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Prospects for New Cannabis-Based Prescription Medicines

Authors:
  • GW Pharmaceuticals and The Guy Foundation

Abstract

Cannabis is now emerging from a period of prohibition and being revisited as a potential source of treatments for conditions ill served by synthetic substances. Previous research focussed primarily on effects produced by synthetic cannabinoids such as THC, or cannabis of unknown cannabinoid content. Chemovars of cannabis characterized by high content of specific cannabinoids (primarily, but not only THC and CBD) have been developed. Clinical research using defined extracts from these chemovars is now underway in the UK.Many diseases are multifactorial; a variety of receptors need to be targeted to produce a therapeutic effect. A defined botanical may better achieve this than a single synthetic compound as the components can act synergistically. A new generation of cannabis based medicinal products takes advantage of increasing understanding of the mode of action of cannabinoids, evidence-based research on clinical uses and new technology for realization of products, in anti-diversionary presentations.
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TABLE 1. Comparison of Some Pharmacological Effects of THC and CBD
Effect THC CBD Reference
CB1 (Brain receptors) ⫹⫹ Pertwee et al., 1998
CB2 (Peripheral receptors) ⫹⫺
CNS Effects
Anticonvulsant
⫺⫺ ⫹⫹ Carlini et al., 1973
Muscle Relaxant ⫺⫺ ⫹⫹ Petro, 1980
Antinociceptive ⫹⫹
Catalepsy ⫹⫹ ⫹⫹
Psychotropic ⫹⫹
Antipsychotic ⫺⫺ ⫹⫹ Zuardi, 1997
Neuroprotective Antioxidant Activity* ⫹⫹Hampson A J et al., 1998
Antiemetic ⫹⫹
Sedation (reduced spontaneous activity) ⫹⫹Zuardi, 1997
Cardiovascular Effects
Bradycardia ⫺⫺ Smiley et al., 1976
Tachycardia ⫹⫺
Hypertension
§
⫹⫺
Hypotension
§
⫺⫹Adams et al., 1977
Anti-inflammatory Brown, 1998
* Effect is CB1 receptor independent.
THC is pro convulsant.
§
THC has a biphasic effect on blood pressure; in naïve patients it may produce postural hypotension and it
has also been reported to produce hypertension on prolonged usage.
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... Cannabis, the plant source of cannabinoids (CB), have been used for millennia for different purposes such as pain control and stress relief. Recently, the delineation of the endocannabinoid system and CB receptors in humans has paved the road for broader applications [5]. Their natural source and the widespread use besides its lower risk of addiction or dependency and relative safety have flagged them for in-depth investigation for potential therapeutic roles. ...
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Context: Chronic pain is highly prevalent in most of the industrialized nations around the world. Despite the documented adverse effects, opioids are widely used for pain management. Cannabinoids, and specifically Cannabidiol, is proposed as an opioid alternative, having comparable efficacy with better safety profile. Objectives: We aim to investigate the impact of full hemp extract cannabidiol (CBD) on opioid use and quality of life indicators among chronic pain patients. Methods: An initial sample of 131 patients was recruited from a private pain management center’s investigative population. Ninety-seven patients completed the 8-week study. The primary inclusion criteria included patients between 30 and 65 years old with chronic pain who have been on opioids for at least 1 year. Data were collected at three different time points: baseline, 4, and 8 weeks. Opioid and other medication use were evaluated via the medication and psychiatric treatment receipt. Improvement was evaluated using four indices: Pain Disability Index (PDI-4); Pittsburgh Sleep Quality Index (PSQI), Pain Intensity and Interference (PEG); and Patient Health Questionnaire (PHQ-4). Results: Over half of chronic pain patients (53%) reduced or eliminated their opioids within 8 weeks after adding CBD-rich hemp extract to their regimens. Almost all CBD users (94%) reported quality of life improvements. The results indicated a significant relationship between CBD and PSQI (p = 0.003), and PEG (p = 0.006). There was a trend toward improvement but no significant relationship between CBD use and PHQ and PDI. Conclusion: CBD could significantly reduce opioid use and improve chronic pain and sleep quality among patients who are currently using opioids for pain management. Key Message: This is a prospective, single-arm cohort study for the potential role of cannabinoids as an alternative for opioids. The results indicate that using the CBD-rich extract enabled our patients to reduce or eliminate opioids with significant improvement in their quality of life indices.
... Bu türler Cannabis sativa, Cannabis indica ve Cannabis ruderalis' tir [1]. Bazı kaynaklarda C. indica ve C. ruderalis, Cannabis sativa' nın bir alt türü olarak gösterilmektedir [2,3,4]. Üç tür arasında anatomik yapı, bitki habitusu, yetiştirilme şekli, çiçeklenme süresi ve ürettikleri kimyasal maddeler bakımından birçok farklılık bulunmaktadır (Şekil 1; [5]). ...
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Kenevir, Cannabaceae familyasında yer alan, tek yıllık, otsu ve çok yönlü kullanım potansiyeli olan bir endüstri bitkidir. Tarihin en eski bitkilerinden biri olan kenevir, ilaç, gıda, kâğıt, biyoyakıt, tekstil, kozmetik, inşaat ve otomotiv sektörüne kadar oldukça geniş yelpazede kullanım alanına sahiptir. Ekolojik ve topografı istekleri bakımından kanaatkâr bir bitki olan kenevirin adaptasyon kabiliyeti geniştir. Kenevir tohumu yaklaşık %35 yağ ve %25 protein içermesinin yanında Omega-3 kaynağı olarak da zengindir. Endüstriyel kenevir, kaliteli lif kaynağı özelliği sayesinde yakın zamanda geniş ekim alanlarında yer bularak endüstriye önemli ölçüde katkı sağlayacak potansiyele ulaşmıştır. Narkotik özelliklerinden dolayı birçok ülkede olduğu gibi ülkemizde de yasaklanan geleneksel kenevirin aksine son yıllarda geliştirilen endüstriyel amaçlı kenevir çeşitleri sayesinde kenevir tarımı birçok ülkede her geçen gün genişlemekte ve ülkelerin ekonomilerine önemli katkı sağlama potansiyeli arz etmektedir.
... Cannabis sativa L. (family Cannabaceae) is the most frequently used illicit plant (marijuana or hashish) and is considered a valuable medicinal plant with a variety of therapeutic benefits [1,2]. A few cannabis-based medicines in the form of pure cannabinoids or cannabis extracts are now available on the pharmaceutical market [3][4][5][6] to treat different medical conditions such as cancer chemotherapy-induced nausea and vomiting, appetite loss, and cachexia in cancer, AIDS, and HIV patients [7][8][9][10], neuropathic and chronic pain, and spasticity in multiple sclerosis [10,11]. ...
Article
Terpenes are the major components of the essential oils present in various Cannabis sativa L. varieties. These compounds are responsible for the distinctive aromas and flavors. Besides the quantification of the cannabinoids, determination of the terpenes in C. sativa strains could be of importance for the plant selection process. At the University of Mississippi, a GC-MS method has been developed and validated for the quantification of terpenes in cannabis plant material, viz., α-pinene, β-pinene, β-myrcene, limonene, terpinolene, linalool, α-terpineol, β-caryophyllene, α-humulene, and caryophyllene oxide. The method was optimized and fully validated according to AOAC (Association of Official Analytical Chemists) guidelines against reference standards of selected terpenes. Samples were prepared by extraction of the plant material with ethyl acetate containing n-tridecane solution (100 µg/mL) as the internal standard. The concentration-response relationship for all analyzed terpenes using the developed method was linear with r2 values > 0.99. The average recoveries for all terpenes in spiked indoor cultivated samples were between 95.0 – 105.7%, with the exception of terpinolene (67 – 70%). The measured repeatability and intermediate precisions (% relative standard deviation) in all varieties ranged from 0.32 to 8.47%. The limit of detection and limit of quantitation for all targeted terpenes were determined to be 0.25 and 0.75 µg/mL, respectively. The proposed method is highly selective, reliable, and accurate and has been applied to the simultaneous determination of these major terpenes in the C. sativa biomass produced by our facility at the University of Mississippi as well as in confiscated marijuana samples.
... Terpenoids and other minor co~nponcnts that may be impos-tan1 to therapeutic effects of cannabis are retained in this fashion (Whittle & Guy, 2001; Whittle, Guy, & Robson, 200 1 ). Dose-metered sublingual/oromucosa1 sprays are currently in Phase I to 111 clinical trials lor a variety of indications, and approval as a prescription medicine for Sativexo, a whole cannabis extract with equal proportions of THC and CBD, was confirmed for central neuropathic pain in multiple sclerosis in Canada in 2005, and is expected for other indications in the United Kingdom, European Union, and British Commonwealth nations subsequently. ...
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The herb cannabis is derived from the Old World species Cannabis sativa L. Cannabis indica and C. ruderalis may also merit species status. Cannabis has a history as an analgesic agent that spans at least 4000 years, including a century of usage in mainstream Western medicine. Quality control issues, and ultimately political fiat eliminated this agent from the modern pharmacopoeia, but it is now resurgent. The reasons lie in the remarkable pharmacological properties of the herb and new scientific research that reveals the inextricable link that cannabinoids possess with our own internal biochemistry. In essence, the cannabinoids form a system in parallel with that of the endogenous opioids in modulating pain. More important, cannabis and its endogenous and synthetic counterparts may be uniquely effective in pain syndromes in which opiates and other analgesics fail.
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Understanding the pharmacodynamics of cannabinoids is an essential subject due to the recent increasing global acceptance of cannabis and its derivation for recreational and therapeutic purposes. Elucidating the interaction between cannabinoids and the vascular system is critical to exploring cannabinoids as a prospective therapeutic agent for treating vascular-associated clinical conditions. This review aims to examine the effect of cannabinoids on the vascular system and further discuss the fundamental pharmacological properties and mechanisms of action of cannabinoids in the vascular system. Data from literature revealed a substantial interaction between endocannabinoids, phytocannabinoids, and synthetic cannabinoids within the vasculature of both humans and animal models. However, the mechanisms and the ensuing functional response is blood vessels and species-dependent. The current understanding of classical cannabinoid receptor subtypes and the recently discovered atypical cannabinoid receptors and the development of new synthetic analogs have further enhanced the pharmacological characterization of the vascular cannabinoid receptors. Compelling evidence also suggest that cannabinoids represent a formidable therapeutic candidate for vascular-associated conditions. Nonetheless, explanations of the mechanisms underlining these processes are complex and paradoxical based on the heterogeneity of receptors and signaling pathways. Further insight from studies that uncover the mechanisms underlining the therapeutic effect of cannabinoids in the treatment of vascular-associated conditions is required to determine whether the known benefits of cannabinoids thus currently outweigh the known/unknown risks.
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Kenevir ve endüstri
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There are four main routes of administration of medicinal cannabis: inhalation, the oral route, topical applications and ‘other routes’ (eg. suppositories, intranasal delivery). Each is associated with different onsets of action and durations of action due to their pharmacokinetic profiles. There are some safety issues associated with cannabis. Many of the safety concerns such as associations between cannabis use and conditions such as cannabis use disorder and various mental health conditions that have been raised in the literature relate to recreational smoking of cannabis. Cannabis is associated with a range of negative side effects that are typically dose-dependent, most of which relate to the tetrahydrocannabinol (THC) component. Cannabidiol (CBD) has less serious side effects than THC. In general, CBD has been found to be well tolerated and safe and does not cause addiction. Both CBD and THC can potentially interact with a range of pharmaceuticals because they are metabolised by many of the cytochrome P450 enzymes that metabolise pharmaceuticals. Clinical trials in epilepsy in which high doses of CBD are used in conjunction with typically several anti-epileptic medications have demonstrated that side effects can occur with certain drugs. However, whether drug-cannabis interactions are common in clinical practice has not been well established.
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The high rise in the population suffering from depression depicts the need for improved and highly effective treatment options for this condition. Efforts to develop existing drugs into user-friendly dosage forms with a number of advantages in major depressive states, including but not limited to: sustained drug release, reduced drug dosing frequency, improved tolerance and adherence, suitability for use in diverse populations and different treatment scenarios, as well as less central nervous system side effects are required. One such non-invasive drug delivery route that could provide the aforementioned benefits in the treatment of depression is the transdermal route. A number of conventional and emerging transdermal delivery strategies have been investigated for some potent antidepressants and results depict the potential of this route as a viable means for systemic delivery of therapeutically relevant doses of the tested agents, with Emsam®, the commercially available patch of selegiline, being an evidence for the same. The investigated approaches include the formulation of transdermal patches, use of vesicular drug carriers, pro-drug approach, microemulsification, chemical as well as physical enhancement technologies. This review provides a comprehensive account of the rationale, developments made till date, scope and future prospects of delivering antidepressants via the transdermal route of administration.
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Adequate evidence exists in the literature indicating a relatively positive shift with regards to the legal acceptance of cannabis and cannabis-derived products for medicinal purposes in some countries. Concomitantly, scientists are showing renewed interest in cannabis-related research work. Over the years, clinical and preclinical studies have demonstrated the therapeutic significance of cannabinoids for diverse indications. Additionally, efforts are being made to develop cannabis-related products into acceptable prescription products. FDA authorization for the commercial use of four cannabinoid-derived products, available as oral dosage forms is a significant progress already. However, there are certain drawbacks associated with the conventional delivery forms of cannabinoids. These include low oral bioavailability due to hepatic degradation, gastric instability, poor water solubility, and the side effects experienced upon the use of high doses of psychotropic cannabinoids associated with heightened plasma concentrations of the drug. These are however, limitable with the aid of transcutaneous drug delivery. Emerging topical and transdermal strategies could be exploited for the successful development of highly effective delivery systems for cannabinoids. This review discusses the feasibility of delivering therapeutic cannabinoids via skin and provides a comprehensive account of the supporting research studies that have been reported in the literature till date.
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Interaction between ethephon and the two ethylene antagonists — silver nitrate and cobalt chloride — applied exogenously to the male Cannabis sativa plants was studied. The feminization effect caused by two sprays of 960 mg· l-1 of ethephon could be overcome by 100 μg of AgNO3 or CoCl2. However, neither of the antagonists could suppress the feminization effect of 1920 mg · l-1 of ethephon sprayed twice.
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A Cannabis germplasm collection was evaluated for traits relevant to the use of hemp as an arable source of paper pulp. The traits were related to stem yield and quality, psychoactive potency, resistance to root-knot nematodes and plant morphology. The present study is directed at diversity for these traits considered together. For the interpretation of diversity patterns, accessions were grouped on the basis of the presumed purpose and status of domestication resulting in the recognition of four ‘plant-use groups’: fibre cultivars, fibre landraces, drug strains, and truly wild or naturalized populations. Principal component analysis showed that stem quality, phenological development, psychoactive potency and host reactions to root-knot nematodes explained most of the total variation among accessions. The plant-use groups were reasonably well separated in the principal component space. Discriminant analysis showed that the a priori defined plant-use groups could be discriminated quite well on the basis of linear combinations of all agronomic and morphological traits. The contents of bark fibre and cannabinoids had the highest grouping value. Reallocations concerned mainly old fibre cultivars which were placed in the group of fibre landraces due to a low content of bark fibre. A genetic characterization of accessions was based on electrophoretic patterns of seed proteins. Isoelectric ocusing patterns of bulk seed extracts showed variation for the presence of six out of 45 protein bands in the H range from 4.75 to 6.40. Banding patterns were however independent from any grouping based on origin or gronomic and morphological traits and did not reflect expected common ancestry of accessions.
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The skin permeation behavior of a tetrahydrocannabinol (THC) is described for the first time. In the design of transdermal delivery systems, Δ8-THC was chosen over Δ9-THC due to the former's better stability and its lower psychotropic potency. Sk permeation kinetic parameters were established through rat and human skin in vitro. The rat skin was found to be about 13-fold more permeable to Δ8-THC than the human skin. Autoradiographs showed that 24 h after application the drug was concentrated in the stratum corneum, in the upper epidermis, and around the hair follicles, indicating that THC penetrates the skin through the lipophilic pathways. A transdermal formulation containing oleic acid as a permeation enhancer was tested in rats. A serum level of about 50 ng/ml cross-reacting cannabinoids (THC + metabolites) was maintained for about 24 h, indicating a sustained delivery of THC to the bloodstream. The transdermal preparation presented in this study is designed for future clinical studies.
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Abnormal-delta8-tetrahydrocannabinol (ABN-delta8-THC) failed to elicit central nervous system and cardiovascular effects in laboratory animals. Abnormal-cannabidiol (ABN-CBD) was also devoid of overt behavioral effects but produced marked hypotension with only slight bradycardia in anesthesized dogs.
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Acute pulmonary physiologic effects of smoked marijuana and oral Δ9-tetrahydrocannabinol were investigated in 32 healthy, experienced male marijuana smokers. After smoking of marijuana assayed at either 1 or 2 per cent Δ9-tetrahydrocannabinol, specific airway conductance increased immediately, reached peak levels at 15 minutes and was still significantly elevated at 60 minutes. In contrast, specific airway conductance decreased after both tobacco smoking and deep-breathing maneuvers that simulated marijuana smoking. Inhalation of 1250 μg of isoproterenol caused specific conductance to rise to less than 60 per cent of the average peak increase observed after 2 per cent marijuana. After ingestion of 10, 15 and 20 mg of Δ9-tetrahydrocannabinol in 12 subjects, specific airway conductance rose significantly as compared with placebo, attained peak levels three hours after ingestion and remained elevated for four to six hours. These findings indicate that both smoked marijuana and oral Δ9-tetrahydrocann...
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The total and regional deposition of aerosol has been compared using four nebulizers; the Pari Boy 37.80, Pari IS-2, RespirGard II and Penta-Sonic. The aerosol was radiolabelled with [99Tcm]DTPA, administered to ten healthy subjects and the distributions monitored by gamma scintigraphy. Median lung aerosol depositions expressed as percentages of the doses initially loaded into the nebulizers were: Pari IS-2 19%, Pari Boy 37.80 13%, RespirGard II 9% and Penta-Sonic 2%. The ratios of the peripheral to central lung deposition, however, were greater with the RespirGard II and Penta-Sonic nebulizers. The choice of the most appropriate nebulizer depends on the pharmaceutical being administered, since aerosol must be delivered to the required site in sufficient quantity, whilst minimizing the incidence of local or systemic side-effects.