Article

Medicinal cannabis: Is Δ9-tetrahydrocannabinol necessary for all its effects?

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Abstract

Cannabis is under clinical investigation to assess its potential for medicinal use, but the question arises as to whether there is any advantage in using cannabis extracts compared with isolated Delta9-trans-tetrahydrocannabinol (Delta9THC), the major psychoactive component. We have compared the effect of a standardized cannabis extract (SCE) with pure Delta9THC, at matched concentrations of Delta9THC, and also with a Delta9THC-free extract (Delta9THC-free SCE), using two cannabinoid-sensitive models, a mouse model of multiple sclerosis (MS), and an in-vitro rat brain slice model of epilepsy. Whilst SCE inhibited spasticity in the mouse model of MS to a comparable level, it caused a more rapid onset of muscle relaxation, and a reduction in the time to maximum effect compared with Delta9THC alone. The Delta9THC-free extract or cannabidiol (CBD) caused no inhibition of spasticity. However, in the in-vitro epilepsy model, in which sustained epileptiform seizures were induced by the muscarinic receptor agonist oxotremorine-M in immature rat piriform cortical brain slices, SCE was a more potent and again more rapidly-acting anticonvulsant than isolated Delta9THC, but in this model, the Delta9THC-free extract also exhibited anticonvulsant activity. Cannabidiol did not inhibit seizures, nor did it modulate the activity of Delta9THC in this model. Therefore, as far as some actions of cannabis were concerned (e.g. antispasticity), Delta9THC was the active constituent, which might be modified by the presence of other components. However, for other effects (e.g. anticonvulsant properties) Delta9THC, although active, might not be necessary for the observed effect. Above all, these results demonstrated that not all of the therapeutic actions of cannabis herb might be due to the Delta9THC content.

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... In vivo, mouse MS-model; more rapid relief from spasticity with the extract than after pure THC but size of antispastic effect is similar; [141] 20% THC, (minor content of CBD, CBN) THC (CBD had no effect) ...
... In vitro, rat brain slice model of epilepsy; more rapid onset of anti-convulsant activity with the extract than with pure THC [141] 20. ...
... Wada et al. (17) demonstrated that ∆ 9 THC may have a prophylactic activity in preventing amygdaloid kindled cats, though this drug seems to be ineffective in fully developed kindled amygdaloid seizures. Though ∆ 9 THC may be active itself, it has been shown that other constituent of medicinal preparations of cannabis also have anticonvulsant properties (18) . This is a very important finding, when someone considers the psychoactive effect of ∆ 9 THC. ...
... Some psychotropic substances may not be necessary for the efficacy of marijuana for controlling seizures. Future medicinal preparations of cannabis used for epilepsy may have other active constituent, separating psychoactivity from anticonvulsant effects (18) . ...
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Article
The medicinal use of components of Cannabis sativa (marijuana) has been studied around the world. Some of these components may have anti-convulsive properties, though the reports are controversial, and sometimes come from single case reports and clinical anecdotes. Because of ethical aspects, as some of the components of cannabis have psychotropic effects, this is a very important issue. New researches have demonstrated that some components of cannabis that don't have psychotropic action may play a role in controlling seizures. This paper reviews the relation between epilepsy and the components of cannabis sativa.
... Early reports from Europe and the USA failed to distinguish any perceived therapeutic efficacy in symptom control of MS (Consroe et al. 1997). However, in experimental models of MS-related spasticity that occurs due to CNS autoimmunity, it could be shown that delta9 tetrahydrocannabinol (Δ9-THC) and the CB 1 R controlled symptoms, with no apparent effect of cannabinol (CBD) on spasticity (Baker et al. 2000;Wilkinson et al. 2003;Pryce and Baker 2007;Pryce et al. 2014). This could suggest that Δ9-THC is the major therapeutic chemical within cannabis, based on the reports that cannabis in North America may have a low CBD content (ElSohly et al. 2000;Wilkinson et al. 2003;EMCDD 2008). ...
... However, in experimental models of MS-related spasticity that occurs due to CNS autoimmunity, it could be shown that delta9 tetrahydrocannabinol (Δ9-THC) and the CB 1 R controlled symptoms, with no apparent effect of cannabinol (CBD) on spasticity (Baker et al. 2000;Wilkinson et al. 2003;Pryce and Baker 2007;Pryce et al. 2014). This could suggest that Δ9-THC is the major therapeutic chemical within cannabis, based on the reports that cannabis in North America may have a low CBD content (ElSohly et al. 2000;Wilkinson et al. 2003;EMCDD 2008). However, pharmaceutical, medical cannabis extracts being developed (Sativex & Cannador) contain essentially equal proportions of Δ9-THC and CBD (Novotna et al. 2011;Zajicek et al. 2012;Langford et al. 2013). ...
Article
Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.
... In another trial, 15 patients with relapsing-remitting multiple sclerosis were enrolled to test the efficacy of nabilone combined with gabapentin, their combination resulted effective and well tolerated in multiple sclerosis -induced neurophatic pain [280]. Currently, Sativex ® extensively explored for multiple sclerosis treatment [281,282], is a spray preparation that alleviates neurophatic pain and spasticity in adult patients not responding to other therapies. In addition, Sativex ® is efficient to treat bladder dysfunction usually observed in multiple sclerosis patients. ...
... In 1982 Nabilone was approved in Canada and is now used for the treatment of emesis in the United States and United Kingdom, [297]. Finally, Sativex ® (GW Pharma, Ltd, Salisbury, Wiltshire, UK), a combination of two extracts CBD and 9 -THC in approximately 1:1 ratio in an alcoholic solution, is administered as oral spray and is used as adjunctive therapy to ameliorate spasticity in adult multiple sclerosis patients unresponsive to other medicines during an initial trial period of therapy in countries like Denmark, Germany, Spain, as well as in Italy, United Kingdom and Canada [281,282]. The advantage obtained with respect to the oral administration consists of a faster plateau of plasma concentration. Additionally, it has been proved that co-administration of 9 -THC and CBD reduces undesired 9 -THC psychoactive effect. ...
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Article
Background: Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs. These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors. Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases. Methods: In this study, starting from the endocannabinoid mechanism of action in neuronal signaling, we highlight and discuss potential application and recent patents of cannabimimetic drugs in neurological disorders. Results: The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression. Conclusions: Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.
... It is worthy of note that the beneficial effects of pure CBD in the inflamed gut have been not observed/evaluated after oral gavage (intragastric) administration, a route of drug administration which is easy to be translated to humans for therapeutic use. In the past few years, the contribution of minor phytocannabinoids to the complex Cannabis pharmacology has been shown (Pertwee, 2008;Hill et al., 2012;McPartland and Russo, 2014) and a number of examples of additive/synergistic effects among the phytocannabinoids have been reported (Williamson and Evans, 2000;Wilkinson et al., 2003;DeLong et al., 2010;Jamontt et al., 2010;Russo, 2011;McPartland and Russo, 2014). This observation prompted the cultivation of specific C. sativa chemotypes (chemical genotypes) with high yields of a specific cannabinoid (Potter, 2014). ...
... The notion that not all of the therapeutic effects of C. sativa are due to its many active psychotropic ingredient THC is well established (Wilkinson et al., 2003;Russo, 2011;Brodie et al., 2015). The contribution of non-THC phytocannabinoids to Cannabis pharmacology has been scientifically demonstrated in a number of experimental diseases, including ulcerative colitis (Duncan and Izzo, 2015). ...
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Article
Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for “CBD botanical drug substance,” on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was evaluated in the experimental model of intestinal hypermotility induced by irritant croton oil. CBD BDS or pure CBD were given - either intraperitoneally or by oral gavage – after the inflammatory insult (curative protocol). The amounts of CBD in the colon, brain, and liver after the oral treatments were measured by high-performance liquid chromatography coupled to ion trap-time of flight mass spectrometry. CBD BDS, both when given intraperitoneally and by oral gavage, decreased the extent of the damage (as revealed by the decrease in the colon weight/length ratio and myeloperoxidase activity) in the DNBS model of colitis. It also reduced intestinal hypermotility (at doses lower than those required to affect transit in healthy mice) in the croton oil model of intestinal hypermotility. Under the same experimental conditions, pure CBD did not ameliorate colitis while it normalized croton oil-induced hypermotility when given intraperitoneally (in a dose-related fashion) or orally (only at one dose). In conclusion, CBD BDS, given after the inflammatory insult, attenuates injury and motility in intestinal models of inflammation. These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD BDS for IBD treatment.
... We investigated this by assessing the effect of the botanical drug substances (BDSs), which comprise Sativex in spasticity in chronic relapsing experimental autoimmune encephalomyelitis (CREAE), an animal model of MS [16]. A cannabis extract containing 20% THC but no CBD has previously been shown to treat experimental spasticity in EAE at a dose of 5 mg/kg i.v. [17]. However, a 1 : 1 mix of CBD : THC was chosen for this study as this is the medicinal product currently licensed and used for the treatment of spasticity in patients with MS, with all the associated benefits that the combination of the two cannabinoids provide to patients in a clinical setting. ...
... The " stiffness " of spastic limbs was assessed by measuring the force required to bend the hind-limb of each mouse to full flexion using a purposebuilt strain gauge. This evaluation has been used effectively in numerous previous studies [17, 18,202122 and is the only reported tool for investigating spasticity related to MS in animals. Moreover, it provides objective and qualitative readouts. ...
Article
This study investigated the antispasticity potential of Sativex in mice. Chronic relapsing experimental allergic encephalomyelitis was induced in adult ABH mice resulting in hind limb spasticity development. Vehicle, Sativex, and baclofen (as a positive control) were injected intravenously and the "stiffness" of limbs assessed by the resistance force against hind limb flexion. Vehicle alone caused no significant change in spasticity. Baclofen (5 mg/kg) induced approximately a 40% peak reduction in spasticity. Sativex dose dependently reduced spasticity; 5 mg/kg THC + 5 mg/kg CBD induced approximately a 20% peak reduction; 10 mg/kg THC + 10 mg/kg CBD produced approximately a 40% peak reduction in spasticity. Sativex has the potential to reduce spasticity in an experimental mouse model of multiple sclerosis (MS). Baclofen reduced spasticity and served as a positive control. Sativex (10 mg/kg) was just as effective as baclofen, providing supportive evidence for Sativex use in the treatment of spasticity in MS.
... If one compound, having no activity of its own, impacts the efficacy of an active molecule to increase activity (i.e., 1 + 0 > 1), this is known as an entourage effect [26]. As cannabis research has evolved, there has been a growing body of evidence that cannabinoids beyond THC demonstrate efficacy in humans [183,184] and that synergy/entourage could potentially play a large role in the bioactivity of cannabis extracts and products [22,185]. ...
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Cannabis is a complex biosynthetic plant, with a long history of medicinal use. While cannabinoids have received the majority of the attention for their psychoactive and pharmacological activities, cannabis produces a diverse array of phytochemicals, such as terpenes. These compounds are known to play a role in the aroma and flavor of cannabis but are potent biologically active molecules that exert effects on infectious as well as chronic diseases. Furthermore, terpenes have the potential to play important roles, such as synergistic and/or entourage compounds that modulate the activity of the cannabinoids. This review highlights the diversity and bioactivities of terpenes in cannabis, especially minor or secondary terpenes that are less concentrated in cannabis on a by-mass basis. We also explore the question of the entourage effect in cannabis, which studies to date have supported or refuted the concept of synergy in cannabis, and where synergy experimentation is headed, to better understand the interplay between phytochemicals within Cannabis sativa L.
... While the anticonvulsant mechanisms of CBD and CBDV are unidentified, their anticonvulsant and tolerability profiles do not suggest interaction with the CB1 cannabinoid receptor (Wallace et al., 2001; Jones et al., 2010; Hill et al., 2012a). An increasing body of evidence suggests that cannabis extracts enriched with a specific pCB can possess as much, or more, pharmacological efficacy/potency than the purified pCB (Wilkinson et al., 2003; Whalley et al., 2004; Ryan et al., 2006; De Petrocellis et al., 2011; Sagredo et al., 2011; Valdeolivas et al., 2012). As an example, amelioration of spasticity associated with multiple sclerosis by Δ 9 tetrahydrocannabinol (THC) and CBD was greater in clinical trials when these two pCBs were combined as two plant extracts rather than as purified pCBs (Russo and Guy, 2006). ...
Article
Epilepsy is the most prevalent neurological disease and is characterised by recurrent seizures. Here we investigate: (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDS) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB1 receptors. The anticonvulsant profiles of two CBDV BDSs (50-422 mg kg(-1) ) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip-strength assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using displacement binding assays. CBDV BDSs exerted significant anticonvulsant effects in the PTZ (≥100 mg kg(-1) ) and audiogenic seizure models (≥87 mg kg(-1) ), and suppressed pilocarpine-induced convulsions (≥100 mg kg(-1) ). The isobolographic study revealed the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip-strength were found. The Δ(9) -THC and Δ(9) -THCV content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV. CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor, and were of comparable efficacy to purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for treatment of epilepsy.
... Williamson (2001) has reviewed the mathematical definitions of synergy. Wilkinson et al. (2005) provided examples of synergy within polypharmaceutical cannabis extracts. CBD may potentiate the behavioural effects of THC via pharmacokinetic mechanisms, for example, increasing the area under the curve of THC in blood and brain (Klein et al., 2011). ...
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Article
Based on evidence that the therapeutic properties of Cannabis preparations are not solely dependent on the presence of Δ9-tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid type-1 (CB1) receptors, thus behaving like first generation CB1 inverse agonists, such as rimonabant. Here we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent preclinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action, and thus appear very unlikely to produce unwanted central nervous system effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low affinity CB1 ligand which can nevertheless affect CB1 activity in vivo in an indirect manner, whilst THCV is a high affinity CB1 ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 antagonism. THCV also has high affinity for CB2 and signals as a partial agonist, a departure from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology, and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target.
... Cannabis extract, but not ∆ 9 -THC, revealed a significant reduction of right-hand tapping frequencies that was also found in schizophrenia (Roser et al., 2009). In vitro, standard cannabis extract as well as ∆ 9 -THC-free extract but not ∆ 9 -THC exerted anticonvulsant activity (Wilkinson et al., 2003). Other researchers observed that either ∆ 9 -THC or to lesser extent cannabidiol induced a catatonic response in mice. ...
Article
Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal symptoms due to blockade of dopamine D2 receptors in the striatum. Interest in medicinal uses of cannabis is growing. Cannabis sativa has been suggested as a possible adjunctive in treatment of Parkinson's disease. The present study aimed to investigate the effect of repeated administration of an extract of Cannabis sativa on catalepsy and brain oxidative stress in-duced by haloperidol administration in mice. Cannabis extract was given by subcutaneous route at 5, 10 or 20 mg/kg (expressed as ∆ 9 -tetrahydrocannabinol) once daily for 18 days and the effect on haloperidol (1 mg/kg, i.p.)-induced catalepsy was examined at selected time in-tervals using the bar test. Mice were euthanized 18 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (the concentrations of nitrite/nitrate) were determined in brain and liver. In saline-treated mice, no catalepsy was observed at doses of cannabis up to 20 mg/kg. Mice treated with haloperidol at the dose of 1 mg/kg, exhibited significant cataleptic response. Mice treated with cannabis and haloperidol showed significant decrease in catalepsy duration, compared with the haloperidol only treated group. This decrease in catalepsy duration was evident on days 1-12 after starting cannabis injection. Later the effect of cannabis was not ap-parent. The administration of only cannabis (10 or 20 mg/kg) decreased brain MDA by 17.5 and 21.8 %, respectively. The level of nitric oxide decreased by 18 % after cannabis at 20 mg/kg. Glucose in brain decreased by 20.1 % after 20 mg/kg of cannabis extract. The ad-ministration of only haloperidol increased MDA (22.2 %), decreased GSH (25.7 %) and in-creased brain nitric oxide by 44.1 %. The administration of cannabis (10 or 20 mg/kg) to haloperidol-treated mice resulted in a significant decrease in brain MDA and nitric oxide as well as a significant increase in GSH and glucose compared with the haloperidol-control group. Cannabis had no significant effects on liver MDA, GSH, nitric oxide in saline or haloperidol-treated mice. It is concluded that cannabis improves catalepsy induced by haloperidol though the effect is not maintained on repeated cannabis administration. Cannabis alters the oxidative status of the brain in favor of reducing lipid peroxidation, but reduces brain glucose, which would impair brain energetics.
... Thus, cannabis preparations may provide advantages over other single-compound synthetic drugs. The therapeutic effects of major constituents may be enhanced by other cannabinoids or non-cannabinoids whereas some unwanted side effects may be mitigated [12,[17][18][19][20][21]. ...
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High performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) has been successfully applied to cannabis plant extracts in order to identify cannabinoid compounds after their quantitative isolation by means of supercritical fluid extraction (SFE). MS conditions were optimized by means of a central composite design (CCD) approach, and the analysis method was fully validated. Six major cannabinoids [tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), cannabidiol (CBD), tetrahydrocannabivarin (THCV), cannabigerol (CBG), and cannabinol (CBN)] were quantified (RSD < 10%), and seven more cannabinoids were identified and verified by means of a liquid chromatograph coupled to a quadrupole-time-of-flight (Q-ToF) detector. Finally, based on the distribution of the analyzed cannabinoids in 30 Cannabis sativa L. plant varieties and the principal component analysis (PCA) of the resulting data, a clear difference was observed between outdoor and indoor grown plants, which was attributed to a higher concentration of THC, CBN, and CBD in outdoor grown plants.
... In addition, use of Sativex ® has been extensively investigated in the management of patients with MS [14,15]. Currently, this spray preparation is used as treatment to alleviate symptoms of spasticity and neurophatic pain in adult MS patients that did not show an appropriate response to other drugs during an initial trial period of therapy. ...
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Article
Nowadays, Cannabis sativa is considered the most extensively used narcotic. Nevertheless, this fame obscures its traditional employ in native medicine of South Africa, South America, Turkey, Egypt and in many regions of Asia as a therapeutic drug. In fact, the use of compounds containing Cannabis and their introduction in clinical practice is still controversial and strongly limited by unavoidable psychotropic effects. So, overcoming these adverse effects represents the main open question on the utilization of cannabinoids as new drugs for treatment of several pathologies. To date, therapeutic use of cannabinoid extracts is prescribed in patients with glaucoma, in the control of chemotherapy-related vomiting and nausea, for appetite stimulation in patients with anorexia-cachexia syndrome by HIV, and for the treatment of multiple sclerosis symptoms. Recently, researcher efforts are aimed to employ the therapeutic potentials of Cannabis sativa in the modulation of cannabinoid receptor activity within the central nervous system, particularly for the treatment of neurodegenerative diseases, as well as psychiatric and non-psychiatric disorders. This review evaluates the most recent available data on cannabinoids utilization in experimental and clinical studies, and highlights their beneficial effects in the prevention of the main neurological diseases and for the clinical treatment of symptoms with them correlated.
... Except for cannabidiol and THC, other ingredients of cannabis (cannabinol, kannabidivarin and tetrahydrocannabidivarin) have also shown anticonvulsant properties in animal models (Gloss and Vickrey, 2014;Jones et al., 2012). Wilkinson et al. (2003) reported that THCfree extract, although devoid of antispastic properties, still had anticonvulsant characteristics. Cannabidiol inhibited the occurrence of tonic-clonic seizures in mice in models of acute seizures induced by the maximal electroshock (MES). ...
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Article
The treatment of epilepsy is still a major challenge. Despite the introduction of many new antiepileptic drugs, approximately 30% of patients still remain drug resistant. In the absence of a satisfactory therapy outcome, which is sometimes associated with numerous side effects, there is a need for new and effective drugs with low toxicity. Cannabinoids have been shown in preliminary animal model studies and in studies of patients with epilepsy to have antiepileptic activity. The aim of this paper is to review current reports on the role of the endocannabinoid system and cannabinoids in the treatment of epilepsy. Articles from PubMed and Scopus published up to 2015 concerning the role of cannabinoids and the endocannabinoid system in the treatment of epilepsy are reviewed. Cannabis has been used for thousands of years in the treatment of various diseases. They contain cannabinoids, which act on the endocannabinoid system which regulates many biochemical and physiological processes. By affecting glutamate and gamma-aminobutyric acid (GABA) neurotransmission cannabinoids have the ability to affect seizure threshold. The best known cannabinoid is cannabidiol, which inhibits the occurrence of seizures without causing significant side effects in humans and animals. However, only a small number of double blind, randomized and placebo controlled studies have been published to date. The role of cannabinoids in the treatment of epilepsy is not well defined because these substances have shown pro-convulsive actions in some animal studies and also there are not many randomized trials performed to date. The existing human data do not support the conclusion that cannabinoids are effective and safe in the treatment of epilepsy, but do encourage further studies on a larger group of patients.
... Whether cannabis components beyond THC contribute to its medicinal effects has been an issue of contention (Wachtel et al., 2002;Ilan et al., 2005). Certainly, some have advocated this concept of herbal synergy (McPartland and Russo, 2001;Williamson, 2001;Wilkinson et al., 2003;Russo, 2011), which is quite akin to combinatorial activity of endocannabinoids via "the entourage effect" of active and inactive metabolites (Ben-Shabat et al., 1998;Mechoulam and Ben-Shabat, 1999). Such synergy would be apparent under conditions in which the activity of a minor component complemented the major, diminished the adverse event profile, or otherwise contributed to a preparation's stability or efficacy. ...
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This overview covers a wide range of cannabis topics, initially examining issues in dispensaries and self-administration, plus regulatory requirements for production of cannabis-based medicines, particularly the Food and Drug Administration “Botanical Guidance.” The remainder pertains to various cannabis controversies that certainly require closer examination if the scientific, consumer, and governmental stakeholders are ever to reach consensus on safety issues, specifically: whether botanical cannabis displays herbal synergy of its components, pharmacokinetics of cannabis and dose titration, whether cannabis medicines produce cyclo-oxygenase inhibition, cannabis-drug interactions, and cytochrome P450 issues, whether cannabis randomized clinical trials are properly blinded, combatting the placebo effect in those trials via new approaches, the drug abuse liability (DAL) of cannabis-based medicines and their regulatory scheduling, their effects on cognitive function and psychiatric sequelae, immunological effects, cannabis and driving safety, youth usage, issues related to cannabis smoking and vaporization, cannabis concentrates and vape-pens, and laboratory analysis for contamination with bacteria and heavy metals. Finally, the issue of pesticide usage on cannabis crops is addressed. New and disturbing data on pesticide residues in legal cannabis products in Washington State are presented with the observation of an 84.6% contamination rate including potentially neurotoxic and carcinogenic agents. With ongoing developments in legalization of cannabis in medical and recreational settings, numerous scientific, safety, and public health issues remain.
... This causes also inflammatory lesions in the CNS and leads to the loss of oligodendroglia and axonal degeneration [10]. Sativex®(GW Pharma, LTd, Salisbury, Wiltshire, UK), a mixture of two cannabinoid extracts in approximately a 1:1 ratio (2.7 mg of Δ 9 -THC and 2.5 mg of CBD in an alcoholic solution), is to date the only commercially available preparation containing cannabinoids introduced in clinical management of symptomatic treatment of chronic pain and spasticity in MS patients which did not show an appropriate response to other drugs during an initial trial period of therapy [11,12]. Although this drug has been approved in several countries, the limits regarding unavoidable psychotropic effects exhibited by Δ 9 -THC remains to be overcome. ...
Article
This study was aimed to investigate whether treatment with purified cannabidiol (CBD) may counteract the development of experimental multiple sclerosis (MS), by targeting the PI3K/Akt/mTOR pathway. Although the PI3K/Akt/mTOR pathway was found to be activated by cannabinoids in several immune and non-immune cells, currently, there is no data about the effects of CBD in the PI3K/Akt/mTOR activity in MS. Experimental Autoimmune Encephalomyelitis (EAE), the most common model of MS, was induced in C57BL/6 mice by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55. After EAE onset, which occurs approximately 14days after disease induction, mice were daily intraperitoneally treated with CBD (10mg/Kg mouse) and observed for clinical signs of EAE. At 28days from EAE-induction, mice were euthanized and spinal cord tissues were sampled to perform immunohistochemical evaluations and western blot analysis. Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR. Also, an increased level of BNDF in CBD-treated mice seems to be involved in the activation of PI3K/Akt/mTOR pathway. In addition, our data demonstrated that therapeutic efficacy of CBD treatment is due to reduction of pro-inflammatory cytokines, like IFN-γ and IL-17 together with an up-regulation of PPARγ. Finally, CBD was found to promote neuronal survival by inhibiting JNK and p38 MAP kinases. These results provide an interesting discovery about the regulation of the PI3K/Akt/mTOR pathway by cannabidiol administration, that could be a new potential therapeutic target for MS management.
... Some authors have advocated the concept of herbal synergy in Cannabis [17,[24][25][26], which is analogous to the combinatorial activity of endocannabinoids via "the entourage effect" [27] of active and inactive metabolites. Such synergy would be apparent under conditions in which the activity of a minor botanical chemical component complemented the major, diminished the adverse event profile, or otherwise contributed to a preparationʼs stability or efficacy. ...
Article
An advanced Mendelian Cannabis breeding program has been developed utilizing chemical markers to maximize the yield of phytocannabinoids and terpenoids with the aim to improve therapeutic efficacy and safety. Cannabis is often divided into several categories based on cannabinoid content. Type I, Δ 9-tetrahydrocannabinol-predominant, is the prevalent offering in both medical and recreational marketplaces. In recent years, the therapeutic benefits of cannabidiol have been better recognized, leading to the promotion of additional chemovars: Type II, Cannabis that contains both Δ 9-tetrahydrocannabinol and cannabidiol, and cannabidiol-predominant Type III Cannabis. While high-Δ 9-tetrahydrocannabinol and high-myrcene chemovars dominate markets, these may not be optimal for patients who require distinct chemical profiles to achieve symptomatic relief. Type II Cannabis chemovars that display cannabidiol- and terpenoid-rich profiles have the potential to improve both efficacy and minimize adverse events associated with Δ 9-tetrahydrocannabinol exposure. Cannabis samples were analyzed for cannabinoid and terpenoid content, and analytical results are presented via PhytoFacts, a patent-pending method of graphically displaying phytocannabinoid and terpenoid content, as well as scent, taste, and subjective therapeutic effect data. Examples from the breeding program are highlighted and include Type I, II, and III Cannabis chemovars, those highly potent in terpenoids in general, or single components, for example, limonene, pinene, terpinolene, and linalool. Additionally, it is demonstrated how Type I – III chemovars have been developed with conserved terpenoid proportions. Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Δ 9-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment.
... The notion that not all of the therapeutic actions of Cannabis herb are due to THC content is well established [25,3]. In addition to THC, the plant contains over 100 phytocannabinoids most of which have not been fully evaluated for their pharmacological activity. ...
... Preserved records of cannabis use in medicine can be found in China and are nearly 5000 years old (Hanuš and Mechoulam, 2005). The healing properties of cannabis products have been recognized for millennia, but because of the psychoactive nature of the major active substance Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and the fact that cannabis is the most commonly used illegal narcotic substance not only in Europe, but around the world, this substance has been criminalized for a long time in most countries in the world (Wilkinson et al., 2003;Hanuš, 2009). Because of this, the legal use in medicine remains controversial. ...
Article
In the last decades, there has been a significant increase in the number of lifestyle and auto-immune diseases, such as various cancers or multiple sclerosis. In countries where cannabis is decriminalized for medical purposes, it is most often prescribed for these diagnoses. Today, over 700 different cannabis genotypes are being bred, and it is very important to describe in detail their cultivation, potential yields, chemical profile and stability, to be recommended to a particular patient with a specific diagnosis. The aim of this study was to evaluate the inflorescence yields and the content of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) of seven traditional genotypes of cannabis – Conspiracy Kush, Nurse Jackie, Jilly Bean, Nordle, Jack Cleaner 2, Jack Skellington and National Health Services. The plants were grown under controlled climatic conditions during six growing cycles at a density of 9 plants/m². Dried inflorescences from each plant were homogenized and analyzed by gas chromatography with flame ionization detection. The average yield per plant was 21.02 ± 3.33 g and the highest yields showed genotype Nurse Jackie (24.74 ± 6.11 g). The lowest yields were shown by genotype Jack Skellington (15.41 ± 4.02 g). Average Δ⁹-THC levels for each variety in all 6 growing cycles ranged from 15.69 ± 2.6 % to 19.31 ± 2.47 % (w/w). The lowest contents of Δ⁹-THC were measured in the Nordle genotype and the highest values were found in the Jack Cleaner 2 and Jack Skellington genotypes. Average CBD levels in the plants ranged from 0.45 ± 0.1 % to 0.57 ± 0.08 % (w/w) over six individual cycles. This study shows that among genotypes studied, the best parameters – high yield and stable cannabinoids production – are shown by genotypes Nurse Jackie and Jilly Bean.
... In the practice of traditional medicine, whole plant extracts or mixtures of plant extracts are used rather than isolated chemical constituents [39,40]. Emerging scientific evidence obtained in recent years suggests that the biological effects of plant extracts are mediated by the synergy of multiple chemical ingredients rather than single isolated compounds [41][42][43][44][45][46][47]. Interaction of chemical ingredients might: (a) provide synergistic multitargeted effects on biological processes; (b) improve pharmacokinetics with enhanced solubility, resorption rate, and bioavailability; (c) overcome resistance mechanisms of pathogenic microorganisms; and (d) neutralize the adverse side effects of individual compounds [48]. ...
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Current methods for the authentication of essential oils focus on analyzing their chemical composition. This study describes the use of nanofluidic protein post-translational modification (PTM) profiling to differentiate essential oils by analyzing their biochemical effects. Protein PTM profiling was used to measure the effects of four essential oils, copaiba, mandarin, Melissa, and turmeric, on the phosphorylation of MEK1, MEK2, and ERK1/2 in the MAPK signaling pathway; Akt and 4EBP1 in the pI3K/Akt/mTOR signaling pathway; and STAT3 in the JAK/STAT signaling pathway in cultured HepG2 cells. The gain or loss of the phosphorylation of these proteins served as direct read-outs for the positive or negative regulatory effects of essential oils on their respective signaling pathways. Furthermore, protein PTM profiling and GC-MS were employed side-by-side to assess the quality of the essential oils. In general, protein PTM profiling data concurred with GC-MS data on the identification of adulterated mandarin, Melissa, and turmeric essential oils. Most interestingly, protein PTM profiling data identified the differences in biochemical effects between copaiba essential oils, which were indistinguishable with GC-MS data on their chemical composition. Taken together, nanofluidic protein PTM profiling represents a robust method for the assessment of the quality and therapeutic potential of essential oils.
... In the multivariate regression analysis of all the patients in this study, the THC concentration, cannabis dose, and duration of cannabis treatment were found to be significantly correlated with pain improvement, and the duration of cannabis treatment was found to be significantly correlated with sleep quality improvement. ese results can be explained by the known fact that THC is an important cannabinoid for pain relief and is much more powerful than CBD [31,32]. e duration of cannabis treatment is important in acquiring experience in using cannabis and also in trying out different species and ways of consumption to ultimately get to the right species with the best benefit to the patient. ...
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Article
Introduction: Medical cannabis (MC) is becoming increasingly popular for the treatment of chronic pain conditions. In this study, we evaluated the effect of MC treatment on pain level and quality of sleep of patients with different medical conditions at the rheumatology clinic. Methods: Patients licensed for the use of MC at the rheumatology clinics at different settings were located and contacted. Their demographic and clinical parameters were documented, including type of medical cannabis consumed, way of consumption, and current monthly consumed amount. These patients were contacted by phone and asked about the effect on pain level and quality of sleep. Results: A total of 351 patients were located, and 319 completed the questionnaire. Mean age was 46 ± 12 years, 76% were female, 82% had fibromyalgia, ∼9% had mechanical problems, ∼4% had inflammatory problems, ∼4% had neurological problems, and ∼1% had other problems. The average monthly consumed dose of MC was 31, 35, 36, and 32 g, with mean pain level reduction of 77%, 82%, 83%, and 57%, and mean sleep quality improvement of 78%, 71%, 87%, and 76% among patients with fibromyalgia, mechanical, neuropathic, and inflammatory problems, respectively. Mean THC and CBD contents were 18.38% ± 4.96 and 2.62% ± 4.87, respectively. The THC concentration, duration of MC consumption, and MC consumption dose had independent significant correlations with pain reduction while only the duration of MC consumption had an independent significant correlation with sleep quality improvement. Conclusions: MC had a favorable effect on pain level and quality of sleep among all spectrums of problems at the rheumatology clinic.
... On the other hand, CBD was seen as a potential safe alternative for alleviating neuroinflammation and neurodegeneration in MS, also with lower toxicity and better psychological outcome (i.e., anxiolytic) in patients compared to Δ9-THC [290,291]. However, CBD has no significant effect on spasticity, which seems more related to CB1R [281,288,292,293]. ...
Article
Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of “personalized medicine” as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.
... Although this "entourage" effect has been suggested in some preclinical studies, such effects remain to be proven in humans. 44,[46][47][48] ...
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Article
Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. Up to 30% of children with epilepsy will be refractory to standard anticonvulsant therapy, and those with epileptic encephalopathy can be particularly challenging to treat. The endocannabinoid system can modulate the physiologic processes underlying epileptogenesis. The anticonvulsant properties of several cannabinoids, namely Δ-tetrahydrocannabinol and cannabidiol (CBD), have been demonstrated in both in vitro and in vivo studies. Cannabis-based therapies have been used for millennia to treat a variety of diseases including epilepsy. Several studies have shown that CBD, both in isolation as a pharmaceutical-grade preparation or as part of a CBD-enriched cannabis herbal extract, is beneficial in decreasing seizure frequency in children with treatment-resistant epilepsy. Overall, cannabis herbal extracts appear to provide greater efficacy in decreasing seizure frequency, but the studies assessing cannabis herbal extract are either retrospective or small-scale observational studies. The two large randomized controlled studies assessing the efficacy of pharmaceutical-grade CBD in children with Dravet and Lennox-Gastaut syndromes showed similar efficacy to other anticonvulsants. Lack of data regarding appropriate dosing and pediatric pharmacokinetics continues to make authorization of cannabis-based therapies to children with treatment-resistant epilepsy challenging.
... Delta-9-tetrahydrocannabinol (THC) that was first described in 1964 is the primary psychoactive compound in Cannabis and is known to display therapeutic potentials as an analgesic, antiemetic and appetite stimulant 2,3,5-8 . Additionally, THC can be used for the treatment of multiple acute and chronic health disorders [9][10][11] . These include treatment of nausea and vomiting associated with cancer chemotherapy, anorexia, and cachexia associated with HIV and AIDS patients, pain and muscle spasms in multiple sclerosis 12 . ...
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Article
Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound in Cannabis, which is studied extensively for its medicinal value. A central gap in the science is the underlying mechanisms surrounding THC’s therapeutic effects and the role of gut metabolite profiles. Using a mass-spectrometry based metabolomics, we show here that intraperitoneal injection of THC in C57BL/6 mice modulates metabolic profiles that have previously been identified as integral to health. Specifically, we investigated the effects of acute (single THC injection denoted here as ‘1X’) and short -term (five THC injections on alternate days denoted as ‘5X’) THC administration on fecal and intestinal tissue metabolite profiles. Results are consistent with the hypothesis that THC administration alters host metabolism by targeting two prominent lipid metabolism pathways: glycerophospholipid metabolism and fatty acid biosynthesis.
... 1. Sativex 1 allows attainment of higher daily doses of oral THC, probably due to oromucosal delivery and the actions of CBD. 2. The AEs attributable to Sativex 1 are significantly less frequent than those reported with other delivery systems of standardized herbal cannabis. The contributions of cannabis components beyond THC to its medicinal effects has been widely debated (103,104) with some authors supporting the concept of herbal synergy (59,105,106), the likes of which has been convincingly demonstrated for endocannabinoids via ''the entourage effect'' of active and seemingly inactive metabolites (107,108). Such synergy would be apparent under conditions in which the activity of a minor component complemented the major, diminished the AE profile, or otherwise contributed to a preparation's stability or efficacy. ...
... An "entourage" effect in which the clinical efficacy of cannabinoids when used in combination are greater than when used individually has been demonstrated in several animal models of epilepsy but has yet to be reported for human trials (25)(26)(27). While we saw clinical efficacy with regards to reduction in seizure frequency and improvements in QoL scores with CBD doses lower than those reported in studies using pharmaceutical grade CBD, the small number of participants reported require caution when interpreting the results and preclude drawing definite conclusions in particular with regards to possible entourage effect. ...
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Article
Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 9-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (C ss, Min) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. C SS,Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. C SS,Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, C SS,Min levels of THC remained lower than what would be expected to cause intoxication. Huntsman et al. Preliminary Results of CARE-E Study Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.
... However, many patients claim (subjectively) that a whole or partially purified extract of Cannabis sativa L. offers advantages over a single isolated ingredient. [116][117][118] In the Netherlands, the unavailability of a legal product forced patients to frequent coffeeshops, which, although not prosecuted according to the Dutch soft-drugs policy, remain illegal. In September 2003, in order to stimulate the conduct of representative clinical trials evaluating the safety and efficacy of medicinal cannabis, whilst simultaneously offering patients access to a prescription product 119 a meeting pharmaceutical quality standards (standardized content; free of micro-biological impurities), legal medicinal cannabis product was introduced in the Netherlands. ...
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Ever since its introduction to the drug-market in the late eighties, early nineties of the last century, irinotecan is fighting its image. Particularly, the unpredictable occurrence and severity of delayed-type diarrhea, its main dose-limiting adverse effect, remains a serious concern for medical oncologists. In this perspective, reliable a priori knowledge of the toxicity profile of irinotecan therapy in the individual patient is of utmost importance, since it would guide physician’s choice and enable adaptive drug administration. In this thesis, different pharmacological aspects of irinotecan therapy have been investigated. Using pharmacokinetic, pharmacogenetic, and phenotyping strategies, as well as pharmacological prophylactic interventions, ways to improve irinotecan tolerability have been investigated. To truly individualize irinotecan treatment, efforts to develop and implement patient-friendly, simple, and feasible limited sampling models and phenotyping and genotyping strategies on a routine basis should be strongly encouraged. Additionally, relations between genotype (UGT1A1*28) and the incidence and severity of adverse effects and therapeutic outcome should be confirmed in large trials, resulting in evidence-based dosing recommendations. Ultimately, lowering the incidence and severity of delayed-type diarrhea will make irinotecan therapy better tolerable and may give this classical topoisomerase I inhibitor the image it deserves in the rapidly changing field of anticancer agents.
... However, using whole Cannabis can be more effective than the single ingredient preparations for some conditions due to the synergy between multiple phytochemicals. In particular, CBD and the terpenes can modulate the effects of THC (Wilkinson et al., 2003;Brenneisen, 2007;Russo, 2011;Andre et al., 2016). For example, CBD can inhibit the metabolism of THC to the more potent 11-OH-THC upon ingestion (Brenneisen, 2007), and can reduce some of the negative side-effects of THC like anxiety, hunger, and sedation (Mechoulam et al., 2002;Russo, 2011;Andre et al., 2016). ...
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Cannabis sativa L. is a diploid species, cultivated throughout the ages as a source of fiber, food, and secondary metabolites with therapeutic and recreational properties. Polyploidization is considered as a valuable tool in the genetic improvement of crop plants. Although this method has been used in hemp-type Cannabis, it has never been applied to drug-type strains. Here, we describe the development of tetraploid drug-type Cannabis lines and test whether this transformation alters yield or the profile of important secondary metabolites: Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), or terpenes. The mitotic spindle inhibitor oryzalin was used to induce polyploids in a THC/CBD balanced drug-type strain of Cannabis sativa. Cultured axillary bud explants were exposed to a range of oryzalin concentrations for 24 h. Flow cytometry was used to assess the ploidy of regenerated shoots. Treatment with 20-40 μM oryzalin produced the highest number of tetraploids. Tetraploid clones were assessed for changes in morphology and chemical profile compared to diploid control plants. Tetraploid fan leaves were larger, with stomata about 30% larger and about half as dense compared to diploids. Trichome density was increased by about 40% on tetraploid sugar leaves, coupled with significant changes in the terpene profile and a 9% increase in CBD that was significant in buds. No significant increase in yield of dried bud or THC content was observed. This research lays important groundwork for the breeding and development of new Cannabis strains with diverse chemical profiles, of benefit to medical and recreational users.
... In the in vitro oxotremorine-M mouse model of epilepsy, excessive neuronal bursting activity can be suppressed with ∆ 9 -THC, but not CBD, while a standardized cannabis extract containing both ∆ 9 -THC and CBD can abolish the abnormal bursting activity faster than purified ∆ 9 -THC alone [45]. In another study, both purified ∆ 9 -THC and CBD can increase intracellular Ca 2+ in rat hippocampal neuronal and glial cells. ...
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Chapter
Epilepsy is a chronic disease of the central nervous system characterized by recurrent unprovoked seizures. Up to 30% of patients continue to have seizures despite treatment with appropriate anticonvulsant medications. The presence of abnormal oscillatory events within neural networks is a major feature of epileptogenesis. The endocannabi-noid system can modulate these oscillatory events and alter neuronal activity making the phytocannabinoids found in Cannabis a potential therapeutic option for patients with treatment resistant epilepsy. Many in vitro and in vivo studies have demonstrated the anticonvulsant effects of several phytocannabinoids including Δ 9-tetrahydrocannabinol (Δ 9-THC) and Cannabidiol (CBD). Several small observational studies demonstrated a favorable response to cannabis herbal extracts (CHE) containing high concentrations of CBD in children with treatment resistant epilepsy. Two large double blinded clinical trials assessing the efficacy of pharmaceutical grade CBD have also been performed in children with treatment resistant seizures in Dravet syndrome and Lennox-Gastaut syndrome. Both studies demonstrated an improvement in seizure reduction in children taking CBD as compared to the placebo groups. To date there is very limited data regarding the use of cannabis based products to treat adult patients with treatment resistant epilepsy with only one randomized double blinded placebo controlled clinical trial underway.
... They also postulated that this helped to explain how botanical drugs were often more efficacious than their isolated components (Mechoulam and Ben-Shabat, 1999). Although the single molecule synthesis remains the dominant model for pharmaceutical development (Bonn-Miller et al., 2018), the concept of botanical synergy has been amply demonstrated contemporaneously, invoking the pharmacological contributions of "minor cannabinoids" and Cannabis terpenoids to the plant's overall pharmacological effect (McPartland and Pruitt, 1999;McPartland and Mediavilla, 2001;McPartland andRusso, 2001, 2014;Russo and McPartland, 2003;Wilkinson et al., 2003;Russo, 2011). Several pertinent examples of the entourage effect in Cannabis are illustrative: ...
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The topic of Cannabis curries controversy in every sphere of influence, whether politics, pharmacology, applied therapeutics or even botanical taxonomy. Debate as to the speciation of Cannabis, or a lack thereof, has swirled for more than 250 years. Because all Cannabis types are eminently capable of cross-breeding to produce fertile progeny, it is unlikely that any clear winner will emerge between the “lumpers” vs. “splitters” in this taxonomical debate. This is compounded by the profusion of Cannabis varieties available through the black market and even the developing legal market. While labeled “strains” in common parlance, this term is acceptable with respect to bacteria and viruses, but not among Plantae. Given that such factors as plant height and leaflet width do not distinguish one Cannabis plant from another and similar difficulties in defining terms in Cannabis, the only reasonable solution is to characterize them by their biochemical/pharmacological characteristics. Thus, it is best to refer to Cannabis types as chemical varieties, or “chemovars.” The current wave of excitement in Cannabis commerce has translated into a flurry of research on alternative sources, particularly yeasts, and complex systems for laboratory production have emerged, but these presuppose that single compounds are a desirable goal. Rather, the case for Cannabis synergy via the “entourage effect” is currently sufficiently strong as to suggest that one molecule is unlikely to match the therapeutic and even industrial potential of Cannabis itself as a phytochemical factory. The astounding plasticity of the Cannabis genome additionally obviates the need for genetic modification techniques.
Chapter
Psychoactive cannabinoids from the marijuana plant (phytocannabinoids), from the body (endocannabinoids), and from the research lab (synthetic cannabinoids) produce their discriminative stimulus effects by stimulation of CB1 receptors in the brain. Early discrimination work with phytocannabinoids confirmed that Δ9-tetrahydrocannabinol (Δ9-THC) is the primary psychoactive constituent of the marijuana plant, with more recent work focusing on characterization of the contribution of the major endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), to Δ9-THC-like internal states. Collectively, these latter studies suggest that endogenous increases in both anandamide and 2-AG seem to be optimal for mimicking Δ9-THC’s discriminative stimulus effects, although suprathreshold concentrations of anandamide also appear to be Δ9-THC-like in discrimination assays. Recently, increased abuse of synthetic cannabinoids (e.g., “fake marijuana”) has spurred discrimination studies to inform regulatory authorities by predicting which of the many synthetic compounds on the illicit market are most likely to share Δ9-THC’s abuse liability. In the absence of a reliable model of cannabinoid self-administration (specifically, Δ9-THC self-administration), cannabinoid discrimination represents the most validated and pharmacologically selective animal model of an abuse-related property of cannabinoids – i.e., marijuana’s subjective effects. The influx of recent papers in which cannabinoid discrimination is highlighted attests to its continued relevance as a valuable method for scientific study of cannabinoid use and abuse.
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Peroxisome proliferator-activated receptor-δ (PPARδ) is a ligand activated receptor that dimerises with another nuclear receptor of the retinoic acid receptor (RXR) family. The formed dimers interact with other co-activator proteins and form active complexes that interact with PPAR-response elements and promote transcription of genes involved in lipid metabolism. It appears that various natural fatty acids and their metabolites serve as endogenous activators of PPARδ, however, there is no consensus in the literature on the nature of the prime activators of the receptor. In vitro and cell based assays of PPARδ activation by fatty acids and their derivatives produce often conflicting results. The search for synthetic and selective PPARδ agonists, which may be pharmacologically useful, is intense. Current rational modelling used to obtain such compounds relies mostly on crystal structures of synthetic PPARδ ligands with the recombinant ligand binding domain of (LBD) the receptor. Here we introduce an original computational prediction model for ligand binding with PPARδ LBD. We employed this model to calculate binding probabilities of 82 different natural and synthetic compounds from the literature that were independently tested in cell-free and cell-based assays for their capacity to bind or activate PPARδ. Here we introduce an original computational prediction model for ligand binding to PPARδ LBD. The model was built based on EC50 data of 16 ligands with available crystal structures and validated by calculating binding probabilities of 82 different natural and synthetic compounds from the literature that were independently tested in cell-free and cell-based assays, leading to prediction accuracy of between 70% and 93% (depending on ligand type). This new computational tool could therefore be used in the search for natural and synthetic agonists of the receptor.
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The major psychoactive constituent of the Cannabis sativa plant, Delta(9)-tetrahydrocannabinol (THC), has been extensively investigated for its therapeutic and toxicological effects. Cannabidiol, another abundant but nonpsychotropic constituent of the Cannabis plant, has recently attracted renewed interest as a therapeutic molecule. Preliminary reports of its antipsychotic, anti hyperalgesic, anticonvulsant, neuroprotective and antiemetic properties, and its ability to counteract certain effects of traditional cannabinoid receptor ligands, have been augmented by the discovery of its affinity for the vanilloid 1 receptor in the transient receptor potential family (TRPV1) and its modulation of endocannabinoid activity. This review discusses the current understanding of the mechanism of action of cannabidiol, focusing on some of the central and peripheral pharmacological effects of this exciting potential therapeutic agent.
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1. One of the main theories of tinnitus is that it is a form of sensory epilepsy, sometimes arising from neuronal hyperactivity in the brainstem cochlear nucleus. 2. Antiepileptic drugs have therefore been explored as one potential treatment option. 3. Increasing evidence suggests that cannabinoid drugs can also have antiepileptic effects. 4. Recently, it has been reported that cannabinoid CB1 and CB2 receptors and the endogenous cannabinoid, 2-arachidonylglycerol (2-AG), are expressed in the cochlear nucleus. 5. CB1 receptors appear to negatively regulate the release of glutamate, and it is possible that their down-regulation during the development of tinnitus is responsible for the neuronal hyperactivity associated with the condition. 6. This chapter explores the possibility that cannabinoid drugs might be useful in the treatment of tinnitus.
Preprint
Aims/Hypothesis Tinnitus is a phantom sound perception affecting both auditory and limbic structures. The mechanisms of tinnitus remain unclear and it is debatable whether tinnitus alters attention to sound and the ability to inhibit repetitive sounds, a phenomenon also known as auditory gating. Methods 22 male C57BL/6J mice were used in this study. Anesthetized mice were exposed to a 9-11 kHz narrow band noise (90 dBSPL for 1 hr) and sham exposed mice were used as controls. Hearing thresholds were measured using auditory brainstem responses (ABRs) and tinnitus was assessed using Gap prepulse inhibition of acoustic startle (GPIAS). After the induction of tinnitus, mice were implanted multi-electrodes to assess auditory event-related potentials (aERPs) in the dorsal hippocampus in response to paired clicks. Alterations of aERPs under nicotine (1.0 mg/kg, intraperitoneal (i.p.) or cannabis extract (100 mg/Kg, i.p.) were evaluated (in isolation or in combination), the latter containing 47.25 mg/kg of tetrahydrocannabinol (THC); 0.43 mg/kg of cannabidiol (CBD) and 1.17 mg/kg of cannabinol (CBN), as analyzed by high-performance liquid chromatography (HPLC). Saline-treated animals were used as controls. Results Our results show that mice with behavioral evidence of tinnitus display auditory gating of repetitive click, but with larger amplitudes and longer latencies of the N40 component. In contrast, no difference was observed in the P80 amplitude and latency between groups or treatments. The combination of cannabis extract and nicotine also improved auditory gating ratio in mice with noise-induced tinnitus without permanent hearing threshold shifts by strongly increasing the first N40 click amplitude but without altering the second click response amplitude. Furthermore, the increased latency of the N40 component suggests altered temporal processing of triggered attention in mice with tinnitus due to an increased sensitivity to the exposure to cannabis extract. Conclusion/Interpretation In summary, we show that nicotine and cannabis extract alter sensory gating in mice with behavioral evidence of tinnitus and propose that the altered central plasticity in tinnitus is more sensitive to the combined actions on the cholinergic and the endocannabinoid systems. We conclude that the limbic system may play a role in the altered sensory gating responses on tinnitus since the hippocampus responses to auditory inputs are altered. These findings could enable a new understanding of which neuronal pathways could be involved in sensory gating in tinnitus.
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Since clinical evaluations started in the early nineties, the anticancer drug docetaxel has obtained a prominent place in the treatment of various human malignancies. Marketing approval currently includes the treatment of patients with breast cancer, non-small-cell lung cancer, androgen-independent prostate cancer (AIPC) and patients with advanced gastric cancer. Following initial introduction much research has focused on docetaxel’s clinical pharmacological properties in an attempt to improve the risk-benefit ratio for docetaxel treatment. In particular, reducing the substantial degree of interindividual variability in docetaxel pharmacokinetics, which is associated with the observed variability in toxicity, is an aspect, which has received much attention.
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Natural product based drugs constitute a substantial proportion of the pharmaceutical market particularly in the therapeutic areas of infectious diseases and oncology. The primary focus of any drug development program so far has been to design selective ligands (drugs) that act on single selective disease targets to obtain highly efficacious and safe drugs with minimal side effects. Although this approach has been successful for many diseases, yet there is a significant decline in the number of new drug candidates being introduced into clinical practice over the past few decades. This serious innovation deficit that the pharmaceutical industries are facing is due primarily to the post-marketing failures of blockbuster drugs. Many analysts believe that the current capital-intensive model-"the one drug to fit all" approach will be unsustainable in future and that a new "less investment, more drugs" model is necessary for further scientific growth. It is now well established that many diseases are multi-factorial in nature and that cellular pathways operate more like webs than highways. There are often multiple ways or alternate routes that may be switched on in response to the inhibition of a specific target. This gives rise to the resistant cells or resistant organisms under the specific pressure of a targeted agent, resulting in drug resistance and clinical failure of the drug. Drugs designed to act against individual molecular targets cannot usually combat multifactorial diseases like cancer, or diseases that affect multiple tissues or cell types such as diabetes and immunoinflammatory diseases. Combination drugs that affect multiple targets simultaneously are better at controlling complex disease systems and are less prone to drug resistance. This multicomponent therapy forms the basis of phytotherapy or phytomedicine where the holistic therapeutic effect arises as a result of complex positive (synergistic) or negative (antagonistic) interactions between different components of a cocktail. In this approach, multicomponent therapy is considered to be advantageous for multifactorial diseases, instead of a "magic bullet" the metaphor of a "herbal shotgun" might better explain the state of affairs. The different interactions between various components might involve the protection of an active substance from decomposition by enzymes, modification of transport across membranes of cells or organelles, evasion of multidrug resistance mechanisms among others.
Article
The purpose of this study was the generation of central nervous system (CNS)-excluded cannabinoid receptor agonists to test the hypothesis that inhibition of spasticity, due to CNS autoimmunity, could be controlled by affecting neurotransmission within the periphery. Procedures included identification of chemicals and modeling to predict the mode of exclusion; induction and control of spasticity in the ABH mouse model of multiple sclerosis; conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide association study in N2(129×ABH) backcross to map polymorphic cannabinoid drug pump; and sequencing and detection of cannabinoid drug-pump activity in human brain endothelial cell lines. Three drugs (CT3, SAB378 and SAD448) were identified that control spasticity via action on the peripheral nerve CB1 receptor. These were peripherally restricted via drug pumps that limit the CNS side effects (hypothermia) of cannabinoids to increase the therapeutic window. A cannabinoid drug pump is polymorphic and functionally lacking in many laboratory (C57BL/6, 129, CD-1) mice used for transgenesis, pharmacology, and toxicology studies. This phenotype was mapped and controlled by 1-3 genetic loci. ABCC1 within a cluster showing linkage is a cannabinoid CNS-drug pump. Global and conditional CB1 receptor-knockout mice were used as controls. In summary, CNS-excluded CB1 receptor agonists are a novel class of therapeutic agent for spasticity.-Pryce, G., Visintin, C., Ramagopalan, S. V., Al-Izki, S., De Faveri, L. E., Nuamah, R. A., Mein, C. A., Montpetit, A., Hardcastle, A. J., Kooij, G., de Vries, H. E., Amor, S., Thomas, S. A., Ledent, C., Marsicano, G., Lutz, B., Thompson, A. J., Selwood, D. L., Giovannoni, G., Baker, D. Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.
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Thesis
Background Cannabis has been used for its therapeutic properties for five millennia and was prescribed for medicinal use in the UK until 1971. Cannabis then became classified as a Class B, Schedule 1 drug under the Misuse of Drugs Act 1971, which declared it has "no medicinal value". However, since then a growing body of evidence derived from clinical trials and case reports have supported the plants claimed therapeutic potential. Consequently, many campaign for the legalisation of cannabis for medicinal use in the UK. Given this is a topic of much current debate, this study explores the views and concerns of the key sectors of UK populations, including healthcare professionals, politicians, lawyers, and students, as well as the general British public, in regards to the legalisation of medicinal cannabis in the UK. Method An anonymous online survey was created using SurveyMonkey. Healthcare professional, lawyers and politicians were contacted via email (contact details found on online websites). Students were targeted through social media and a paper survey which was handed out in Bournemouth University lectures. Members of the general public were also targeted through social media and a paper survey which was handed out in Bournemouth Town Centre. There was representative sample of 392 respondents. Results A statistically significant proportion (70%) of the key UK populations (as defined by this study) believe cannabis should be legalised for medicinal use. Furthermore, there is a common consensus among those surveyed that cannabis should be recognised for its medicinal value. A breakdown is below: • Healthcare professionals - 65% • Lawyers - 68% • Politicians - 58% • Students - 81% Among the most common concerns of the overall key UK populations in regards to the potential legalisation of medicinal cannabis use were related to the mental health of the consumer (71%) and the risk of giving young people the wrong impression, suggesting cannabis is a harmless drug (61.4%). Conclusion Current literature provides supporting evidence for the safety and efficacy of the drug. However, good quality, controlled clinical trials are lacking due to the Schedule I classification of cannabis. It is the opinion of this report that the Government should listen to the overall majority of the representative sample examined in this study and reclassify cannabis as a Schedule IV drug. This will allow more research to be done, remove patients already using cannabis from the criminal justice system, and improve the quality, safety and accessibility of the drug for patients suffering a medical condition that cannabis has purported benefits for. This study does recognise how evocative a proposal this is and recommends further research to support the thesis before action is taken.
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The paper provides an overview and review of the use, knowledge and importance of cannabidiol (CBD) on stakeholders in the sports system, on the example of members of the Sports Community of the City of Zadar. In particular, a review is given of the possible harmfulness of taking substances that contain prohibited amounts and ingredients for athletes, ie unfounded and unconfirmed independent research. The method and purpose of taking cannabidiol by the stakeholders of the sports system are presented, with special reference to athletes in the field of recreation. The survey, through a questionnaire, determined whether athletes and sports professionals are sufficiently aware of what are cannabidiols, and what is the impact on the health status of athletes when using cannabidiol and the possible harm to the health of athletes in uncontrolled cannabidiol intake. In conclusion, research has shown that athletes and sports professionals do not know enough about what are cannabidiols, and what is the impact of their use on athletes and recreational athletes. Therefore, the conclusion is that it is necessary to educate these stakeholders in sports and conduct future research.
Article
In recent years there has been a growing appreciation by regulatory authorities that cannabis-based medicines can play a useful role in disease therapy. Although often conflagrated by proponents of recreational use, the legislative rescheduling of cannabis-derived compounds, such as cannabidiol (CBD), has been associated with the steady increase in the pursuit of use of medicinal cannabis. One key driver in this interest has been the scientific demonstration of efficacy and safety of CBD in randomised, placebo-controlled clinical trials in children and young adults with difficult-to-treat epilepsies, which has encouraged increasing numbers of human trials of CBD for other indications and in other populations. The introduction of CBD as the medicine Epidiolex in the US (in 2018) and as Epidyolex in the EU (in 2019) as the first cannabis-derived therapeutic for the treatment for seizures was underpinned by preclinical research performed at the University of Reading. This work was awarded the British Pharmacological Society Sir James Black Award for Contributions to Drug Discovery 2019 and is discussed in the following review article.
Article
Introduction: Cannabis sativa L. medicinal oils are good therapeutic options due to their wide spectrum of pharmacological applications and the easy adjustment of individual doses. The lack of standardization of methodology in the preparation of medicinal oil using the Cannabis crude extract results in elevated variability of cannabinoid concentration in the final product. The elevated variability impairs the understanding of beneficial and adverse effects related to dose-response pharmacological activities. Objective: This study aimed to conduct a review on the current methods of Cannabis oil preparation present in the literature, to demonstrate the most appropriate methodologies to ensure a product with high content of cannabinoids and terpenes. Results: The decarboxylation stage is essential for the conversion of acid cannabinoids into neutral cannabinoids, which are substances with the highest bioavailability. Lower temperatures for longer periods of time instead of high temperatures in less time are highly recommended to ensure that all the acidic cannabinoids have passed through decarboxylation. For the guarantee of a high terpene content, the separate addition of essential oil to the fixed oil prepared from the crude extract should be considered. Ultrasound-assisted extraction is one of the best performing methodologies because it is cheaper than other techniques, such as supercritical fluid extraction, besides that, ultrasound extraction is effective in short extraction times and uses small amounts of solvent when compared with other techniques. Conclusion: Although the literature about the methods of preparation of Cannabis medicinal oil is scarce, it is possible to standardize an optimized, low-cost, and effective Cannabis extractive methodology from the results found in the literature; however, this will depend on new research for methodological validation.
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Book
Cannabis Sativa has been used for medicinal and other purposes for millennia. In the 1990s the CB1 and CB2 receptors and the endogenous ligands of the endo-cannabinoid system proper were discovered: Anandamide N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG). External mediation of the bodily endo-cannabinoid system with exogenous phytochemical cannabinoids and other active compounds within Cannabis representative of the full interactive proliferation of naturally occurring constituents appears from manifest interdigitated cross-mediational systemic complexity and phylogenetic receptor analysis to imply the likelihood of potential synergistic therapeutic efficacy via evolutionary adaptations beginning from as far back as the Cambrian period or more. This approach utilizing the full proliferation of interactive compounds or some selected intra-active multi-constituent portion thereof, has been demonstrably curtailed by legal, political and systemic interference. This document will spell out the demonstrated functional potential and implied therapeutic utility of cannabinoids and cannabis extracts, support the aforementioned evolutionary hypothesis and demonstrated multifunctional medical utility with both phylogenetic and historical analysis, and then detail what appears to be the suppressed approach that may lead to the speedy and inexpensive treatment or cure of many dread diseases using Cannabis extracts, including but not limited to cancer. It is also clearly implied and well supported from historical and current medical perspectives that the raw drug itself is safe and effective in treating many conditions and should be available to dispense via prescription by all qualified medical professionals.
Article
Chandraprabha Vati (CPV), a multi-ingredient phyto formulation, is widely used in Ayurveda for the treatment of liver and kidney disorders. In this study, we attempt to elucidate the mode of action of CPV. We specifically focus on the effects of CPV on the transcriptional regulation of Pregnane-X-Receptor (PXR) and its subsequent effects on interleukins, Peroxisome Proliferator-Activated Receptor-γ (PPARγ) and type 4 Glucose Transporter (GLUT4). Our results show that CPV up-regulates PXR moderately in contrast to its individual ingredients such as chebulinic acid or linalool that down regulate PXR. Further, the expression of Cytochrome P450 3A4 (CYP3A4), the gene involved in drug elimination, is only moderately up-regulated by CPV, again in contrast to the effect of some of its ingredients. CPV down regulates the levels of pro-inflammatory cytokines and upregulates the levels of PPARγ, which in turn upregulates GLUT4 expression. These together suggest that the therapeutic properties of CPV can be attributed to its multi-pronged action, viz., prevention of inflammation, moderate expression of PXR that activates several downstream pathways and tight regulation of CYP3A4 thereby slowing down the elimination of the chemical constituents. In addition, these results emphasize on the need for multi-ingredient approach towards designing effective therapeutic formulations.
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This review summarizes studies that examined the effectiveness of cannabinoids in treating spasticity, with a focus on understanding the relevance of the existing evidence to paediatric populations. MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched to identify studies that examined the use of cannabinoids in spasticity. We identified 32 studies in adult and paediatric populations. Results were summarized by condition, with adult and paediatric studies considered separately. There is evidence from randomized controlled clinical trials that cannabinoids are more effective than placebo in reducing symptoms of spasticity in adults with multiple sclerosis. Most positive effects were based on patient‐rated rather than clinician‐rated measures, were modest in size, and should be considered in the context of the narrow therapeutic index of cannabinoids for spasticity and adverse effects. There were comparatively few, and no large studies, of spasticity in conditions other than multiple sclerosis. Few studies have been conducted in paediatric populations. Paediatric studies of spasticity provide low quality evidence and are inadequate to inform clinical practice. • Cannabinoids have modest efficacy in reducing muscle spasticity in adults with multiple sclerosis. • There is limited evidence of efficacy for cannabinoid use in other conditions, particularly in paediatric populations. • Studies in paediatric populations have been of low quality and are insufficient to inform clinical practice.
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Research
Cannabinoids are a group of terpenophenolic compounds present in Cannabis (Cannabis sativa L). The broader definition of cannabinoids refers to a group of substances that are structurally related to delta-9-tetrahydrocannabinol (Δ9-THC) or that bind to cannabinoid receptors. Before the 1980’s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. There are currently two known types of cannabinoid receptors, termed CB1 and CB2. The cannabinoid system has been around for over 600 million years…even before the dinosaurs!! The cannabinoid system is present in species such as hydra, mollusks, and insects, leading to speculation on the physiological importance of such a system preserved throughout evolution. To date, the presence in the central nervous system of specific lipids that bind naturally to the CB1/CB2 cannabinoid receptors has been documented. Pharmacological experiments have shown that injection of those compounds induces cannabimimetic effects. The family of endogenous cannabinoids or endocannabinoids comprises Arachidonoylethanolamine, 2-araquidonylglycerol, Virodhamine, noladinether and N-arachidonyldopamine. The endocannabinoids have an active role in modulating diverse neurobiological functions, such as learning and memory, feeding, pain perception and sleep generation. The system of endogenous cannabinoids is present in several species, including humans, leading to speculation regarding the neurobiological role of the endocannabinoid system in diverse functions. Hence, I thought it was time to bring out an editorial book on the subject containing advanced and up-to-date scientific information on this special and exclusive topic. I expect that such a book is likely to attain global circulation among students, teachers and researchers alike. Fortunately, in response to our appeal, a number of leading scientists in the field across the globe agreed to contribute to the book. Thus, this book deals with various aspects of the cannabinoid and endocannabinoid system, from phenomena to molecular processes. I am sincerely grateful to all the contributors for keeping. The purpose of the book is to provide a comprehensive understanding of the endocannabinoid system with adequate emphasis on the pharmacological and molecular foundation and is directed at all who are interested in cannabinoid research.
Article
Cannabis sativa has been employed for thousands of years, primarily as a source of a stem fiber (both the plant and the fiber termed “hemp”) and a resinous intoxicant (the plant and its drug preparations commonly termed “marijuana”). Studies of relationships among various groups of domesticated forms of the species and wild-growing plants have led to conflicting evolutionary interpretations and different classifications, including splitting C. sativa into several alleged species. This review examines the evolving ways Cannabis has been used from ancient times to the present, and how human selection has altered the morphology, chemistry, distribution and ecology of domesticated forms by comparison with related wild plants. Special attention is given to classification, since this has been extremely contentious, and is a key to understanding, exploiting and controlling the plant. Differences that have been used to recognize cultivated groups within Cannabis are the results of disruptive selection for characteristics selected by humans. Wild-growing plants, insofar as has been determined, are either escapes from domesticated forms or the results of thousands of years of widespread genetic exchange with domesticated plants, making it impossible to determine if unaltered primeval or ancestral populations still exist. The conflicting approaches to classifying and naming plants with such interacting domesticated and wild forms are examined. It is recommended that Cannabis sativa be recognized as a single species, within which there is a narcotic subspecies with both domesticated and ruderal varieties, and similarly a non-narcotic subspecies with both domesticated and ruderal varieties. An alternative approach consistent with the international code of nomenclature for cultivated plants is proposed, recognizing six groups: two composed of essentially non-narcotic fiber and oilseed cultivars as well as an additional group composed of their hybrids; and two composed of narcotic strains as well as an additional group composed of their hybrids.
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Thesis
Tesi hau bi zutabe nagusitan banatzen da. Lehenengoan ardo hondakinen balioa handitzeko metodologia bat garatu da. Lehenik, ardo hondakinetatik polifenolak eta gantz azidoak bakoitza bere aldetik erauzteko jariakin gainkritiko bidezko erauzketa (SFE) optimizatu da. Polifenolak ez dira oso egonkorrak ordea eta gorputzean bioeskuragarritasun baxua dute. Arazo hauek konpontzeko polifenolak zurrusta-bibrazio bidezko mikrokapsularatzearen (VNM) bidez enkapsulatu dira. Bigarren zutabean etorkizun hurbilean kannabisa sendagai bezala erabili ahal izateko 3 urrats eman dira. Alde batetik, landare ezberdinak efektu ezberdinekin lotzea ahalbidetu dezakeen landareen kannabinoideen hatz-marka osatzeko fragmentazio bikoitzeko masa-espektometriari akoplaturiko eraginkortasun handiko likido kromatografia (HPLC-MS/MS) bidezko metodo bat garatu da. Bestalde, gernuan eta plasman kannabinoideak eta euren metabolitoak kuantifikatzeko metodo bat ere garatu da, hidrolisi entzimatiko-alkalino bikoitza eta HPLC-MS/MS analisi teknika erabiliz. Azkenik, konposatu puruen eta landare mota jakinen produkzioa optimizatzeko, kemotipo ezberdineko landareen hazkuntzan zeharreko kannabinoideen eta terpenoen garapena aztertu da
Article
Epilepsy is a chronic and often progressive disorder characterized by the occurrence of epileptic seizures, affecting about 50 million people worldwide. The prescribed synthetic drugs for the treatment of epilepsy are associated with severe side effects and addiction liabilities upon long term uses. Thus, researchers around the globe are searching for newer, effective and safer drugs from natural resources. The present review emphasizes pharmacological reports on anticonvulsant plants, plant products and formulations. Various chemical constituents (with structures) isolated from different plants responsible for anticonvulsant activity and their possible mechanism of actions have been incorporated in this review. The review has been compiled using references from major databases like Chemical Abstracts, Medicinal and Aromatic Plants Abstracts, PubMed, Scirus, Google scholar, Open J Gate, Scopus, Science Direct and Online Journals, and includes 599 references. Preliminary anticonvulsant activity studies have been carried out on crude extracts of traditonally used and medicinally promising plants. Such plants need to be explored properly with a view to isolate anticonvulsant constituents, and to evaluate their possible mode of actions.
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Article
. A central tenet underlying the use of botanical remedies is that herbs contain many active ingredients. Primary active ingredients may be enhanced by secondary compounds, which act in beneficial syn-ergy. Other herbal constituents may mitigate the side effects of dominant active ingredients. We reviewed the literature concerning medical can-nabis and its primary active ingredient, ∆ 9 -tetrahydrocannabinol (THC). Good evidence shows that secondary compounds in cannabis may enhance the beneficial effects of THC. Other cannabinoid and non-cannabinoid compounds in herbal cannabis or its extracts may reduce THC-induced anxiety, cholinergic deficits, and immunosuppression. Cannabis terpenoids and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activ-ity. [Article copies available for a fee from The Haworth Document Delivery Service: and: Cannabis Therapeutics in HIV/AIDS (ed: Ethan Russo) The Haworth Integrative Healing Press, an imprint of The Haworth Press, Inc., 2001, pp. 103-132. Single or multiple copies of this arti-cle are available for a fee from The Haworth Document Delivery Service [1-800-342-9678, 9:00 a.m. -5:00 p.m. (EST). E-mail address: getinfo@haworthpressinc.com].
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Article
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by delta 9-THC in normal volunteers, and whether this effect occurs by a general block of the action of delta 9-THC or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg delta 9-THC, 1 mg/kg CBD, a mixture containing 0.5 mg/kg delta 9-THC and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by delta 9-THC, however this effect also extended to marihuana-like effects and to other subjective alterations induced by delta 9-THC. This antagonism does not appear to be caused by a general block of delta 9-THC effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of delta 9-THC. These results suggest that the effects of CBD, as opposed to those of delta 9-THC, might be involved in the antagonism of effects between the two cannabinoids.
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Article
The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
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Article
The endogenous cannabinoid receptor agonist anandamide (AEA) and the related compound palmitoylethanolamide (PEA) are inactivated by transport into cells followed by metabolism by fatty acid amide hydrolase (FAAH). The cellular uptake of AEA has been characterized in detail, whereas less is known about the properties of the PEA uptake, in particular in neuronal cells. In the present study, the pharmacological and functional properties of PEA and AEA uptake have been investigated in mouse Neuro-2a neuroblastoma and, for comparison, in rat RBL-2H3 basophilic leukaemia cells. Saturable uptake of PEA and AEA into both cell lines were demonstrated with apparent KM values of 28 μM (PEA) and 10 μM (AEA) in Neuro-2a cells, and 30 μM (PEA) and 9.3 μM (AEA) in RBL-2H3 cells. Both PEA and AEA uptake showed temperature-dependence but only the AEA uptake was sensitive to treatment with Pronase and phenylmethylsulfonyl fluoride. The AEA uptake was inhibited by AM404, 2-arachidonoylglycerol (2-AG), R1- and S1-methanandamide, arachidonic acid and olvanil with similar potencies for the two cell types. PEA, up to a concentration of 100 μM, did not affect AEA uptake in either cell line. AEA, 2-AG, arachidonic acid, R1-methanandamide, Δ9-THC, and cannabidiol inhibited PEA transport in both cell lines. The non-steroidal anti-inflammatory drug indomethacin inhibited the AEA uptake but had very weak effects on the uptake of PEA. From these data, it can be concluded that PEA is transported in to cells both by passive diffusion and by a facilitated transport that is pharmacologically distinguishable from AEA uptake. British Journal of Pharmacology (2001) 132, 1743–1754; doi:10.1038/sj.bjp.0704029
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Article
Psychoactive effects of cannabinoids are thought to be mediated, at least in part, by suppression of both glutamate and GABA release via CB1 cannabinoid receptor. Two types of cannabinoid receptor (CB1 and CB2) have been cloned so far. The CB1 receptors are abundantly expressed in the nervous system, whereas CB2 receptors are limited to lymphoid organs (Matsuda et al., 1990; Munro et al., 1993). Immunocytochemical and electrophysiological studies revealed that in the hippocampus CB1 receptors are expressed on axon terminals of GABAergic inhibitory interneurons (Tsou et al., 1999; Katona et al., 1999) and activation of these receptors decreases GABA release (Hájos et al., 2000). Other physiological studies pointed out the involvement of CB1 receptors in the modulation of hippocampal glutamatergic synaptic transmission and long-term potentiation (Stella et al., 1997; Misner and Sullivan, 1999), but anatomical studies could not confirm the existence of CB1 receptors on glutamatergic terminals. Here we examined cannabinoid actions on both glutamatergic and GABAergic synaptic transmission in the hippocampus of wild type (CB1+/+) and CB1 receptor knockout mice (CB1-/-). The synthetic cannabinoid agonist WIN55,212-2 reduced the amplitudes of excitatory postsynaptic currents in both wild type and CB1-/- mice, while inhibitory postsynaptic currents were decreased only in wild type mice, but not in CB1-/- animals. Our findings are consistent with a CB1 cannabinoid receptor-dependent modulation of GABAergic postsynaptic currents, but a novel cannabinoid-sensitive receptor must be responsible for the inhibition of glutamatergic neurotransmission.
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Article
Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.
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Although smoked marijuana contains at least 60 cannabinoids, delta(9)-tetrahydrocannabinol (delta(9)-THC) is presumed to be the cannabinoid primarily responsible for many marijuana-related effects, including increased food intake and subjective effects. Yet, there has been no systematic comparison of repeated doses of oral delta(9)-THC with repeated doses of smoked marijuana in the same individuals. To compare the effects of oral delta(9)-THC and smoked marijuana in humans under controlled laboratory conditions. Eleven healthy research volunteers, who reported smoking an average of six marijuana cigarettes per day, completed an 18-day residential study. Marijuana cigarettes (3.1% delta(9)-THC, q.i.d.) were smoked or delta(9)-THC (20 mg, q.i.d.) was taken orally using a staggered, double-blind, double-dummy procedure for three consecutive days. Four days of placebo administration separated each active drug condition. Psychomotor task performance, subjective effects, and food intake were measured throughout the day. Relative to placebo baseline, oral delta(9)-THC and smoked marijuana produced similar subjective-effect ratings (e.g., "high" and "mellow"), although some effects of smoked marijuana were more pronounced and less prone to the development of tolerance. Additionally, participants reported "negative" subjective effects (e.g., "irritable" and "miserable") during the days after smoking marijuana but not after oral delta(9)-THC. Both drugs increased food intake for 3 days of drug administration, but had little effect on psychomotor performance. These results indicate that the behavioral profile of effects of smoked marijuana (3.1% delta(9)-THC) is similar to the effects of oral delta(9)-THC (20 mg), with some subtle differences.
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To determine whether plant-derived cannabis medicinal extracts (CME) can alleviate neurogenic symptoms unresponsive to standard treatment, and to quantify adverse effects. A consecutive series of double-blind, randomized, placebo-controlled single-patient cross-over trials with two-week treatment periods. Patients attended as outpatients, but took the CME at home. Twenty-four patients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1). Whole-plant extracts of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), 1:1 CBD:THC, or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5-120 mg/24 hours. Measures used: Patients recorded symptom, well-being and intoxication scores on a daily basis using visual analogue scales. At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales, administered standard measures of disability (Barthel Index), mood and cognition, and recorded adverse events. Pain relief associated with both THC and CBD was significantly superior to placebo. Impaired bladder control, muscle spasms and spasticity were improved by CME in some patients with these symptoms. Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME. Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to standard treatments. Unwanted effects are predictable and generally well tolerated. Larger scale studies are warranted to confirm these findings.
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Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.
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Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a mouse model of chronic-progressive multiple sclerosis (MS) characterized by Th1-mediated CNS demyelination and spastic hindlimb paralysis. Existing MS therapies reduce relapse rates in 30% of relapsing-remitting MS patients, but are ineffective in chronic-progressive disease, and their effects on disability progression are unclear. Experimental studies demonstrate cannabinoids are useful for symptomatic treatment of spasticity and tremor in chronic-relapsing experimental autoimmune encephalomyelitis. Cannabinoids, however, have reported immunosuppressive properties. We show that the cannabinoid receptor agonist, R+WIN55,212, ameliorates progression of clinical disease symptoms in mice with preexisting TMEV-IDD. Amelioration of clinical disease is associated with downregulation of both virus and myelin epitope-specific Th1 effector functions (delayed-type hypersensitivity and IFN-gamma production) and the inhibition of CNS mRNA expression coding for the proinflammatory cytokines, TNF-alpha, IL1-beta, and IL-6. Clinical trials investigating the therapeutic potential of cannabinoids for the symptomatic treatment of MS are ongoing, and this study demonstrates that they may also have potent immunoregulatory properties.
Article
In recent years there has been a growing interest in the use of cannabis as a medicine, particularly for pain. This paper seeks to update readers on current thought on the basic science, the potential uses and the problems of cannabinoids. A substantive reading list is included for those who wish to study the subject in more depth. From the outset it is important to recognise that only the medicinal use is being considered here (as if we were discussing the medical use of heroin or cocaine). The issues around the recreational use are of no relevance here and will not be discussed further.
Article
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ?9-TCH.
Article
(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. (+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent. British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327
Article
The presence of central cannabinoid receptor (CB1), involving the N-terminal 14 amino acid peptide, was demonstrated in the rat brain by immunohistochemistry. Intensely stained neurons were observed in the principal neurons of the hippocampus, striatum, substantia nigra, cerebellar cortex, including the Purkinje cells. Moderate CB1-IR cell bodies and fibers were present in the olfactory bulb, cingulate, entorhinal and piriform cortical areas, amygdala and nucleus accumbens. The perivascular glial fibers have shown moderate to high density CB1-IR in olfactoric and limbic structures. Low density was detected in the thalamus and hypothalamus and area postrema. The CB1 receptor was widely distributed in the forebrain and sparsely in the hindbrain.These new data support the view that the endogenous cannabinoids play an important role in different neuronal functions as neuromodulators or neurotransmitters.
Article
Age-related changes in pre-/postsynaptic muscarinic (mAChR) and metabotropic-glutamate (mGluR) responsiveness were studied in slices of olfactory cortex from both immature [postnatal day 16-22 (P16-P22)] and adult (>/=P40) rats, using a conventional intracellular recording technique. In adult neurons, bath application of the mAChR agonist oxotremorine-M (OXO-M; 10 microM), or the selective mGluR agonist 1-aminocyclopentane-1S-3R-dicarboxylic acid (1S,3R-ACPD; 10 microM) evoked sustained membrane depolarizations, increases in input resistance, intense repetitive firing, and the appearance of a slow poststimulus afterdepolarizing potential (sADP). Excitatory postsynaptic potentials (EPSPs) evoked by local electrical stimulation of association fiber terminals were also depressed. In contrast, in neurons from immature slices, the 10 microM OXO-M-induced membrane depolarization was followed by the appearance of spontaneous rhythmic epileptiform activity, which was voltage independent and reversible on drug wash out. Epileptiform bursts were abolished or reduced by coapplication of tetrodotoxin (1 microM), atropine (1 microM), pirenzepine (100-200 nM), the N-methyl-D-aspartate (NMDA) receptor antagonist -amino-5-phosphonovaleric acid (-APV; 100 microM), the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 5-20 microM), the anesthetic-sedative barbiturate pentobarbitone (100 microM), or by raising the extracellular Mg2+ concentration, whereas a clear facilitatory effect was exhibited by the selective gamma-aminobutyric acid-A (GABAA) receptor blocker (-)-bicuculline methiodide (10 microM). The epileptogenic effects induced by OXO-M were indistinguishable from those produced by 4-aminopyridine (4-AP; 100-200 microM), although these latter actions were unaffected by atropine. In slices from immature animals, electrical stimulation of layer III association fibers in the presence of 10 microM OXO-M was accompanied by a dramatic prolongation of evoked depolarizing postsynaptic potentials (PSPs), with the appearance of recurrent superimposed spike discharges. This effect was readily reversed on wash out of OXO-M. No comparable age-dependent differences were observed in the nature or time course of 1S,3R-ACPD-evoked pre- (or post)synaptic responses, even in immature cells where muscarinic epileptiform activity had previously been demonstrated. We suggest that the overall susceptibility toward muscarinic-induced epileptiform discharge in immature olfactory cortical neurons may depend on the functional integrity of presynaptic inhibitory mAChRs; additional contributing mechanisms were also considered.
Article
The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.
Article
This review will summarize the pharmacokinetic properties of Δ1-tetrahydrocannabinol mainly in man, since only limited information is available in experimental animals. We will also review the metabolites of Δ1-THC, with particular emphasis on those metabolites which have either psychotomimetic properties similar to Δ1-THC or which are eliminated in man. Metabolic tranformations have mainly been elucidated in various in vitro systems and in experimental animals. Only recently, more extensive information on the metabolism of Δ1-THC in man has become available. The pharmacokinetics of the isomer of Δ1-THC, viz. Δ6-THC, will be dealt with very briefly, because it only represents a minute constituent of marihuana. Two other major cannabinoids, cannabinol (CBN) and cannabidiol (CBD), will also only be briefly reviewed, because available data for these compounds is somewhat limited. We will review only more significant and recent results, since an extensive survey of all published material in the area would be too voluminous. Thus, much of the early literature not directly related to pharmacokinetics and metabolisms is referred to in review articles and in proceedings of symposia. Unfortunately, two almost equally popular numbering systems are in use today. The biogenetically based monoterpene system (Δ1-THC) is used in this survey since it is applicable to both Δ1-THC, CBD, and CBN. The dibenzopyran (Δ9-THC) system which is also shown cannot be used for CBD but has lately been adopted by Chemical Abstracts. The use of these two systems has caused even more confusion when dealing with the metabolites. The chemistry of cannabinoids has been reviewed recently by Mechoulam and Harvey. Of more than 60 cannabinoids - the term cannabinoid is used for the typical C21-compounds and their transformation products - only Δ1-THC has profound psychoactive properties. CBN i.v. shows about 1/10 the potency of Δ1-THC in man, whereas CBD is devoid of psychotomimetic properties. Δ6-THC is about equipotent with Δ1-THC itself but is usually present in very small amounts compared to Δ1-THC, CBD, and CBN. The latter three compounds occur in marihuana-type cannabis preparations in concentrations usually around 1 to 2%.
Article
1 Conditions have been worked out for a reliable estimation of the cataleptic activity of delta'-trans-tetrahydrocannabinol (THC) after oral administration to mice, using the ring test over a period of 6 h. 2 By this method, the activity of cannabis herb and 5 crude fractions were measured against THC; at the same time the THC contents were determined chemically. 3 The B/C ratio (biological activity divided by chemical assay) was calculated for each. With cannabis herb the value was 3.3 and with extracts prepared with ethanol or 70% ethanol the values ranged from 3.2 to 7.1, indicating that in all samples the activity was much higher than would be expected from their THC content. 4. The cannabinoids were completely extracted from a sample of herb using petroleum spirit and the marc examined for a possible synergist. Surprisingly, it contained a powerful inhibitor of the action of THC, which could be restored by intraperitoneal prostaglandin E2 (3 microgram/kg). Some crude fractions had inhibitory activities about 10 times that of aspirin. 5 In contrast, the petroleum spirit extract (referred to in 4) had a surprisingly high B/C ratio of 23, indicating that a powerful synergist of THC activity is present. 6 The net effect of the herb and ethanol extracts is probably due to a balance of synergist and inhibitor.