SR141716 (Rimonabant®). Additionally, the concept of “clinical endogenous cannabinoid deficiency” is explored as a possible factor in migraine, idiopathic bowel disease, fibromyalgia and other clinical pain states. The concept of analgesic synergy of cannabinoids and opioids is addressed. A cannabinoid-mediated improvement in night vision at the retinal level is discussed, as well as its potential application to treatment of retinitis pigmentosa and other conditions. Additionally noted is the role of cannabinoid treatment in neuroprotection and its application to closed head injury, cerebrovascular accidents, and CNS degenerative diseases including Alzheimer, Huntington, Parkinson diseases and ALS. Excellent clinical results employing cannabis based medicine extracts (CBME) in spasticity and spasms of MS suggests extensi...

A Single Centre, Placebo-Controlled, Four Period, Crossover, Tolerability Study Assessing, Pharmacodynamic Effects, Pharmacokinetic Characteristics and Cognitive Profiles of a Single Dose of Three Formulations of Cannabis Based Medicine Extracts (CBMEs) (GWPD9901), Plus a Two Period Tolerability Study Comparing Pharmacodynamic Effects and Pharmacokinetic Characteristics of a Single Dose of a Cannabis Based Medicine Extract Given via Two Administration Routes (GWPD9901 EXT)

SUMMARY This study was the first study of GW's CBME in man. It was performed in six healthy subjects, employing test treatments consisting of CBD:THC sublingual drops (GW-1011-01): 5 mg Δ9-tetrahydrocannabinol (THC) + 5 mg cannabidiol (CBD) per ml of glycerol:ethanol (Eth):propylene glycol (PG) (4:4:2), with peppermint flavouring, High CBD sublingual drops (GW-3009-01): 5 mg CBD per ml of glycerol: Eth:PG (4:4:2), with peppermint flavouring, High THC sublingual drops (GW-2009-01): 5 mg THC per ml of glycerol:Eth:PG (4:4:2), with peppermint flavouring, placebo sublingual drops (GW-4003-01): glycerol: Eth:PG (4:4:2), with peppermint flavouring, aerosol (GW-1009-01): 5 mg CBD + 5 mg THC per ml formulated in propellant:Eth (80:20), and nebuliser (GW-1012-01): 10 mg CBD + 10 mg THC per ml of cremophor (Crem) (0.4):PG (1.5):macrogol (1):dodecanol (0.8):H2O (7.4), and placebo nebuliser (administered to subjects 005 and 006 instead of the active nebuliser test treatment): Crem (0.4):PG (1.5):macrogol (1):dodecano...

Introduction: Cannabis: From Pariah to Prescription

SUMMARY Cannabis has been employed in human medicine for more than 4000 years. In the last century, political prohibition led to its disappearance from the conventional pharmacopoeia, but this trend is reversing due to the broad acceptance and application of this forbidden medicine by patients with chronic and intractable disorders inadequately treated by available therapeutics. This study addresses the “road back” for cannabis medicines, and reacceptance as prescription products. Current pharmacology of the two primary therapeutic phytocannabinoids, THC and CBD, is reviewed with respect to herbal synergy and as pertains to treatment of pain, spasm and the wide range of therapeutic applications and adverse effects of cannabis. In particular, the efforts of GW Pharmaceuticals to develop cannabis based medicine extracts (CBME) are documented including cultivation of genetically-selected medical-grade cannabis cloned strains in glass houses with organic and integrated pest management techniques, and their pr...