Article

A Comparison of the Ocular and Central Effects of Δ 9 Tetrahydrocannabinol and Cannabigerol

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Abstract

Both DELTA-9-tetrahydrocannabinol (DELTA-9-THC) and cannabigerol, two naturally occurring marihuana cannabinoids, produced only a modest fall in intraocular pressure after acute topical application to the eyes of cats. After chronic administration unilaterally to the cornea via Alzet (R) osmotic minipumps and connecting extraocular cannulas, however, a considerable fall in ocular tension amounting to 4 to 7 mm Hg occurred. After systemic administration of DELTA-9-THC to rats, polyspike discharges appeared in the cortical electroencephalogram initially during wakefulness and behavioral depression. These polyspikes subsequently became evident within rapid eye movement sleep episodes. Cannabigerol was devoid of this effect. After removal of either sympathetic or parasympathetic input to the eyes of cats, the intraocular pressure lowering effect of DELTA-9-THA was not changed. Neither DELTA-9-THC nor cannabigerol altered the rate of formation of aqueous humor. On the other hand, both cannabinoids produced a two-to three-fold increase in aqueous outflow facility. These results suggest that cannabigerol and related cannabinoids may have therapeutic potential for the treatment of glaucoma.

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... Cannabigerol (CBG) is a non-psychoactive component found in cannabis (Gaoni and Mechoulam, 1964b;Mechoulam et al., 1970), but little work has focused on this extract. CBG has been shown to increase fluid drainage from the eye, reducing intraocular pressure, demonstrating its efficacy in the treatment of glaucoma (Colasanti et al., 1984;Colasanti, 1990). CBG also has potential in the treatment of psoriasis as it inhibits keratinocyte proliferation in a concentration-dependent manner (Wilkinson and Williamson, 2007). ...
... Another non-psychoactive cannabinoid found in marihuana is cannabigerol (CBG, Gaoni and Mechoulam, 1964b;Mechoulam, 1970). CBG has shown potential for the treatment of glaucoma (Colasanti et al., 1984;Colasanti, 1990), psoriasis (Wilkinson and Williamson, 2007), and pain (De Petrocellis et al., 2008). CBG also shows antitumor activity in vitro (Ligresti et al., 2006) and displays antibacterial properties (Eisohly et al., 1982), making it a potential candidate for the treatment of antibiotic resistant bacteria (Appendino et al., 2008). ...
... Activation of the CB1 receptor in the ciliary muscle may also determine vasodilatation with consequent reduction of aqueous humor production [39]. While AEA and CP55,940 act on the ciliary muscle THC isomer called trans-delta-9-tetrahydrocannabinol (delta-9-THC, Figure 2) and cannabigerol determines Schlemm's canal dilation and consequent outflow facilitation [40]. Both AEA and delta-9-THC also enhance COX-2 expression with consequent increased production of prostaglandin E2 (PGE2) and metalloproteinases 1, 3, and 9 [41]. ...
... The enhanced transduction of these molecules determines extracellular matrix remodeling with consequent IOP lowering [41]. While the above-mentioned effects of cannabinoids have been demonstrated by several clinical studies [37][38][39][40][41], the exact role of these molecules in the physiological regulation of IOP is still unclear and needs to be clarified through further clinical trials. ...
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Glaucoma is one of the principal causes of irreversible blindness worldwide. Yet, intraocular pressure (IOP) is the main modifiable risk factor for disease progression. In the never-ending challenge to develop new and effective drugs, several molecules have been tested as anti-glaucoma agents thanks to their pressure-lowering capabilities. Among these molecules, the cannabinoids have been investigated as possible anti-glaucoma drugs since the early 1970s. Cannabinoids are a large class of chemical compounds that exploit their effects by interaction with cannabinoid receptors 1 and 2. These receptors are widely expressed in the human retina where they may influence important functions such as photo-transduction, amacrine cell network maintenance, and IOP regulation. Therefore, in past years several studies have been conducted in order to assess the IOP lowering effects of cannabinoids. PRISMA guidelines have been used to perform a literature search on Pubmed and Scopus aiming to investigate the mechanism of IOP lowering effects and the potential benefits of orally administered, inhaled, topical, and intravenous cannabinoids in the treatment of glaucoma patients.
... The cannabinoids' ocular hypotensive effect following systemic administration is associated with undesirable psychotropic effects [12,14,17,22,25,32]. Numerous attempts to use cannabinoid derivatives topically have resulted in equivocal effects on IOP [4,11,34 ] due to their extremely low aqueous solubility. Because of these shortcomings cannabinoids are not as yet used as therapeutic agents. ...
... The constituent of marijuana most widely studied for its effect on IOP is ∆ 9 -THC, which acts as an ocular hypotensive agent when administered systemically, whether intravenously [12,17,22,25,32 ], through smoking [14] or orally [34]. Reports on topical application of either ∆ 9 -THC or related synthetic analogs were equivocal [4,29,34]. ...
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To study the ocular hypotensive effect of a nonpsychotropic cannabinoid, HU-211 (11 -hydroxy-delta8-tetra-hydrocannabinol, dimethylheptyl), an N-methyl-D-aspartate (NMDA) agonist, in normotensive rabbits. The cannabinoid HU-211, being lipophilic, was incorporated into a stable oil-in-water submicron sterile emulsion, consisting of 0.12% (w/w) HU-211. A single- dose, randomized and double-masked study was designed, using a Digilab 30R pneumotonometer to measure intraocular pressure (IOP) in normotensive rabbits. Application of a single dose of HU-211 ophthalmic preparation resulted in an IOP reduction of 5.3 mmHg (24% of baseline), first evident at 1.5 h post application and persisting for over 6 h. A small but significant lowering of pressure (12.5% of baseline) occurred in the contralateral eyes of HU-211 treated rabbits, lasting for 4 h post treatment. Our work demonstrated that HU-211, incorporated into submicron emulsion, caused a 6-h-long reduction in IOP in the treated eye, with a lesser reduction in the contralateral untreated eye.
... Ohlsson et al. reported the oral bioavailability of D9-THC in a chocolate cookie was 6 AE 3%. Low rates of absorption after oral administration of D9-THC can occur for many different reasons, including considerable first pass metabolism to active/inactive metabolites in the liver, degradation of drug in the digestive system and various absorption[33,39]. Administration of a liposomeentrapped preparation of D9-THC through intratracheal route lowered IOP more efficiently compared to intraperitoneal way indicating rapid absorption of the drug from alveoli to systemic circulation. ...
... Systemic or topical administration of cannabigerol or D9-THC increase dimension of Schlemm's canal and make the aqueous humor excretion easier. Activation of kinase metaloproteinkinase P42/44 using noladin ether (endocannabinoid agonist) increased sphericity of trabecular mesh cells and reduced the production of actin stress fibers and focal adhesion[39]. Nonpsychotropic cannabinoids like HU-211, abnormal cannabidiol (abn-CBD), and cannabigerol-dimethyl heptyl (CBGDMH) could decrease IOP independent to CB receptors[87]. These findings highlight the potential therapeutic effect of cannabinoids in the reduction of IOP. ...
Article
Glaucoma represents several optic neuropathies leading to irreversible blindness through progressive retinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiable factor in the treatment of this disorder. Application of exogenous cannabinoids to lower IOP has attracted attention of scientists as potential agents for the treatment of glaucoma. Accordingly, neuroprotective effect of these agents has been recently described through modulation of endocannabinoid system in the eye. In the present work, pertinent information regarding ocular endocannabinoid system, mechanism of exogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, and neuroprotection property of cannabinoids will be discussed according to current scientific literature. In addition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects of application of cannabinoids in glaucoma will be reviewed.
... Vasodilation in the eye is observed as conjunctival reddening after THC exposure (Dewey 1986). THC and some other cannabinoids decrease intraocular pressure (Colasanti 1990, Pate 2002. CB 1 receptors in the eye are involved in this effect while CB 2 receptor agonists do not reduce intraocular pressure (Laine et al. 2003). ...
... The non-psychotropic cannabinoids cannabigerol (CBG) and cannabichromene (CBC) showed sedative effects. CBG has been observed to decrease intraocular pressure (Colasanti 1990), showed antitumor activity against human cancer cells (Baek et al. 1998) and has antibiotic properties. ...
Article
Our knowledge of the pharmacodynamics of cannabinoids, that is, “the study of the biochemical and physiologic effects of drugs and their mechanisms of action” (The Merck Manual), has considerably increased within the past decade due to the detection of an endogenous cannabinoid system with specific receptors and their endogenous ligands. THC (δ⁹-tetrahydrocannabinol), the main source of the pharmacological effects caused by the use of cannabis including the medicinal benefits of the plant, is an agonist to both the CB1 and the CB2 subtype of these receptors. Its acid metabolite THC-COOH (11-nor-9-carboxy-THC), the non-psychotropic cannabidiol (CBD), analogues of these natural compounds, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues (spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart, etc.). Additionally, there is evidence for non-receptor dependent mechanisms of cannabinoids. Five endogenous cannabinoids, anandamide, 2-arachidonylglycerol, noladine ether, virodhamine, and NADA, have been detected. There is evidence that besides the two cannabinoid receptor subtypes cloned so far, additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of endocannabinoids that include, for example, motor coordination, memory procession, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. At doses exceeding the psychotropic threshold, ingestion of exogenous CB1 receptor agonists or cannabis, respectively, usually causes an enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important potential adverse acute 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 damages on psyche and cognition, immune system, fertility and on pregnancy remain controversial. They are reported to be low in humans and do not preclude a legitimate therapeutic use of cannabis based drugs. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.
... The presence of CB 1 receptors in the tissues of both inflow and outflow pathways in the eye (Straiker et al., 1999;Porcella et al., 2000;Stamer et al., 2001) indicates that activation of CB 1 at multiple sites probably contributes to a net decrease in IOP. Consistent with this, changes in aqueous inflow (Chien et al., 2003) and outflow (Colasanti, 1990;Beilin et al., 2000) have been observed following cannabinoid administration. Although cannabinoid actions on individual tissues of the outflow pathway have not been extensively examined, a study in ciliary muscle, a tissue that is responsible for accommodation of the lens and traction on the TM, has demonstrated that the cannabinoid agonists, CP55940 ...
Article
Trabecular meshwork (TM) is an ocular tissue involved in the regulation of aqueous humour outflow and intraocular pressure (IOP). CB1 receptors (CB1) are present in TM and cannabinoid administration decreases IOP. CB1 signalling was investigated in a cell line derived from human TM (hTM). CB1 signalling was investigated using ratiometric Ca2+ imaging, western blotting and infrared In-Cell Western analysis. WIN55212-2, a synthetic aminoalkylindole cannabinoid receptor agonist (10-100 microM) increased intracellular Ca2+ in hTM cells. WIN55,212-2-mediated Ca2+ increases were blocked by AM251, a CB1 antagonist, but were unaffected by the CB2 antagonist, AM630. The WIN55,212-2-mediated increase in [Ca2+]i was pertussis toxin (PTX)-insensitive, therefore, independent of Gi/o coupling, but was attenuated by a dominant negative Galpha(q/11) subunit, implicating a Gq/11 signalling pathway. The increase in [Ca2+]i was dependent upon PLC activation and mobilization of intracellular Ca2+ stores. A PTX-sensitive increase in extracellular signal-regulated kinase (ERK1/2) phosphorylation was also observed in response to WIN55,212-2, indicative of a Gi/o signalling pathway. CB1-Gq/11 coupling to activate PLC-dependent increases in Ca2+ appeared to be specific to WIN55,212-2 and were not observed with other CB1 agonists, including CP55,940 and methanandamide. CP55940 produced PTX-sensitive increases in [Ca2+]i at concentrations>or=15 microM, and PTX-sensitive increases in ERK1/2 phosphorylation. This study demonstrates that endogenous CB1 couples to both Gq/11 and Gi/o in hTM cells in an agonist-dependent manner. Cannabinoid activation of multiple CB1 signalling pathways in TM tissue could lead to differential changes in aqueous humour outflow and IOP.
... Of recent scientific interest is CBG, which has been found to activate alpha(2)-adrenoceptors, to block 5-HT 1A and CB 1 receptors and bind to CB 2 receptors . It possesses antibacterial (Appendino et al. 2008) and antitumoural (Baek et al. 1998) activity and may serve as a treatment for glaucoma (Colasanti et al. 1984;Colasanti 1990). Data on neuronal activity are currently lacking. ...
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Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (Δ(9)-THCV) and cannabigerol (CBG). We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice. All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile. These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.
... 2,18 Cannabinoids have ophthalmologic effects as well, such as decreasing intraocular pressure (IOP) and causing conjunctival hyperemia without pupillary dilatation. 11,21,24,25 Topical application of AEA also has ophthalmologic effects. 21 Cannabinoid receptors have been identified in the eye. ...
Article
This study aimed to investigate the effects of anandamide or arachidonylethanolamide (AEA), an endogenous cannabinoid receptor agonist, on intraocular inflammation in an endotoxin-induced uveitis (EIU) model in rabbits. Forty New Zealand albino male rabbits were used (5 groups, 8 animals in each). After establishment of sufficient anesthesia, animals were taken under surgery for intravitreal injections. A maximum amount of 50 μL of solution was injected into the central vitreous with a 30-gauge needle. In the control group, sterile saline was injected into the right eyes of the animals. Likewise, AEA (10(-5) M) in the second group, lipopolysaccharide (LPS; 100 ng) in the third group, and AEA (10(-5) M) and LPS (100 ng) in the fourth group were administered. Fifth group received 0.1 mL subtenon injection of AM251 (10(-5) M), a CB(1)-receptor antagonist, 30 min prior to intravitreal LPS (100 ng) and AEA (10(-5) M) injection. At 24 h after the surgical intervention, clinical evaluation was performed and animals were then euthanized with 100 mg/kg intravenous pentobarbital injections. Immediately after the induction of pentobarbital anesthesia, the anterior chamber of the eyes was quickly punctured using a 30-gauge needle to drain aqueous humor (AH) and obtained specimens were used for cell count, protein measurement, and microbiological contamination tests. After AH collection, enucleation was performed and enucleated material was kept for the pathological evaluation. AEA caused an overall worsening of EIU in studied eyes. It significantly increased the detrimental effects of endotoxin, as assessed by clinical investigation of ocular inflammation, AH leukocyte content, and AH protein concentrations. CB(1)-receptor antagonist AM251 administration reversed some components of this AEA-induced exacerbation to significant extents. AEA exacerbated EIU in rabbit eyes. AM251 has been found beneficial to prevent AEA's aggravating impact on EIU. As AEA is a treatment choice for lowering intraocular pressure in ophthalmology practice, concurrent use of CB(1)-receptor antagonists may be a questionable strategy in cases of secondary glaucoma, to avoid aggravation of the present inflammation.
... This pathway has often been associated with reduction of the D 6 double bond, leading to the formation of 8-hydroxy-6,7-dihydro-CBG. Another common route by which 12 is metabolized is epoxidation at the D 6 double bond and subsequent hydrolysis to give 6,7-dihydroxy-6,7-dihydro-CBG (Harvey and Brown 1990). CBG (12) has potential in the treatment of glaucoma (Colasanti 1990), psoriasis (Wilkinson and Williamson 2007), and pain (De Petrocellis et al. 2008). ...
Article
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Cannabis spp. are some of the most controversial medicinal plants in the world. They contain great amounts of biologically active secondary metabolites, including the typical phenolic compounds called cannabinoids. Because of their low toxicity and complex biological activities, cannabinoids can be useful in the therapy of various diseases, but adverse psychological effects (of Δ9-THC in particular) raise concerns. This review summarizes the current knowledge of selected active C. indica compounds and their therapeutic potential. We summarize the main compounds contained in cannabis, the mechanisms of their effects, and their potential therapeutic applications. Further, we mention some of the clinical tests used to evaluate the efficacy of cannabinoids in therapy.
... Relatively few studies have sought to investigate the pharmacological actions of this compound [17,18]. CBG was shown to exert antiproliferative [19] , antibacte- rial [20] and anti-glaucoma [21] actions and to antagonize the antinausea effect of CBD [22]. Potential targets of CBG actions include transient receptor potential (TRP) channels [23], cyclooxygenase (COX-1 and COX-2) enzymes [24], as well as cannabinoid, 5-HT 1A and a 2 adrenergic receptors [25]. ...
... Also its homologue, cannabidivarin (CBDV) revealed anticonvulsant activity in rodents (Hill et al., 2012). Further on, cannabigerol (CBG) and cannabichromene (CBC) are both described as non-psychoactive and anti-inflammatory substances (Colasanti, 1990;Borrelli et al., 2013;Izzo et al., 2012), but additional studies are required to verify definite medical effects. ...
... The presence of CBG in urine may have diagnostic value in forensic cases and can help us to make the GC/MS analysis of an extensive urinary cannabinoid profile and the indirect investigation of the consumed plant source material. CBG and the related cannabinoids may have therapeutic potential for the treatment of glaucoma because of the activity in reducing intra-ocular pressure (Colasanti 1990). Thus, a further benefit of our study could be to find out whether CBG could be a parent compound to create a more active "soft" drug variety for the treatment of glaucoma (Buchwald et al. 2000(Buchwald et al. , 2002, based on the "soft" drug approach of Nicholas Bodor (Bodor and Buchwald 2004). ...
Article
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Kemp et al. (1995) could detect delta9-tetrahydrocannabinol (delta9-THC), cannabinol and cannabidiol, three neutral cannabinoids, and the metabolites of delta9-THC in urine samples of Cannabis consumers. In this study we aimed to identify cannabigerol (CBG), which in its acid form is one of the main intermediate compounds of the biosynthesis of cannabinoids in hemp, in authority urine samples of proved Cannabis consumers. For this reason we applied the modified method of Kemp et al. to test for CBG, since enzymatic hydrolysis seems to be necessary for the formation of free neutral cannabinoids from conjugates. After extraction, derivatisation with N-Methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) and GC/MS analysis, peaks of characteristic fragment ions (m/z 337, 391, 377 and 460) of bis-trimethylsilyl derivative of CBG appeared at 12.48 minutes in both real sample and the urine spiked with CBG. It shows that CBG enters the body during Cannabis smoking and is excreted with urine in a conjugated form, like other neutral cannabinoids. Analysing the chromatograms of hydrolysed and trimethylsilylated extracts we checked for the presence of CBG-metabolites based on the study of Harvey and Brown (1990). We detected a compound in the Cannabis consumers' urine extracts, having fragment ions at m/z 425, 465 and 479 at the retention time of 14.19 min which is presumed to be the 4"-hydroxy-CBG or 5"-hydroxy-CBG. However, it could not be identified completely by GC/MS. This peak was absent in non-hydrolysed urine samples, indicating that it is also excreted in glucuronated form.
... The interest in the pharmacological activity of the other cannabinoids present in lower concentration in the inflorescence has recently grown. One example is cannabigerol (CBG), deriving from cannabigerolic acid (CBGA), the stem cell of all cannabinoids, which proved to relieve intraocular pressure (Colasanti, 1990). ...
Article
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Introduction: Cannabis sativa L. is a powerful medicinal plant and its use has recently increased for the treatment of several pathologies. Nonetheless, side effects, like dizziness and hallucinations, and long-term effects concerning memory and cognition, can occur. Most alarming is the lack of a standardised procedure to extract medicinal cannabis. Indeed, each galenical preparation has an unknown chemical composition in terms of cannabinoids and other active principles that depends on the extraction procedure. Objective: This study aims to highlight the main differences in the chemical composition of Bediol® extracts when the extraction is carried out with either ethyl alcohol or olive oil for various times (0, 60, 120 and 180 min for ethyl alcohol, and 0, 60, 90 and 120 min for olive oil). Methodology: Cannabis medicinal extracts (CMEs) were analysed by liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS) using an untargeted metabolomics approach. The data sets were processed by unsupervised multivariate analysis. Results: Our results suggested that the main difference lies in the ratio of acid to decarboxylated cannabinoids, which dramatically influences the pharmacological activity of CMEs. Minor cannabinoids, alkaloids, and amino acids contributing to this difference are also discussed. The main cannabinoids were quantified in each extract applying a recently validated LC-MS and LC-UV method. Conclusions: Notwithstanding the use of a standardised starting plant material, great changes are caused by different extraction procedures. The metabolomics approach is a useful tool for the evaluation of the chemical composition of cannabis extracts. Copyright © 2017 John Wiley & Sons, Ltd.
... 631 CBG has antidepressant effects, 633 and a potent 5HT1A receptor antagonist that has been a proposed mechanism for potential antidepressant activity. 631 Benefits have been described for several issues including Huntington's disease, 634 as an appetite stimulant, 635 antibacterial effects against MRSA strains, 367 antifungal effects, 636 psoriasis, 381 inflammatory bowel disease, 637 anti-proliferative/ pro-apoptotic against tumor cell lines of multiple organ systems, 178,179,368,638,639 glaucoma, 630,640 and potential benefit for detrusor overactivity and bladder pain. 641,642 CBC is a potent TRPA1 agonist 177 that may reflect a potential role in analgesia, and a weak AEA reuptake inhibitor. ...
Article
Background.—Comprehensive literature reviews of historical perspectives and evidence supporting cannabis/ cannabinoids in the treatment of pain, including migraine and headache, with associated neurobiological mechanisms of pain modulation have been well described. Most of the existing literature reports on the cannabinoids Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), or cannabis in general. There are many cannabis strains that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and strain characteristics. Knowledge of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids is necessary to cross-breed strains to obtain optimal standardized synergistic compositions. This will enable targeting individual symptoms and/or diseases, including migraine, headache, and pain. Objective.—Review the medical literature for the use of cannabis/cannabinoids in the treatment of migraine, headache, facial pain, and other chronic pain syndromes, and for supporting evidence of a potential role in combatting the opioid epidemic. Review the medical literature involving major and minor cannabinoids, primary and secondary terpenes, and flavonoids that underlie the synergistic entourage effects of cannabis. Summarize the individual medicinal benefits of these substances, including analgesic and anti-inflammatory properties. Conclusion.—There is accumulating evidence for various therapeutic benefits of cannabis/cannabinoids, especially in the treatment of pain, which may also apply to the treatment of migraine and headache. There is also supporting evidence that cannabis may assist in opioid detoxification and weaning, thus making it a potential weapon in battling the opioid epidemic. Cannabis science is a rapidly evolving medical sector and industry with increasingly regulated production standards. Further research is anticipated to optimize breeding of strain-specific synergistic ratios of cannabinoids, terpenes, and other phytochemicals for predictable user effects, characteristics, and improved symptom and diseasetargeted therapies.
... 39 CBG may also reduce intraocular pressure, as shown after chronic topic administration to the eyes of cats. 40 Terpenes found in hemp, which confer the typical aroma and flavor, may also exert multiple biologically relevant effects. b-Myrcene and limonene are among the most abundant terpenes in hemp. ...
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The term "hemp" refers to Cannabis sativa cultivars grown for industrial purposes that are characterized by lower levels of tetrahydrocannabinol (THC), the active principle responsible for Cannabis psychotropic effects. Hemp is an extraordinary crop, with enormous social and economic value, since it can be used to produce food, textiles, clothing, biodegradable plastics, paper, paint, biofuel, and animal feed, as well as lighting oil. Various parts of the hemp plant represent a valuable source of food and ingredients for nutritional supplements. While hemp inflorescence is rich in nonpsychoactive, yet biologically active cannabinoids, such as cannabidiol (CBD), which exerts potent anxiolytic, spasmolytic, as well as anticonvulsant effects, hempseed has a pleasant nutty taste and represents a valuable source of essential amino acids and fatty acids, minerals, vitamins, and fibers. In addition, hempseed oil is a source of healthy polyunsaturated fatty acids, and hemp sprouts are rich in antioxidants. This review article aims to provide a comprehensive outlook from a multidisciplinary perspective on the scientific evidence supporting hemp beneficial properties when consumed as food or supplement. Marketing of hemp-derived products is subjected to diversified and complex regulations worldwide for several reasons, including the fact that CBD is also the active principal of pharmaceutical agents and that regulatory bodies in some cases ban Cannabis inflorescence regardless of its THC content. Some key regulatory aspects of such a complex scenario are also analyzed and discussed in this review article.
... Interestingly, cannabinoids are able to reduce intraocular pressure, and therefore exhibit potential in treating tension-associated glaucoma [55]. Δ 9 THC, Δ 8 THC, and CBG reduce ocular pressure without altering aqueous humor production but enhancing aqueous humor outflow [56,57]. It has also been shown that CBN exhibits similar hypotensive properties and that CBG does not exhibit the adverse effects (e.g., ocular toxicity) due to Δ 9 THC or CBN [58]. ...
Article
While natural Δ⁹-tetrahidrocannabinol (Δ⁹THC), cannabidiol (CBD), and their therapeutic potential have been extensively researched, some cannabinoids have not been widely investigated. The present article compiles data from the literature that highlights research on and the therapeutic possibilities of lesser known phytocannabinoids, which we have divided into varinic, acidic, and “minor” (i.e., cannabinoids that are not present in high quantities in common varieties of Cannabis sativa L). A growing interest in these compounds, which are enriched in some cannabis varieties, has already resulted in enough preclinical information to show that they are promising therapeutic agents for a variety of diseases. Each phytocannabinoid has a “preferential” mechanism of action, and often target the cannabinoid receptors CB1 and/or CB2. The recent resolution of the structure of cannabinoid receptors demonstrates the atypical nature of cannabinoid binding, and that different binding modes depend on the agonist or partial agonist/inverse agonist, which allows for differential signaling, even acting on the same cannabinoid receptor. In addition, other players and multiple signaling pathways may be targeted/engaged by phytocannabinoids, thereby expanding the mechanistic possibilities for therapeutic use.
... 33 Also related to this action at TRPM8, CBG reduced the viability of glioblastoma tumor and stem cells comparably to THC, 34 and its combination with CBD was more efficacious than THC in induction of caspasedependent apoptosis. CBG mildly lowers blood pres-sure 35 and intraocular pressure through an increase in aqueous outlflow, 36 suggesting therapeutic use in glaucoma. Its ability to reduce proliferation of keratinocytes 37 also suggests utility to treat psoriasis. ...
Article
Introduction: Cannabigerol (CBG), and its precursor before decarboxylation, cannabigerolic acid is sometimes labeled the "mother of all cannabinoids." The purpose of the present study was to investigate reasons for use and self-reported therapeutic effects in CBG-predominant cannabis users. Usage patterns and adverse effects, including withdrawal symptoms were also explored. Methods: Cannabidiol-predominant cannabis users were recruited online to complete an online survey assessing CBG use patterns, conditions treated with CBG-predominant cannabis (containing >50% CBG), perceived efficacy, associated adverse events, and withdrawal symptoms. One hundred twenty-seven eligible participants (U.S. residents ages 21+ who reported using CBG-predominant cannabis in the past 6 months) completed the survey. Results: Most of the samples (n=65; 51.2%) reported use of CBG-predominant products solely for medical purposes (n=46; 36.2% reported use for medical and recreational purposes; n=8; 6.3% reported recreational use only, and n=8 were missing). The most common conditions the complete sample reported using CBG to treat were anxiety (51.2%), chronic pain (40.9%), depression (33.1%), and insomnia/disturbed sleep (30.7%). Efficacy was highly rated, with the majority reporting their conditions were "very much improved" or "much improved" by CBG. Furthermore, 73.9% claimed superiority of CBG-predominant cannabis over conventional medicines for chronic pain, 80% for depression, 73% for insomnia, and 78.3% for anxiety. Forty-four percent of CBG-predominant cannabis users reported no adverse events, with 16.5% noting dry mouth, 15% sleepiness, 11.8% increased appetite, and 8.7% dry eyes. Around 84.3% reported no withdrawal symptoms, with sleep difficulties representing the most frequently endorsed withdrawal symptom (endorsed by two respondents). Conclusions: This is the first patient survey of CBG-predominant cannabis use to date, and the first to document self-reported efficacy of CBG-predominant products, particularly for anxiety, chronic pain, depression, and insomnia. Most respondents reported greater efficacy of CBG-predominant cannabis over conventional pharmacotherapy, with a benign adverse event profile and negligible withdrawal symptoms. This study establishes that humans are employing CBG and suggests that CBG-predominant cannabis-based medicines should be studied in randomized controlled trials.
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Delta(9)-Tetrahydrocannabinol (THC) exhibits antitumor effects on various cancer cell types, but its use in chemotherapy is limited by its psychotropic activity. We investigated the antitumor activities of other plant cannabinoids, i.e., cannabidiol, cannabigerol, cannabichromene, cannabidiol acid and THC acid, and assessed whether there is any advantage in using Cannabis extracts (enriched in either cannabidiol or THC) over pure cannabinoids. Results obtained in a panel of tumor cell lines clearly indicate that, of the five natural compounds tested, cannabidiol is the most potent inhibitor of cancer cell growth (IC(50) between 6.0 and 10.6 microM), with significantly lower potency in noncancer cells. The cannabidiol-rich extract was equipotent to cannabidiol, whereas cannabigerol and cannabichromene followed in the rank of potency. Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by s.c. injection into athymic mice of human MDA-MB-231 breast carcinoma or rat v-K-ras-transformed thyroid epithelial cells and reduced lung metastases deriving from intrapaw injection of MDA-MB-231 cells. Judging from several experiments on its possible cellular and molecular mechanisms of action, we propose that cannabidiol lacks a unique mode of action in the cell lines investigated. At least for MDA-MB-231 cells, however, our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: direct or indirect activation of cannabinoid CB(2) and vanilloid transient receptor potential vanilloid type-1 receptors and cannabinoid/vanilloid receptor-independent elevation of intracellular Ca(2+) and reactive oxygen species. Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.
Article
This study was undertaken to investigate the effect of some cannabinoid agonists on the bovine ciliary muscle. Both anandamide and CP 55,940 (cis-3-(2-hydroxy-4-(1,1-dimethyl heptyl) phenyl)-trans-4-(3-hydroxypropyl) cyclohexanol) produced a concentration-dependent contractile response in ciliary muscle. These responses were inhibited by SR 141716A (N-[piperidin-1-yl]-5-(4-cholophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) (0.1 and 1 microM) but not by SR 144528 (N-[1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl] 5-(4-chloro-3-methylphenyl)-1-(4 methoxy benzyl)-pyrazole-3-carboxamide) (1 and 10 microM). A preincubation with G(i/o) protein inhibitor pertussis toxin (500 ng/ml) for 20 min inhibited the contractile action of anandamide and CP 55,940. In addition, the phospholipase C inhibitor U73122 (1[6-[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl] amino] hexyl]-1H-pyrrole-2,5-dione) blocked the anandamide- and CP 55,940-induced contractions, whereas the protein kinase C activator, phorbol 12,13 dibutyrate (PDBu) significantly potentiated the contractions evoked by cannabinoid receptor agonists. We evaluated the binding of [(3)H]CP 55,940, which specifically labelled a single class of cannabinoid sites with affinity in low subnanomolar range (K(d)=0.6 nM) and the maximal number of binding sites of 1243 fmol/mg protein. Binding of [(3)H]CP 55,940 was inhibited by ligands having a major selectivity for cannabinoid (CB(1)) receptors. These findings provide strong evidence of the involvement of cannabinoid CB(1) receptors promoting contraction in the bovine ciliary muscle. Furthermore, the action of cannabinoid receptor agonists appears to be mediated via phospholipase C. These data also contribute to elucidate the cannabinoid CB(1) receptor pivotal role in the modulation of intraocular pressure and to show that cannabinoid receptor agonists may be regarded as potential antiglaucoma agents.
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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.
Article
We used reverse transcriptase polymerase chain reaction to detect the expression of the central and peripheral cannabinoid receptors (CB1 and CB2, respectively) mRNA, and Western blotting to show the presence of the CB1 protein in subregions of the human eye. CB2 mRNA transcripts were undetectable, while levels of CB1 mRNA were significantly expressed in the human retina (25.8 +/- 2.46%), ciliary body (210 +/- 11.55%) and iris (62.7 +/- 5.94%) when compared with those of the normalizing reference gene beta2 microglobulin. The CB1 gene encodes a functional protein which is detected in its glycosylated (63 kDa) and unglycosylated (54 kDa) form in the same areas by a specific purified antibody raised against the amino terminus (residues 1-77) of the CB1 receptor. These results further support the proposed role of the CB1 receptor in controlling intraocular pressure, helping to explain the antiglaucoma properties of marijuana.
Article
Arachidonylethanolamide (AEA) was the first anandamide to be identified as an endogenous ligand for the cannabinoid receptor of porcine brain. Since cannabinoids have shown some value in the reduction of ocular hypertension, the title compound was evaluated in normotensive rabbits as a possible topically applied agent for reducing intraocular pressure. AEA was dissolved in an aqueous solution of 2-hydroxy-propyl-beta-cyclodextrin. Single eyedrops (25 microliters) containing 3.13, 6.25, 31.25, 62.5 or 125.0 micrograms of AEA were instilled unilaterally into eyes of normotensive albino and pigmented rabbits. The intraocular pressures (IOPs) of these rabbits were then measured at fixed time intervals. The effect of AEA on IOP in treated and untreated (contralateral) eyes was similar in both types of rabbits. Administration of 31.25 micrograms of AEA caused an immediate IOP reduction in the treated eyes. AEA doses of 62.5 micrograms caused an initial increase and subsequent decrease of IOP in the treated eyes. In the untreated eyes, a marginal ocular hypotensive response of limited duration occurred immediately after administration of AEA at doses 31.25 or 62.5 micrograms. A significant increase (without subsequent decrease below baseline) in IOP occurred in treated eyes after a dose of 125.0 micrograms. The lowest dose (3.13 micrograms) did not have an effect on IOP. This study constitutes the first published demonstration that topical, unilateral administration of AEA significantly decreases IOP in normotensive albino and pigmented rabbits. Although the mechanism of action by which this compound produces its hypotensive effect in the eye is not known, the results suggest that AEA may prove useful in the investigation of glaucoma therapy.
Chapter
Despite its small size, the trabecular meshwork (TM, including the inner wall of Schlemm’s canal) is functionally complex, containing multiple cell “types” segregated by location and playing a central role in intraocular pressure (IOP) homeostasis. TM cells are functionally coupled through multiple mechanisms, including paracrine signaling; through transmission of biomechanical stimuli (stretch and shear stress); and, hydrodynamically, through the funneling effect. This tight cellular coordination appears to be central to TM function and its many roles. For example, TM cells maintain an intricate extracellular matrix which is turned over rapidly and appears to play an important role in determining IOP. They are avidly phagocytic, particularly in the inner TM, so as to protect the narrow flow channels of the outer TM and inner wall of Schlemm’s canal. They are mechanoresponsive to multiple stimuli, which appears to play a key role in IOP homeostasis. They are dynamically contractile, and their acto-myosin tone influences their contractile properties and stiffness. Significantly, these contractile properties are pivotal for overall TM function; indeed, the recently introduced cytoskeletal relaxing agents directly target their contractility for therapeutic benefit. Further, the TM contains a resident population of stem cells that likely play a role in maintaining tissue function over a lifetime. Because TM cells are lost at a higher rate in glaucoma, there exists the possibility of restoring TM function through stem cell-based therapies. In this chapter, we provide a holistic view of TM cellular phenotype and function, identifying opportunities for therapeutic intervention and unsolved questions about this enigmatic tissue.
Article
The interaction between two non-psychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG), which have been reported to act as a 5-hydroxytryptamine 1A (5-HT(1A)) agonist and antagonist, respectively, was evaluated. To evaluate the potential of CBG to reverse the anti-nausea, anti-emetic effects of CBD. In experiment 1, rats were pre-treated with CBG (0.0, 1, 5, and 10 mg/kg, ip), 15 min prior to being treated with CBD (experiment 1a: VEH or 5 mg/kg, ip) or 8-OH-DPAT (experiment 1b: VEH or 0.01 mg/kg, ip). Thirty minutes later, all rats received a pairing of 0.1% saccharin solution and LiCl (20 ml/kg of 0.15 M, ip). Seventy-two hours later, the rats received a drug-free taste reactivity test with saccharin to evaluate the effects of the treatments on the establishment of conditioned gaping reactions (a model of nausea). As well, conditioned saccharin avoidance was measured. In experiment 2, Suncus murinus were injected with CBG (5 mg/kg, ip) or VEH 15 min prior to CBD (5 mg/kg) or VEH and 30 min later were injected with LiCl (60 ml/kg of 0.15 M, i.p.), and the number of vomiting episodes were measured. CBD (5 mg/kg) suppressed conditioned gaping in rats and vomiting in shrews, which were reversed by pre-treatment with all doses of CBG. CBG also prevented the anti-nausea effects of 8-OH-DPAT. Interactions between moderate doses of CBG and CBD may oppose one another at the 5-HT(1A) receptor in the regulation of nausea and vomiting.
Article
The objective of our study was to examine the pharmacology of the intraocular pressure (IOP)-lowering actions of the behaviorally inactive cannabinoids, abnormal cannabidiol (abn-CBD), and a cannabigerol analog, cannabigerol-dimethyl heptyl (CBG-DMH), in comparison to that of the nonselective cannabinoid 1 receptor (CB(1)R) and CB(2)R agonist, WIN55,212-2, in Brown Norway rats. The IOP was measured noninvasively using a hand-held tonometer in nonanesthetized animals. The IOP measurements were taken every 15 min for a period of 2 h after drug administration. All drugs were administered via intraperitoneal (i.p.) injections, and abn-CBD and CBG-DMH were also given topically. Both abn-CBD and CBG-DMH reduced IOP when administrated i.p. at doses of ≥2.5 mg/kg or topically at concentrations of 1%-2%. The IOP-lowering effects of abn-CBD and CBG-DMH were reduced by i.p. administration of O-1918 (2.5 mg/kg), a selective antagonist of the abn-CBD-sensitive cannabinoid-related receptor (CBx), but were unaffected by the CB(1)R antagonist, AM251 (2.5 mg/kg), or the CB(2)R antagonist, AM630 (2.5 mg/kg). In contrast, the IOP-lowering action of WIN55,212-2 was completely blocked by the CB(1)R-selective antagonist, AM251, and was unaffected by the CBx receptor antagonist, O-1918. However, similar to the nonpsychotropic cannabinoids, the ocular hypotensive actions of WIN55,212-2 were also insensitive to block by the CB(2)R antagonist, AM630. Consistent with this, the selective CB(2)R agonist, HU-308 (2 mg/kg) failed to reduce IOP in Brown Norway rats. Concurrent application of a dose of WIN55,212-2 that was subthreshold to reduce IOP (0.25 mg/kg), together with a topical dose of either abn-CBD (0.5%) or CBG-DMH (0.25%), respectively, potentiated the ocular hypotensive effect of either compound applied alone. This study demonstrates that the atypical cannabinoid, abn-CBD, and the cannabigerol analog, CBG-DMH, decrease IOP in the normotensive Brown Norway rat eye independent of CB(1)R or CB(2)R activation, via activation of CBx receptors. The enhanced decrease in IOP seen after coapplication of the CB(1)R agonist, WIN55,212-2, together with either abn-CBD or CBG-DMH, respectively, further suggests that the ocular pharmacodynamics of abn-CBD and CBG-DMH are mediated by receptor targets distinct from CB(1)R. These results indicate that both CBG-DMH and abn-CBD have the potential for further investigation as novel ocular hypotensive cannabinoids devoid of CB(1)R-mediated side-effects.
Article
A series of anandamide-type compounds were synthesized and studied for their effect on the intraocular pressure (IOP) of normotensive pigmented rabbits. Each test compound was dissolved in an aqueous 2-hydroxypropyl-β-cyclodextrin solution and administered (31.25 – 62.5 μg) unilaterally to the eye. The most promising anandamides caused a statistically significant reduction of IOP in treated eyes, usually preceded by an initial transient elevation of IOP, compared to saline controls. In the contralateral untreated eyes, only a marginal or short hypotensive response was observed. Indomethacin pre-treatment (12.5 Mg, S.c.) eliminated the IOP response to administered anandamides and arachidonic acid.
Chapter
Intraocular pressure (IOP) is maintained by the dynamics of ocular aqueous humor that involves its secretion, circulation throughout the anterior chamber, and drainage into the iridocorneal angle. The measurable components of aqueous humor dynamics include aqueous flow, outflow facility, uveoscleral outflow, and episcleral venous pressure. Multiple methods are available to assess these components. Interpretation of data collected by these methods requires an understanding of the inherent assumptions and limitations of each method applicable to the species of animal under investigation. Despite the inevitable problems associated with each method, invaluable information has been collected regarding normal circadian rhythms and interspecies differences in aqueous humor dynamics. Additionally, studies of animal models of spontaneous and induced glaucoma have enhanced our understanding of human glaucoma and facilitated the design of improved pharmacological treatments and surgical procedures. This chapter describes the various methods to assess aqueous humor dynamics and summarizes findings from the animal species that have contributed the most to our understand of aqueous humor dynamics.
Chapter
The Cannabis plant (Cannabis sativa L.) has a long history as a recreational drug, but also as part of traditional medicine in many cultures. Based on the number of publications, it is one of the best-studied plants in the world. The relatively recent discovery of cannabinoid receptors and the human endocannabinoid system has opened up a new and exciting field of research. But despite the pharmaceutical potential of Cannabis, its classification as a narcotic drug has prevented its successful development into modern medicine. Fortunately, the chemistry of Cannabis has been studied in much detail. In particular the psychoactive cannabinoid tetrahydrocannabinol (THC) has received great scientific attention, and much is known about its biological effects and mechanisms of action. Besides an extensive description of the chemistry of the cannabinoids, this chapter also introduces the lesser-known terpenoids, flavonoids, and other constituents of the Cannabis plant. Comprehensive information on a variety of subjects is presented, including chromatographic analytical methods, pharmacokinetics, and structure-activity relationships. The known biological effects of Cannabis constituents are discussed in relationship to the development of modern cannabinoid-based medications. Finally, some practical aspects of working with Cannabis are discussed.
Article
The two main modes of cannabinoid administration, oral ingestion of tetrahydrocannabinol (THC) and smoking of dry cannabis plant material, both have specific advantages and disadvantages. Disadvantages of oral ingestion include slow and erratic absorption, delayed onset of action and low systemic bioavailability, whereas disadvantages of smoking include mucosal damage and short duration of effect. In recent years several new modes of cannabinoid delivery have been tested. Alternative routes of systemic pulmonary administration include inhalation with a vaporizer and the use of cannabinoids in aerosol form. They avoid or reduce the formation of carcinogenic combustion products found in cannabis smoke. Sublingual (buccal) administration of liquid cannabis extracts has been tested in clinical trials in the UK. This mode is easy to administer and might enable easier dose titration than oral capsules. Transdermal delivery achieves a sustained and steadier action than inhalation or oral administration of THC, and is being investigated in preclinical studies by groups in the US and Israel. Use of ethosomal carriers has been shown to enhance skin permeation by the lipophilic cannabinoids. Rectal administration of THC-hemisuccinate suppositories has been tested in some patients; systemic bioavailability is twice as high as with oral administration because of the reduced first-pass effect. Water-soluble agonists to the cannabinoid receptor that allow intravenous administration have been developed. Dexanabinol, a non-psychotropic neuroprotective cannabinoid derivative, was given intravenously in clinical studies to decrease the consequences of severe closed head injuries. Increasing water solubility, for example by the use of cyclodextrin technology, also improved the possibilities of topical cannabinoid administration to the eye for glaucoma treatment. Several of these new approaches to cannabinoid delivery now under preclinical and clinical investigation may find their way into clinical practice within a few years.
Article
Full-text available
The evolution of major cannabinoids and terpenes during the growth of Cannabis sativa plants was studied. In this work, seven different plants were selected: three each from chemotypes I and III and one from chemotype II. Fifty clones of each mother plant were grown indoors under controlled conditions. Every week, three plants from each variety were cut and dried, and the leaves and flowers were analyzed separately. Eight major cannabinoids were analyzed via HPLC-DAD, and 28 terpenes were quantified using GC-FID and verified via GC-MS. The chemotypes of the plants, as defined by the tetrahydrocannabinolic acid/cannabidiolic acid (THCA/CBDA) ratio, were clear from the beginning and stable during growth. The concentrations of the major cannabinoids and terpenes were determined, and different patterns were found among the chemotypes. In particular, the plants from chemotypes II and III needed more time to reach peak production of THCA, CBDA, and monoterpenes. Differences in the cannabigerolic acid development among the different chemotypes and between monoterpene and sesquiterpene evolution patterns were also observed. Plants of different chemotypes were clearly differentiated by their terpene content, and characteristic terpenes of each chemotype were identified.
Article
The two main modes of cannabinoid administration, oral ingestion of tetrahydrocannabinol (THC) and smoking of dry cannabis plant material, both have specific advantages and disadvantages. Disadvantages of oral ingestion include slow and erratic absorption, delayed onset of action and low systemic bioavailability, whereas disadvantages of smoking include mucosal damage and short duration of effect. In recent years several new modes of cannabinoid delivery have been tested. Alternative routes of systemic pulmonary administration include inhalation with a vaporizer and the use of cannabinoids in aerosol form. They avoid or reduce the formation of carcinogenic combustion products found in cannabis smoke. Sublingual (buccal) administration of liquid cannabis extracts has been tested in clinical trials in the UK. This mode is easy to administer and might enable easier dose titration than oral capsules. Transdermal delivery achieves a sustained and steadier action than inhalation or oral administration of THC, and is being investigated in preclinical studies by groups in the US and Israel. Use of ethosomal carriers has been shown to enhance skin permeation by the lipophilic cannabinoids. Rectal administration of THC-hemisuccinate suppositories has been tested in some patients; systemic bioavailability is twice as high as with oral administration because of the reduced first-pass effect. Water-soluble agonists to the cannabinoid receptor that allow intravenous administration have been developed. Dexanabinol, a non-psychotropic neuroprotective cannabinoid derivative, was given intravenously in clinical studies to decrease the consequences of severe closed head injuries. Increasing water solubility, for example by the use of cyclodextrin technology, also improved the possibilities of topical cannabinoid administration to the eye for glaucoma treatment. Several of these new approaches to cannabinoid delivery now under preclinical and clinical investigation may find their way into clinical practice within a few years.
The rate of aqueous humour formation in vervet monkeys was determined with a dilution method during stepwise reductions in mean arterial blood pressure produced by bleeding the animals. The mean rate of aqueous humour formation at a mean arterial blood pressure of 119 ± 7 mm Hg was 2.64 ± 0.22 μl/min (n = 11). Bleeding the animals to a pressure of 70–90 mm Hg had little effect on the rate of aqueous formation. Further reductions in mean arterial blood pressure usually decreased aqueous formation markedly. Interruption of the sympathetic supply to the eye under study had no appreciable effect on the relationship between rate of aqueous humour formation and mean arterial blood pressure.
Article
Se hizo un estudio comparativo de la actividad del 9-tetrahidrocannabinol, cannabinol, y cannabidiol en producir efectos similares a la marihuana cuando son inyectados i.v. a humanos. Estas substancias son los componentes predominantes de la marihuana o del hashish. Se encontro que a las dosis inyectados cannabidiol no tiene ninguna potencia, y que cannabinol es capaz de producir efectos tipicos de la marihuana, aunque a dosis varias veces mas grandes que las del 9-tetrahidrocannabinol.
Article
Recordings of the electroencephalogram (EEG) and the electromyogram (EMG) were collected continuously from rats equipped with permanent cortical and temporalis muscle electrodes. Automatic injections of mescaline were administered through indwelling i.p. cannulas at an initial dose of 30 mg/kg every 6 hrs for the first 2 days. This dose was then increased to 60 mg/kg 6 hr which was given for the duration of the study. The initial injections of the mescaline induced an immediate desynchronization of the EEG and behavioral arousal of the rat, which endured for 2-3 hrs. After this time, slow wave (SW) sleep and rapid eye movement (REM) sleep episodes reappeared, with the return of regular alternations of the sleep-wakefulness cycle. Upon continued administration of the drug, partial tolerance to the arousal effects of mescaline developed, which was reflected by a gradual reduction in the latencies to onset of SW sleep and REM sleep. Rats rendered tolerant to mescaline in this manner were found to be cross tolerant to lysergic acid diethylamide (LSD) and N,N-diethyl-tryptamine (DET). In contrast, cross tolerance did not occur to amphetamine, which exerts similar arousal and EEG desynchronizing effects. These results agree with physiological and behavioral studies of tolerance and cross tolerance among hallucinogens and support the usefulness of the EEG as a quantitative indicator of central nervous system function.
Article
Three nitrogen-containing can-nabinoids caused a dose-dependent fall of intraocular pressure when administered either topically or orally to rabbits. Concentrations of 0.001 to 1% applied topically and 0.3 mg/kg orally were effective. Topical concentrations of 0.5% caused a substantial decrease of intraocular pressure in rhesus monkeys. These compounds may prove therapeutically useful in the treatment of elevated intraocular pressure.
Article
Sympathetic input to the anterior segment of the eyes of cats was unilaterally removed by either superior cervical ganglionectomy or treatment with 6-hydroxydopamine. Parasympathetic input was unilaterally removed by extirpation of the ciliary ganglion. delta 9-tetrahydrocannabinol (delta 9-THC; 20 micrograms/hr) was delivered unilaterally to the denervated eyes and to eyes of surgically intact control cats via osmotic minipumps and connecting extraocular cannulas over a total period of nine days. The results indicated that the degree of reduction of intraocular pressure by delta 9-THC was not affected by removal of input from either branch of the autonomic nervous system. Outflow facility during chronic administration of THC showed a two-to-three fold increase. Ciliary ganglionectomy alone produced a moderate decrease in intraocular pressure that endured for one week. These findings indicate that neither adrenergic nor cholinergic input to the cat eye is apparently required for the mediation of the tension lowering effect of THC. They additionally suggest that cholinergic input may normally play a role in the regulation of steady-state intraocular pressure levels, presumably by modulating aqueous humor formation.
Article
Clinical studies of a variety of cannabis constituents and THC isomers, homologs and metabolites have elucidated some structure activity relationships. The fundamental structure of THC is required for pharmacological activity, but potency may be altered greatly among different double bond isomers, by changing length of side chain or by metabolic hydroxylations. No material has been found in nature, either in cannabis itself or in the metabolites of THC, which differs qualitatively from THC.
Article
Fluid secretion in the isolated rabbit ciliary body was measured with zero pressure gradient across the tissue and fluid flows were measured under an hydrostatic pressure gradient. The active component of marihuana, Δ1-tetrahydrocannabinol (Δ1-THC), when applied in vitro to the tissue reduced secretion and increased passive permeability. The effective concentrations of Δ1-THC were equivalent to those found in human plasma following absorption of the drug. Fluid secretion was reduced by about 70% at 5×10−5 mg/ml, and the short-circuit current was reduced by about 45%. The hydraulic conductivity increased by 70% over control values. Intravenously administered Δ1-THC (giving a plasma concentration of 50×10−6 mg/ml for a plasma volume of 200 ml) produced the following results in the living rabbit: (a) a transient increase in heart rate of 15% after 10–15 min; (b) a reduction in intraocular pressure, with a maximum of 25–30% after 50–60 min; (c) an increase of 60–70% in total facility, and (d) an increase (100%) in aqueous protein. Marihuana reduces intraocular pressure and may act by causing a reduction in ciliary capillary pressure which would cause a decreased formation rate. Vasoconstriction could also cause an increase in aqueous outflow, since aqueous and blood compete for the same episcleral outflow vessels.
Article
delta-9-Tetrahydrocannabinol (delta 9-THC) or cannabichromene, a structurally diverse naturally occurring cannabinoid, was delivered unilaterally to the corneas of cats either acutely by application of single drops or chronically via osmotic minipumps over a period of nine days. While delta 9-THC only reduced intraocular pressure (IOP) minimally after acute administration, this cannabinoid produced substantial reductions in ocular tension during the entire period of chronic administration. Ocular toxicity during chronic treatment, however, was pronounced; conjunctival chemosis, erythema, and hyperemia were sustained, and corneal opacities approximating the site of drug delivery became evident within three to five days. In contrast, cannabichromene did not significantly alter IOP either acutely or during the nine days of chronic administration, and ocular toxicity was not apparent. After systemic administration of delta 9-THC to rats, a dose-related increase in the appearance of 8-13 Hz polyspike discharges became evident in the electrocorticogram during wakefulness and behavioral depression. These polyspikes subsequently reappeared during rapid eye movement (REM) sleep episodes. Cannabichromene was devoid of this effect. These results indicate that, in contrast with acute administration, chronic delivery of delta 9-THC to cat eyes produces substantial reductions in IOP. The tension lowering effect, however, is accompanied by considerable ocular toxicity and neurotoxicity. As cannabichromene lacked these activities, the terpenoid portion of the cannabinoid structure appears to be important for their mediation.
Article
A method is described for near-continuous determination of aqueous humor flow. The anterior chamber is perfused with push-pull coupled syringes at a low rate with a fluid containing labelled albumin. An external circuit is used to determine continuously the anterior chamber concentration of the labelled protein. The dilution data are analysed on-line by a minicomputer which permits rapid calculation of the anterior chamber volume and the rate of flow of aqueous humor. The technique and some experiments of technical interest are reported. Experiments in monkeys with different anaesthetics resulted in flow values of 0.99 +/- 0.02, 1.47 +/- 0.09 and 0.99 +/- 0.04 microliter min-1 for pentobarbital, urethane and ketamine anaesthesia, respectively. By using 125I-labelled albumin in one eye and 131I-labelled albumin in the other, it was possible to determine flow in both eyes. Highly significant correlation coefficients between the two sides were found for the rate of aqueous flow, intraocular pressure and anterior chamber volume. Rapid changes in inflow into the anterior chamber from the posterior chamber were produced by elevating and then lowering the intraocular pressure; the delay inherent in the method was about 6 min. Indomethacin, 3 mg kg-1 body wt., had no effect on aqueous humor flow in eyes cannulated with a minimum of trauma. In eyes with problematic cannulation indomethacin at this dose tended to delay an irritation response. Changes in temperature of the fluid perfused through the anterior chamber had no clear effect on the rate of aqueous flow. Warming the animals about 3-4 degrees C above the normal temperature tended to increase the rate of aqueous flow. Cooling by 3-4 degrees C had no clear effect. Cooling after an initial warming also had no clear effect. The rate of flow of aqueous humor from the anterior chamber to the general circulation was calculated from data for the accumulation of labelled albumin in the general circulation. The difference between the rate of aqueous flow determined from the dilution data and the flow into blood was assumed to represent uveoscleral flow. In 14 animals with an aqueous flow of 1.19 +/- 0.08 microliters min-1 the flow to the general circulation was 0.57 +/- 0.055 and uveoscleral flow 0.61 +/- 0.09 microliters min-1. The procedure and mathematical treatment will be applicable to flow determinations with other large molecules and in other systems.
Article
Cannabinol or cannabigerol was administered to cats topically in doses of 250, 500 and 1000 micrograms as a single drop or chronically via osmotic minipumps (20 micrograms hr-1) over a period of 9 days. While cannabinol had a modest effect on intraocular pressure after a single dose, it caused a more significant reduction in ocular tension during chronic administration. Cannabigerol had similar effects, but the magnitude of response to its chronic administration was greater. Cannabinol but not cannabigerol caused conjunctival erythema and hyperemia. After systemic administration of cannabinol (20, 40 or 80 mg kg-1) to rats, 8-13 Hz polyspike discharges appeared in the electrocorticogram during wakefulness and during rapid eye movement sleep episodes. Cannabigerol (10, 30 and 100 mg kg-1) lacked this effect. These results indicate that chronic administration of these cannabinoids lowers ocular tension considerably. Like marihuana and delta-9-tetrahydrocannabinol, cannabinol produced both ocular toxicity and neurotoxicity. As cannabigerol lacked these toxicities, it appears that the ocular hypotensive effect of this cannabinoid is somewhat dissociable from both the adverse central and ocular effects accompanying marihuana intake.
Comparative electroencephalographic (EEG) and behavioral effects of some cannabinoids
  • B K Colasanti
  • C R Craig
Colasanti, B.K. and Craig, C.R. Comparative electroencephalographic (EEG) and behavioral effects of some cannabinoids. Fed. Proc. 45: 560, 1986.
A9-tetrahydrocannabinol, euphoria and intra-ocular pressure in man
  • W D Parnell
  • J M Gregg
Parnell, W.D. and Gregg, J.M. A9-tetrahydrocannabinol, euphoria and intra-ocular pressure in man. Ann. Ophthalmol. 7: 921-923, 1975.