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Effect of Sublingual Application of Cannabinoids on Intraocular Pressure: A Pilot Study
Abstract
The purpose of this study was to assess the effect on intraocular pressure (IOP) and the safety and tolerability of oromucosal administration of a low dose of delta-9-tetrahydrocannabinol (Delta-9-THC) and cannabidiol (CBD).
A randomized, double-masked, placebo-controlled, 4 way crossover study was conducted at a single center, using cannabis-based medicinal extract of Delta-9-THC and CBD. Six patients with ocular hypertension or early primary open angle glaucoma received a single sublingual dose at 8 AM of 5 mg Delta-9-THC, 20 mg CBD, 40 mg CBD, or placebo. Main outcome measure was IOP. Secondary outcomes included visual acuity, vital signs, and psychotropic effects.
Two hours after sublingual administration of 5 mg Delta-9-THC, the IOP was significantly lower than after placebo (23.5 mm Hg vs. 27.3 mm Hg, P=0.026). The IOP returned to baseline level after the 4-hour IOP measurement. CBD administration did not reduce the IOP at any time. However, the higher dose of CBD (40 mg) produced a transient elevation of IOP at 4 hours after administration, from 23.2 to 25.9 mm Hg (P=0.028). Vital signs and visual acuity were not significantly changed. One patient experienced a transient and mild paniclike reaction after Delta-9-THC administration.
A single 5 mg sublingual dose of Delta-9-THC reduced the IOP temporarily and was well tolerated by most patients. Sublingual administration of 20 mg CBD did not reduce IOP, whereas 40 mg CBD produced a transient increase IOP rise.
... ∆ 9 -THC has been administered in doses ranging from 5 mg to 80 mg in previous studies [8]. As such, a variety of clinical studies have investigated the effects of oral ∆ 9 -THC and synthetic cannabinoids, such as nabilone, BW146Y, or dronabinol, and demonstrated transient ocular hypotensive effects [93][94][95][96][97]. This IOP-lowering effect was at its strongest 2-4 h after administration, reaching approximately 10-30% [8]. ...
... However, these studies only reported transient effects of cannabinoids, raising the issue that frequent daily doses are required for a thera- peutic effect. Based on the IOP-lowering effects of 3-4 h [95], medical marijuana would need to be consumed at least 6-8 times a day and glaucoma patients would be placed at risk for substance dependence [99]. ...
... In contrast to oral ∆ 9 -THC, orally administered CBD failed to lower IOP. In a randomized, double-masked, placebo-controlled four-way crossover study by Tomida et al., patients with ocular hypertension or early primary open-angle glaucoma received a single sublingual dose of 5 mg ∆ 9 -THC, 20 mg CBD, 40 mg CBD, or placebo [95]. In this study, CBD did not exert an IOP-lowering effect, and the higher dose of 40 mg CBD even resulted in a transient increase in IOP 4 h after administration [95]. ...
Glaucoma is a leading cause of irreversible blindness worldwide. To date, intraocular pressure (IOP) is the only modifiable risk factor in glaucoma treatment, but even in treated patients, the disease can progress. Cannabinoids, which have been known to lower IOP since the 1970s, have been shown to have beneficial effects in glaucoma patients beyond their IOP-lowering properties. In addition to the classical cannabinoid receptors CB1 and CB2, knowledge of non-classical cannabinoid receptors and the endocannabinoid system has increased in recent years. In particular, the CB2 receptor has been shown to mediate anti-inflammatory, anti-apoptotic, and neuroprotective properties, which may represent a promising therapeutic target for neuroprotection in glaucoma patients. Due to their vasodilatory effects, cannabinoids improve blood flow to the optic nerve head, which may suggest a vasoprotective potential and counteract the altered blood flow observed in glaucoma patients. The aim of this review was to assess the available evidence on the effects and therapeutic potential of cannabinoids in glaucoma patients. The pharmacological mechanisms underlying the effects of cannabinoids on IOP, neuroprotection, and ocular hemodynamics have been discussed.
... Most RCTs evaluated medical cannabis use, overseen by a physician (n = 27); the remaining six studies conducted experiments in laboratory settings, evaluating the immediate effects of cannabis [20,59,69,80,83,90]. Nineteen RCTs used a parallel-group design [61-64, 66, 68, 70, 71, 73-76, 78, 79, 81, 82, 85, 86] and 17 used a cross-over design [20,59,60,65,67,69,72,77,80,83,84,[87][88][89][90][91][92]. ...
... Additional stand-alone conditions and indications. Six RCTs [20,61,73,81,84,92], five cohort studies [121,136,137,145,159], and one cross-sectional study [141] evaluated the effects of cannabis use on a variety of other patient conditions and indications and reported a mix of findings. ...
... • Diabetes: a high-dose cannabis preparation (10 mg Tetrahydrocannabivarin + 200 mg CBD) was found to significantly increase the risk of depression in an RCT [73] • Intraocular hypertension: 40 mg CBD significantly increased both blood pressure (at 60 and 90 minutes) and intraocular pressure, respectively, while low-dose THC (5 mg) significantly increased heart rate at 90 minutes but had no effect on intraocular pressure in an RCT [84]. ...
Background
Cannabis legalization has enabled increased consumption in older adults. Age-related mental, physical, and physiological changes may lead to differences in effects of cannabis in older adults compared to younger individuals.
Objective
To perform a scoping review to map the evidence regarding the health effects of cannabis use for medical and non-medical purposes in older adults.
Methods
Electronic databases (MEDLINE, Embase, PsycINFO, Cochrane Library) were searched for systematic reviews (SRs), randomized controlled trials (RCTs) and non-randomized/observational studies (NRSs) assessing the health effects and associations of cannabis use (medical or non-medical) in adults ≥ 50 years of age. Included studies met age-related inclusion criteria or involved a priori identified health conditions common among older adults. Records were screened using a liberal accelerated approach and data charting was performed independently by two reviewers. Descriptive summaries, structured tables, effect direction plots and bubble plots were used to synthesize study findings.
Findings
From 31,393 citations, 133 publications describing 134 unique studies (26 SRs, 36 RCTs, 72 NRSs) were included. Medical cannabis had inconsistent therapeutic effects in specific patient conditions (e.g., end-stage cancer, dementia), with a number of studies suggesting possible benefits while others found no benefit. For medical cannabis, harmful associations outnumbered beneficial, and RCTs reported more negative effects than NRSs. Cannabis use was associated with greater frequencies of depression, anxiety, cognitive impairment, substance use and problematic substance use, accidents/injuries, and acute healthcare use. Studies often were small, did not consistently assess harms, and did not adjust for confounding.
Discussion
The effects of medical cannabis are inconsistent within specific patient conditions. For older adults, generally, the available evidence suggests cannabis use may be associated with greater frequencies of mental health issues, substance use, and acute healthcare use, and the benefit-to-risk ratio is unclear. Studies with a balanced assessment of benefits and harms may guide appropriate public health messaging to balance the marketing pressures of cannabis to older adults.
... This is in contrast to previously published data in the literature, where a decrease in IOP was reported after administration of THC. 37,[42][43][44] Similarly, no cannabinoid-induced tachycardia was detected as observed in other studies. 45,46 The reason for these differences is not entirely clear but could be related to the higher drug concentrations 37 or the different application methods 43,44 used in previous trials. ...
... 37,[42][43][44] Similarly, no cannabinoid-induced tachycardia was detected as observed in other studies. 45,46 The reason for these differences is not entirely clear but could be related to the higher drug concentrations 37 or the different application methods 43,44 used in previous trials. In this context, it also needs to be considered that most previous studies included glaucoma or ocular hypertensive patients with elevated IOP. ...
... Thus, one could speculate that a potential IOPlowering effect of dronabinol is more pronounced in this population than in healthy subjects as included in the present study. 42,43 Our study has several strengths. In particular, the current study takes advantage of a recently introduced custom-built Doppler OCT system, which allows for the assessment of TRBF with high precision and excellent reproducibility. ...
Purpose: The present study was performed to investigate the effect of oral dronabinol, a synthetic tetrahydrocannabinol derivate, on retinal hemodynamics in healthy subjects in a randomized, double-masked, placebo-controlled, 2-way crossover design. Methods: Twenty-four subjects received 5 mg dronabinol on 1 study day and placebo on the other study day. Total retinal blood flow (TRBF) was measured using a custom-built Doppler Optical Coherence Tomography system. Oxygen saturation of major retinal vessels was measured with a commercially available Dynamic Vessel Analyzer. Based on these parameters, retinal oxygen extraction was calculated. Measurements were performed before and after drug administration on both study days. Results: Placebo had no effect on TRBF, retinal arterial or venous oxygen content, and retinal oxygen extraction (P > 0.1 each). In contrast, dronabinol induced a significant increase in TRBF from 38.9 ± 6.1 to 40.7 ± 6.7 μL/min (P < 0.001), which was accompanied by a significant increase in retinal venous oxygen content (from 0.129 ± 0.008 to 0.132 ± 0.009 mL O2/mL, P = 0.02). As no change in retinal arterial oxygen content occurred (P = 0.12), retinal oxygen extraction remained stable (2.2 ± 0.4 μL vs. 2.2 ± 0.4 μL O2/min, P = 0.29). Conclusions: These results indicate that orally administered dronabinol increases TRBF in healthy subjects without altering retinal oxygen extraction. The drug may therefore be a candidate for improving perfusion in patients with ocular vascular disease.
... In an uncontrolled, unblinded study conducted by Flach et al. [36] among 9 patients with open-angle glaucoma not responding to conventional treatment, 4 patients achieved the set target IOP over a treatment period of 1-9 months, the reduction in IOP being in the range of 1-5 mm Hg. Tomida et al. [35] conducted a placebo-controlled, 4-way crossover study to assess the effects of sublingual THC and CBD among 6 patients with ocular hypertension or early primary openangle glaucoma. While the IOP reduction with CBD was not significantly different from that obtained with placebo, THC produced significant reductions (mean IOP reduction compared with baseline values, 6.55 vs. 5.17 mm Hg, respectively). ...
... Tomida et al. [35] in their study of THC and two doses of CBD sublingually in 6 patients reported oral pain/ discomfort, dizziness, hypotension, nausea, panic, and photopsia with the former (3 patients); diastolic pressure increased, dizziness, disturbed attention with 20 mg CBD (2 patients); oral pain/discomfort, pharyngitis, bad taste, feeling hot, throat irritation with 40 mg CBD (5 patients); oral pain/discomfort, diastolic pressure increased, headache, hypoesthesia with placebo (2 patients). Majority of the events were mild, and there were no serious or severe AEs. ...
Background Glaucoma is an ocular disease with significant health burden. Despite the availability of many antiglaucoma drugs, a significant proportion of patients may experience worsening of the disease. Hence, there is a need for newer antiglaucoma drugs. Summary Natural and synthetic derivatives of cannabis plants have been studied in the treatment of glaucoma since the 1970s. This review describes the potential mechanisms of the cannabinoids in the treatment of glaucoma, summarizes the findings of clinical studies describing the efficacy of these compounds, and describes the adverse effects observed with the various cannabinoid formulations evaluated in clinical studies of glaucoma in health volunteers and patients. The implications of these findings in terms of the potential clinical status of cannabinoids in the treatment of glaucoma and the challenges involved have also been described. Key messages Cannabinoids lower intraocular pressure. However, the effect is short-lived. There is also a lack of well-formulated ocular delivery system. The available evidence is inadequate to recommend the use of cannabinoids for the routine treatment of glaucoma.
... Of note, a small pilot study comprising only 6 participants, with an unclear risk of bias, found no differences between cannabinoids (e.g., THC, CBD) on measures of intraocular pressure in patients with glaucoma (Tomida et al., 2006). (3), nabilone (1), THC/CBD (4, 2 of which also including dronabinol), ECP002A (1) and smoked THC (1). ...
... Moderate (Sekar and Pack, 2019) ( No significant differences were found between cannabinoids (e.g., THC, CBD) on measures of intraocular pressure in patients with glaucoma. (Tomida et al., 2006) ...
Los cannabinoides se dirigen principalmente al sistema endocannabinoide (ECS), que surge como un objetivo terapéutico potencialmente interesante debido a su importante papel en la modulación de procesos biológicos clave en todo el organismo. Como tal, los cannabinoides ya se han propuesto como, por ejemplo, antieméticos, agentes antiespásticos, estimulantes del apetito, antiepilépticos, analgésicos, depresores de la presión intraocular o como agentes para controlar los trastornos del movimiento en el síndrome de Tourette. Aquí revisamos las pruebas de investigación disponibles sobre el uso del cannabis y los cannabinoides para un conjunto de aplicaciones terapéuticas sugeridas, y abordamos algunos de los riesgos a corto y largo plazo que se han correlacionado con el uso de estas sustancias. Encontramos escasas pruebas científicas que apoyen el uso de productos basados en el cannabis para la mayoría de las aplicaciones sugeridas, así como ninguna necesidad médica no satisfecha que no esté ya abordada por los medicamentos existentes (algunos basados en cannabinoides) en el mercado. En este escenario, los riesgos potenciales asociados al uso crónico de estas sustancias pueden disuadir su uso médico.
... Of note, a small pilot study comprising only 6 participants, with an unclear risk of bias, found no differences between cannabinoids (e.g., THC, CBD) on measures of intraocular pressure in patients with glaucoma (Tomida et al., 2006). (3), nabilone (1), THC/CBD (4, 2 of which also including dronabinol), ECP002A (1) and smoked THC (1). ...
... Moderate (Sekar and Pack, 2019) ( No significant differences were found between cannabinoids (e.g., THC, CBD) on measures of intraocular pressure in patients with glaucoma. (Tomida et al., 2006) ...
Cannabinoids mainly target the endocannabinoid system, which emerges as a potentially interesting therapeutical target due to its major role in modulating key biological processes throughout the body. As such, cannabinoids have already been proposed as, for example, anti-emetics, antispasticity agents, appetite stimulants, anti-epileptic, analgesic, depressants of intraocular pressure or as agents to control movement disorders in Tourette syndrome. Here, we reviewed the research evidence available regarding the use of cannabis and cannabinoids for a set of suggested therapeutical applications, and addressed some of the short- and long-term risks that have been correlated with the use of these substances. We found scarce scientific evidence supporting the use of cannabis-based products for most of the suggested applications, as well as no unmet medical need that is not already tackled by existing medicines (some cannabinoid-based) in the market. In such a scenario, the potential risks associated with the chronic use of these substances may deter their medical use.
... Only a very small cross-over trial [94] tested the effects of dronabinol and nabiximols on ocular hypertension (Additional file 4: Fig. S13). Dronabinol produced a transient benefit (SMD − 1.28, 95% CI − 2.36 to − 0.20; P = 0.02), while nabiximols (CBD combined with small amounts of dronabinol) resulted in a transient worsening (SMD − 0.82, P = 0.08). ...
... We searched in eight databases using Medical Subject Heading (MeSH) terms on all literature published until May 2021 (updated in October 2021) separately for dronabinol, nabilone, cannabidiol and nabiximols (Fig. 1, Additional file 2: Table S1) [12,59,94,. Studies identified by our search that fulfilled the inclusion criteria given below were reviewed by both authors and disagreements were solved through discussion or by consulting colleagues with long-standing expertise in the field of medical cannabinoids. ...
Background
Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events.
Methods
We systematically reviewed (registered at PROSPERO: CRD42021229932) eight databases for randomized controlled trials (RCTs) of dronabinol, nabilone, cannabidiol and nabiximols for chronic pain, spasticity, nausea /vomiting, appetite, ALS, irritable bowel syndrome, MS, Chorea Huntington, epilepsy, dystonia, Parkinsonism, glaucoma, ADHD, anorexia nervosa, anxiety, dementia, depression, schizophrenia, PTSD, sleeping disorders, SUD and Tourette. Main outcomes and measures included patient-relevant/disease-specific outcomes, retention and adverse events. Data were calculated as standardized mean difference (SMD) and ORs with confidence intervals (CI) via random effects. Evidence quality was assessed by the Cochrane Risk of Bias and GRADE tools.
Results
In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD − 0.5[CI − 0.62, − 0.38] high grade) and Parkinsonism (− 0.41[CI − 0.75, − 0.08] moderate grade). There is moderate evidence for dronabinol for chronic pain (− 0.31[CI − 0.46, − 0.15]), appetite (− 0.51[CI − 0.87, − 0.15]) and Tourette (− 1.01[CI − 1.58, − 0.44]) and moderate evidence for nabiximols on chronic pain (− 0.25[− 0.37, − 0.14]), spasticity (− 0.36[CI − 0.54, − 0.19]), sleep (− 0.24[CI − 0.35, − 0.14]) and SUDs (− 0.48[CI − 0.92, − 0.04]). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid.
Conclusions
Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.
... Furthermore, assuming that CBD is efficacious in inflammatory ocular disorders, its impact on intraocular pressure (IOP) must be determined before considering it as a potential therapeutic option. Indeed, reports on the subject are conflicting, as some indicate that CBD does not affect IOP Green et al., 1982;Liu and Dacus, 1987;Waller et al., 1984), others show that CBD reduces IOP (Colasanti et al., 1984;Green et al., 1978) while two studies reveal an increase in IOP due to topical CBD instillation (Miller et al., 2018;Tomida et al., 2006). This potential side-effect is critical, as elevated IOP is the main risk factor in the pathogenesis of glaucoma (Sit and Liu, 2009), a leading cause of blindness in developed countries (Sun et al., 2022). ...
... There are conflicting reports on CBD's impact on IOP in different species. In a small scale clinical trial, 40 mg sublingual CBD raised the IOP of human patients with ocular hypertension or early primary open angle glaucoma (Tomida et al., 2006) , while in two other studies in rabbits (Green et al., 1978) and cats (Colasanti et al., 1984), topically applied CBD decreased the IOP. While the present study shows promising results regarding the anti-inflammatory effect of CBD, the potential effect of our formulations on IOP must be determined before they can be considered as a prospective therapeutic option. ...
Cannabidiol (CBD) is a phytocannabinoid that has a great clinical therapeutic potential. Few studies have been published on its efficacy in ocular inflammations while its impact on intraocular pressure (IOP), a major risk factor for glaucoma, remains unclear. Moreover, due to its lability and high lipophilicity, its formulation within a prolonged stable topical ophthalmic solution or emulsion able to penetrate the highly selective corneal barrier is challenging. Therefore, various CBD nanoemulsions (NEs) were designed and evaluated for stability in accelerated conditions. Further, the optimal formulation was tested on a murine LPS-induced keratitis inflammation model. Lastly, increasing CBD concentrations were topically applied, for two weeks, on mice eyes, for IOP measurement. CBD NEs exhibited optimal physicochemical characteristics for ocular delivery. A specific antioxidant was required to obtain the stable, final, formulation. In vivo, 0.4 to 1.6% CBD w/v reduced the levels of key inflammatory cytokines, depending on the concentration applied. These concentrations decreased or did not affect the IOP. Our results showed that a well-designed CBD ocular dosage form can be stabilized for an extended shelf life. Furthermore, the significant decrease in inflammatory cytokines levels could be exploited, provided that an adequate therapeutic dosage regimen is identified in humans.
... Although not yet adopted in clinical practice, prior studies have demonstrated the intraocular pressure (IOP)-lowering effects of cannabis (1)(2)(3)(4). Inhaled marijuana has been shown to decrease IOP by 25% in some studies while intravenous THC lowered IOP by 37% (3,4). Topically applied THC in animal models and sublingual THC in humans have likewise demonstrated significant IOP-lowering effects (1,2). ...
... Inhaled marijuana has been shown to decrease IOP by 25% in some studies while intravenous THC lowered IOP by 37% (3,4). Topically applied THC in animal models and sublingual THC in humans have likewise demonstrated significant IOP-lowering effects (1,2). Despite the IOP-lowering effects of cannabis, clinical adoption of THC for the treatment of elevated IOP has been limited. ...
Background
Δ9-tetrahydrocannabinol (THC) has been shown to decreased intraocular pressure (IOP). This project aims to define the relationship between plasma THC levels and IOP in healthy adult subjects.
Methods
Eleven healthy subjects received a single dose of inhaled cannabis that was self-administered in negative pressure rooms. Measurements of IOP and plasma THC levels were taken at baseline and every 30 min for 1 h and afterwards every hour for 4 h. IOP reduction and percent change in IOP over time were calculated. Linear regression models were used to measure the relationship between IOP and plasma THC levels. Two line linear regression models with F-tests were used to detect change points in the regression. Then, Pearson correlations were computed based on the change point.
Results
Twenty-two eyes met inclusion criteria. The average peak percentage decrease in IOP was 16% at 60 min. Percent IOP reduction as well as total IOP reduction demonstrated a negative correlation with THC plasma levels showing r-values of −0.81 and −0.70, respectively. F -tests revealed a change point in the regression for plasma levels >20 ng/ml. For levels >20 ng/ml, the correlation coefficients changed significantly with r -values of 0.21 and 0.29 ( p < 0.01).
Conclusion
Plasma THC levels are significantly correlated with IOP reduction up to plasma levels of 20 ng/ml. Plasma levels >20 ng/ml were not correlated with further decrease in IOP. More research is needed to determine the efficacy of THC in reducing IOP for eyes with ocular hypertension and glaucoma.
... THC is well documented and is consistently shown to decrease IOP [63][64][65][66][67][68][69]. However, the effect of CBD on IOP is much more controversial (Table 2). ...
... However, the effect of CBD on IOP is much more controversial (Table 2). So far, nine independent reports have published regarding the effects of CBD on IOP: Four reports indicate that CBD has no effect on IOP [70][71][72][73], three reports demonstrate that CBD decreases IOP [74][75][76], and two reports show an CBD-induced increase in IOP [63,64]. ...
Cannabidiol (CBD), the major non-intoxicating constituent of Cannabis sativa, has gained recent attention due to its putative therapeutic uses for a wide variety of diseases. CBD was discovered in the 1940s and its structure fully characterized in the 1960s. However, for many years most research efforts related to cannabis derived chemicals have focused on D9-tetrahydrocannabinol (THC). In contrast to THC, the lack of intoxicating psychoactivity associated with CBD highlights the potential of this cannabinoid for clinical drug development. This review details in vitro and in vivo studies of CBD related to the eye, the therapeutic potential of cannabidiol for various ocular conditions, and molecular targets and mechanisms for CBD-induced ocular effects. In addition, challenges of CBD applications for clinical ocular therapeutics and future directions are discussed.
... In 2006, Tomida et al conducted a pilot study administering sublingual CBD or THC and found a short-term reduction in IOP reduction following 5 mg THC, which was well tolerated in patients. 20 No IOP reduction was seen with 20 mg CBD, while short-term increased IOP was demonstrated with 40 mg CBD 20 (Table 5). ...
Cannabis is the most used drug worldwide with an estimated 219 million users. This narrative review aims to explore the adverse effects and therapeutic applications of cannabis and cannabinoids on the eye, given its growing clinical and non-clinical uses. The current literature reports several adverse ocular effects of cannabis and cannabinoids, including eyelid tremor, ptosis, reduced corneal endothelial cell density, dry eyes, red eyes, and neuro-retinal dysfunction. Cannabinoids may transiently impair night vision, depth perception, binocular and monocular contrast sensitivity, and dynamic visual acuity. Cannabinoids are not currently considered a first-line treatment option for any ocular conditions. Δ-9-tetrahydrocannabinol been shown to result in short-term intraocular pressure reduction, but insufficient evidence to support its use in treating glaucoma exists. Potential therapeutic applications of cannabinoids include their use as a second-line agent for treatment-refractory blepharospasm, for dry eye disease given corneal anti-inflammatory properties, and for suppression of pendular nystagmus in individuals with multiple sclerosis, which all necessitate further research for informed clinical practices.
... essas questões de forma abrangente e colaborativa, visando melhorar o acesso e a qualidade dos cuidados de saúde relacionados à Cannabis medicinal. Embora haja uma quantidade crescente de estudos sobre o tema, ainda há uma necessidade de mais pesquisas para elucidar completamente os mecanismos de ação da Cannabis medicinal, bem como seu potencial de interação com outros medicamentos(Tomida et al., 2017). Além disso, estudos de longo prazo são necessários para avaliar os efeitos a longo prazo do uso da Cannabis em diferentes populações e condições médicas.Outro aspecto importante a ser considerado é a necessidade de educação e treinamento adequados para profissionais de saúde que desejam prescrever Cannabis medicinal. ...
Introdução: A crescente atenção pela Cannabis medicinal, reflete interesses em suas propriedades terapêuticas, que são exploradas desde os povos ancestrais. Compostos como o tetra-hidrocanabinol (THC) e o canabidiol (CBD) despertam interesse científico devido às suas potenciais aplicações medicinais. Objetivo: Fornecer uma visão abrangente do potencial terapêutico da Cannabis medicinal e suas aplicações clínicas. Métodos: Trata-se de uma revisão integrativa da literatura científica disponível nas bases de dados PubMed (US National Library of Medicine), SciELO (Scientific Electronic Library Online) e Web of Science. Foram selecionados estudos que se relacionavam com o uso terapêutico da Cannabis em diferentes condições médicas, utilizando os seguintes critérios de inclusão: descritores cadastrados do Decs (((Medical Marijuana) AND (Therapy)) AND (Clinical)) AND (Diseases)), textos completos gratuitos, publicados em revistas revisadas por pares, artigos disponíveis em inglês e português, e publicados nos últimos 5 anos (2019 a 2024). Os estudos que não estavam diretamente relacionados ao tema proposto foram excluídos da análise. Resultados: Esta revisão analisou um total de 81 artigos, dos quais apenas 8 foram considerados pertinentes para o tema em estudo. O estudo evidenciou uma variedade de aplicações clínicas da Cannabis medicinal, incluindo alívio da dor, redução da ansiedade e controle de convulsões em pacientes com epilepsia, entre outros. Esses resultados fornecem informações valiosas para profissionais de saúde e pesquisadores interessados no potencial terapêutico da Cannabis. Conclusão: A Cannabis medicinal apresenta um potencial terapêutico significativo em várias aplicações clínicas, oferecendo uma alternativa promissora para pacientes que buscam tratamentos complementares ou alternativos. No entanto, são necessárias mais pesquisas para elucidar os mecanismos de ação e otimizar sua utilização clínica.
... There is a small body of literature that has assessed the effects of cannabinoids (mainly THC) in the eye, with a limited number of studies showing benefit of CBD in models of diabetic retinopathy and corneal hyperalgesia [129]. There is only one clinical trial in this field that examined the effects of THC (5 mg) or CBD (20 and 40 mg, acute dose, sublingual) in patients with ocular hypertension or early primary open angle glaucoma [130]. Although THC reduced intraocular pressure 2 h after administration, CBD did not reduce intraocular pressure at any time, and in fact the higher dose produced a transient increase in intraocular pressure at 4 h. ...
The use of cannabidiol (CBD) for therapeutic purposes is receiving considerable attention, with speculation that CBD can be useful in a wide range of conditions. Only one product, a purified form of plant-derived CBD in solution (Epidiolex), is approved for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Appraisal of the therapeutic evidence base for CBD is complicated by the fact that CBD products sometimes have additional phytochemicals (like tetrahydrocannabinol (THC)) present, which can make the identification of the active pharmaceutical ingredient (API) in positive studies difficult. The aim of the present review is to critically review clinical studies using purified CBD products only, in order to establish the upcoming indications for which purified CBD might be beneficial. The areas in which there is the most clinical evidence to support the use of CBD are in the treatment of anxiety (positive data in 7 uncontrolled studies and 17 randomised controlled trials (RCTs)), psychosis and schizophrenia (positive data in 1 uncontrolled study and 8 RCTs), PTSD (positive data in 2 uncontrolled studies and 4 RCTs) and substance abuse (positive data in 2 uncontrolled studies and 3 RCTs). Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT. Limited evidence supports the use of CBD for the treatment of Parkinson’s (3 positive uncontrolled studies and 2 positive RCTs), autism (3 positive RCTs), smoking cessation (2 positive RCTs), graft-versus-host disease and intestinal permeability (1 positive RCT each). Current RCT evidence does not support the use of purified oral CBD in pain (at least as an acute analgesic) or for the treatment of COVID symptoms, cancer, Huntington’s or type 2 diabetes. In conclusion, published clinical evidence does support the use of purified CBD in multiple indications beyond epilepsy. However, the evidence base is limited by the number of trials only investigating the acute effects of CBD, testing CBD in healthy volunteers, or in very small patient numbers. Large confirmatory phase 3 trials are required in all indications.
... An additional study determined that CBD did not increase chromosomal damage [75]. Tomida et al. found that CBD did not reduce intraocular pressure when participants received a 20-mg dose at any time, while 40 mg of CBD produced a transient increase in intraocular pressure 4 hours after administration [64]. Last, three studies investigated the safety and tolerability of CBD; all studies found that CBD was generally well tolerated even at a single-arm dose of 6000 mg [92,93,97]. ...
Background: Legislative changes have fueled the global availability of cannabis and cannabis-derived compounds, such as cannabidiol. Little is known about the effectiveness and safety of cannabidiol for treating health conditions other than seizure disorders.
Objective: A systematic review of the literature was performed to investigate other health conditions, characteristics of the studied populations, and the effectiveness of cannabidiol in randomized clinical trials.
Methods: Seven publication databases were searched from February to March 2021. The inclusion criteria for studies were: (1) utilized a randomized clinical trial design; (2) published in a peer-reviewed journal or thesis/dissertation; (3) published in English; (4) investigated either prescription (i.e., Epidiolex) or non-prescription CBD that was derived from the Cannabis sativa plant with < 3% ∆9-tetrahydrocannabinol; and (5) reported at least one outcome. This review excluded seizure-related disorders as several previous reviews have been done on this topic; it also excluded published protocols, other systematic reviews, or meta-analyses of randomized clinical trials that investigated cannabidiol. Independent reviewing, risk of bias assessment, and data abstraction were performed by two authors.
Results: Fifty-eight studies from eight countries were included in this review. Twenty-seven studies (47%) were conducted in healthy populations, 14% were restricted to male individuals (n = 8), and 72% had sample sizes of fewer than 40 participants. Doses of cannabidiol used in these studies ranged from 400 µg to 6000 mg. The effect of cannabidiol on mental health was the most studied topic (53%), which focused mainly on anxiety, psychosis, schizophrenia, and substance use disorders. The remaining studies investigated neurological conditions (19%) and a myriad of other health conditions or outcomes. While cannabidiol appears to be anxiolytic, its effectiveness for other conditions was highly variable.
Conclusions: This review highlights the inconsistencies of cannabidiol as a treatment for non-seizure-related health conditions or outcomes. Studies incorporating larger sample sizes in more diverse populations are encouraged. While cannabidiol was generally safe and well tolerated even in high doses among the included studies, clearer dosing guidelines and increased regulation of cannabidiol products are also needed.
... Despite the capacity of ∆9-THC to reduce IOP levels, the effects of CBD on IOP are contradictory. According to some studies, the cannabinoid CBD caused an increase in IOP after sublingual administration (40 mg of CBD, oromucosal spray) in glaucoma patients [69,70] and topical instillation (5 mM; 0.16% w/v in Tocrisolve®vehicle (1:4 ratio soybean oil/water emulsified with Pluronic F68)) in mice [71]. Miller et al. also showed that, aside from its IOP-increasing effect, CBD also prevented the THC IOP-decreasing effect, raising concerns about its use by patients suffering ocular hypertension with glaucoma risk. ...
The interest in the pharmacological applications of cannabinoids is largely increasing in a wide range of medical areas. Recently, research on its potential role in eye conditions, many of which are chronic and/or disabling and in need of new alternative treatments, has intensified. However, due to cannabinoids’ unfavorable physicochemical properties and adverse systemic effects, along with ocular biological barriers to local drug administration, drug delivery systems are needed. Hence, this review focused on the following: (i) identifying eye disease conditions potentially subject to treatment with cannabinoids and their pharmacological role, with emphasis on glaucoma, uveitis, diabetic retinopathy, keratitis and the prevention of Pseudomonas aeruginosa infections; (ii) reviewing the physicochemical properties of formulations that must be controlled and/or optimized for successful ocular administration; (iii) analyzing works evaluating cannabinoid-based formulations for ocular administration, with emphasis on results and limitations; and (iv) identifying alternative cannabinoid-based formulations that could potentially be useful for ocular administration strategies. Finally, an overview of the current advances and limitations in the field, the technological challenges to overcome and the prospective further developments, is provided.
... There has been increasing interest on ocular CBD for lowering intraocular pressure and its therapeutic potential in treating glaucoma [166][167][168]. Although the ocular route is mainly for local treatment, systemic absorption from the eyes is possible due to the highly vascularized conjunctiva [132]. ...
The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.
... multiple sclerosis) [1], reduced appetite in patients with cancer or AIDS [2], chronic pain, both of oncologic and neuropathic origin [3,4], resistant to the conventional anti-pain drugs (i.e. corticosteroids, opioids) [5], chemotherapy-related nausea and vomiting [6] and many others [7][8][9][10][11][12]. ...
Nowadays, oral oil extracts of Cannabis represent the most relevant galenic plant-derived formulations employed in clinics. Nevertheless, the low and variable Δ9-tetrahydrocannabinol (THC) oral bioavailability due to hepatic first-pass metabolism and low solubility in biological fluids makes Cannabis pharmacological response highly unpredictable. In this scenario, new formulation strategies appear crucial to improve cannabinoids bioavailability and stability, administration comfort and patient compliance. Here, we present a nanoemulsion (NE) for the buccal administration of olive oil extract from a Cannabis sativa L. variety (Bedrocan®). A preliminary study was carried out on olive oil-based NE to identify the optimal formulation conditions to achieve a stable system. The Bedrocan®-loaded NE were then prepared and characterized for size, polydispersity index, stability upon delivery by the common buccal nebulizers.
THC content and release in simulated buccal fluids and permeation studies across porcine buccal mucosa. The Bedrocan® NEs ensured THC stability and solubility in the buccal medium as compared with the Cannabis oil extract. Furthermore, the nanoemulsification process led to a THC diffusion and absorption on buccal mucosa 20-folds and 2-folds higher than olive oil extract, respectively. Overall, the results suggest that Bedrocan® NE represents a novel formulation strategy for the buccal administration of Cannabis extracts that can overcome the limits associated with conventional oily formulations.
... Moreover, FAAH inhibition was found to have neuroprotective effects in rat models of high intraocular pressure (IOP)-induced ischemia [49] and optic nerve axotomy [33] by enhancing eCB levels that acted on both CB1Rs and TRPV1 channels. In addition to the aforementioned neuroprotective effects, ∆-9-THC and the synthetic CB1R agonist WIN55212-2 reduce high IOP in patients with glaucoma [50,51]. These modulatory effects of cannabinoids in IOP, however, are mediated by CB1 receptors localised to nonneural tissues in the anterior part of the eye which regulate aqueous humor production (see [40,52] for reviews). ...
The endocannabinoid (eCB) system is critically involved in the modulation of synaptic transmission in the central nervous system, playing an important role in the control of emotional responses, neurodevelopment and synaptic plasticity among other functions. The eCB system is also present in the retina, with studies indicating changes in function after application of cannabinoid receptor agonists, antagonists and in knockout models. Whether eCBs are tonically released in the retina and their physiological functions is, however, still unknown. We investigated the role of the eCB system in the modulation of response strength of retinal ganglion cells (RGCs) to light stimulation, their receptive field organization, contrast sensitivity and excitability properties by performing whole-cell patch-clamp recordings in mouse RGCs before and after bath application of URB597, an inhibitor of the enzyme that degrades the eCB anandamide. Our results show that URB597 application leads to a reduction in the strength of synaptic inputs onto RGCs but paradoxically increases RGC excitability. In addition, URB597 was shown to modulate receptive field organization and contrast sensitivity of RGCs. We conclude that tonically released eCBs modulate retinal signaling by acting on traditional cannabinoid receptors (CB1R/CB2R) as well as on non-cannabinoid receptor targets. Thus, a thorough understanding of the effects of drugs that alter the endogenous cannabinoid levels and of exogenous cannabinoids is necessary to fully comprehend the impact of their medical as well as recreational use on vision.
... Most patients discontinued the study due to side effects including dizziness, confusion, sleepiness, anxiety, and depression. [44,45] Palmitoyl ethanolamide (PEA) is a congener of the endogenous cannabinoid, anandamide (AEA) that is cosynthesized with AEA in many human cells. It prolongs the action of AEA by competing with fatty acid amide hydrolase involved in the hydrolysis of AEA. ...
The burden of irreversible vision loss from Glaucoma continues to rise. While the disease pathogenesis is not well understood, intraocular pressure (IOP) is the only modifiable risk factor identified to prevent glaucomatous vision loss. Medical management remains the first-line of treatment in most adult glaucomas and the evolution of medical therapy for glaucoma has followed an exponential curve. This review tracks the rapid development of new medications and drug delivery systems in the recent years. Introduction of Rho kinase inhibitors with an entirely new mechanism of action from that of the currently used anti glaucoma medications has been a significant milestone. Latanoprostene Bunod is a novel, single molecule which provides two active metabolites that work through two different pathways for reducing intra ocular pressure. Bimatoprost implants and travoprost punctum plugs attempt to ease chronic medication use in glaucoma patients. Nanotechnology is an evolving route of drug delivery. Role of cannabinoids in medical management of glaucoma remain equivocal. The relatively short term effect on IOP, the risks of developing tolerance and side effects impacting patients' neurocognitive health greatly outweigh the potential benefit. Research on Latrunculin B, Adenosine receptor agonists, Specific gene silencing and Stem cell therapy are poised to make an impact on glaucoma treatment. While there is some evidence to support the role of Brimonidine in neuroprotection, further research is needed to clarify the role of Memantine and Neurotrophins. Evidence for benefit from dietary supplementation with Alpha lipoic acid, Forskolin , and Ginko Biloba is limited.
... Alternatively, a sublingual administration has been tested in a pilot study by Tomida et al. demonstrating that a single 5-mg dose of THC significantly lowers the IOP compared to placebo (23.5 mmHg vs. 27.3 mmHg, p = 0.026) [50]. Recently, Inmed Pharmaceuticals has introduced CBN and Cannabigerolic Acid (CBGA) as innovative IOP-lowering drugs in clinical development. ...
Glaucoma is a blinding eye disease that affects about 70 million patients globally today. The cannabinoid receptors and the endocannabinoid system have found attention for new drug concepts. This review will analyze the potential of cannabinoids, primarily tetrahydrocannabinol, THCVS, and cannabinol, as drug candidates and the role of CB1/CB2 receptors with regard to the pathophysiology of glaucoma. The mode of action of cannabinoids as innovative drug candidates and recent formulations for topical delivery will be discussed. Cannabinoid receptors with associated TRPV channels will be evaluated for their potential as drug targets. Especially the role of the endocannabinoid system (fatty acid amide hydrolase, monoacylglycerol lipase) impacting the prostaglandin network (cyclooxygenase, PGE, PGF) and neuroprotection by inhibition of nitric oxide radical formation is in the focus of this review. Delivery systems, including recent clinical trials, will be analyzed to evaluate the potential for innovative future ophthalmological drugs.
... 6 Another small study suggested that sublingually administered THC lowered IOP for up to 4 hours in a group of six human subjects. 7 Although these and other published studies have confirmed that THC lowers IOP, this has not translated to the adoption or use of THC in clinical practice. There are many reasons for this. ...
... Alguns canabinóides podem melhorar o dano neuronal óptico através da supressão da hiperexcitabilidade do receptor N-metil-D-aspartato, estimulação da microcirculação neural e a supressão de apoptose e das reações prejudiciais dos radicais livres, entre outros mecanismos. A separação das ações terapêuticas dos efeitos colaterais agora parece ser possível por meio de uma gama diversificada de novas estratégias químicas, farmacológicas e de formulação (51) . Segundo Marlatt (11) , o uso cotidiano da maconha não leva à tolerância. ...
A obra intitulada “Abordagens contemporâneas nas ciências da saúde vol. 1”, publicada pela Brazilian Journals Publicações de Periódicos e Editora, apresenta um conjunto de vinte e seis capítulos que visa abordar diversas áreas do conhecimento da área da saúde. Logo, os artigos apresentados neste volume abordam: morbidade materna na gravidez, parto e puerpério em Araguari e Minas Gerais; o consumo alimentar de crianças com transtorno do espectro autista está correlacionado com alterações sensório-oral e o comportamento alimentar; efetividade da emdr no tratamento do transtorno de estresse pós- traumático: uma revisão integrativa; efeito modulador da uva rubi (vitis vinífera) na supressão de tumores epiteliais induzidos por doxorrubicina em drosophila melanogaster; estimulação cerebral profunda no tratamento da doença de parkinson: revisão de literatura, entre outros. Dessa forma, agradecemos aos autores por todo esforço e dedicação que contribuíram para a construção dessa obra, e esperamos que este livro possa colaborar para a discussão e entendimento de temas relevantes para a área da saúde, orientando docentes, estudantes, gestores e pesquisadores à reflexão sobre os assuntos aqui apresentados.
... Female mice show lower ocular pressure under CBD administration, whereas it is not the case for male mice [174]. Furthermore, a low dose of CBD administration may have no significant IOP-lowering effect [27,175]. However, these different mechanisms remain unclear. ...
Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/β-catenin pathway in glaucoma, associated with overactivation of the GSK-3β signaling. WNT/β-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/β-catenin pathway and decrease of the GSK-3β activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/β-catenin pathway. CBD downregulates GSK3-β activity, an inhibitor of WNT/β-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/β-catenin pathway.
... The other main source of limitation stems from methodological limitations in the included trials as identified during quality assessment [30,31], specifically pertaining to selective outcome reporting, and inadequate description of methods of randomization, allocation concealment, and blinding. Additionally, many included RCTs investigated only modestly sized samples [41,42,44,50,57]. Small samples render studies particularly underpowered when estimating serious and less serious adverse outcomes, which by their nature may not occur frequently. ...
Background
Cannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age ≥50 years.
Methods and findings
A systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of ≥50 years for all indications, evaluating the safety/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 ± 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD. THC:CBD combination (RR: 1.40 [95% CI, 1.08 to 1.80]) but not THC alone (RR: 1.18 [95% CI, 0.89 to 1.57]) significantly increased risk of AE-related withdrawals. CBD alone did not increase the incidence of all-cause AEs (IRR: 1.02 [95% CI, 0.90 to 1.16]) or other outcomes as per qualitative synthesis. AE-related withdrawals were significantly associated with THC dose in THC only [QM (df = 1) = 4.696, p = 0.03] and THC:CBD combination treatment ([QM (df = 1) = 4.554, p = 0.033]. THC-containing CBMs significantly increased incidence of dry mouth, dizziness/light-headedness, and somnolence/drowsiness. Study limitations include inability to fully exclude data from those <50 years of age in our primary analyses as well as limitations related to weaknesses in the included trials particularly incomplete reporting of outcomes and heterogeneity in included studies.
Conclusions
This pooled analysis, using data from RCTs with mean participant age ≥50 years, suggests that although THC-containing CBMs are associated with side effects, CBMs in general are safe and acceptable in older adults. However, THC:CBD combinations may be less acceptable in the dose ranges used and their tolerability may be different in adults over 65 or 75 years of age.
... 52,53 Hypotension Hypotension was reported in 9 studies. 31,36,[54][55][56][57][58][59][60] The pooled relative risk for hypotension was 3.14 (95% CI 1.16e8.56) with moderate heterogeneity, I 2 ¼ 27.8%. ...
Aim: The objective of this study was to evaluate the cardiovascular toxicity associated with medical use of cannabinoids. Methods: A two-stage systematic review (SR) approach was undertaken to assess current evidence on cannabinoid-associated cardiovascular events reported among randomized controlled trials (RCT). First, we searched for SRs in multiple sources until June 2019. Second, RCTs identified from SRs were included if they assessed medical cannabis and reported cardiovascular events. The outcomes of interest were all types of cardiovascular events. Data were extracted by two independent reviewers. Study quality was assessed using the Cochrane risk of bias. A statistical test of heterogeneity was performed. The summary risk ratios and 95% Confidence Intervals (CIs) were calculated using a random-effects model. Results:
A total of 47 studies involving 2,800 patients were included. The median duration of cannabinoid use was 15.8 days (range 1 to 322) and 45% of studies excluded patients with underlying cardiovascular diseases. Cannabinoid use was significantly associated with increased risks of orthostatic hypotension (RR 3.16; 95% CI 2.27 – 4.40; I2 = 2.3%), and hypotension (RR 3.55; 95% CI 1.45 – 8.71; I2 = 31.8%) with a trend of increased risk of tachycardia (RR 1.94; 95% CI 0.81 – 4.64; I2 = 48.6%). No study reported serious cardiovascular events. Conclusions: Cannabinoid use was associated with tachycardia, hypotension, and orthostatic hypotension. There is a paucity of data for other cardiovascular events among medical cannabis users. More data especially long-term effects among patients with existing cardiovascular diseases are needed.
Within the last decade the role of the endocannabinoid system (ECS) has been a significant part of ophthalmic research, including both ocular physiology and the development of eye pathologies. It is known that this widespread cell-signaling system is involved in retinal neurobiological processes, including visual signal processing, as well as neurotransmission. Furthermore, various research indicated the involvement of ECS in the molecular basis of various pathologies, mostly glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). Therefore, the researchers believe that this biological system, its receptors, pathways, and ligands might be considered as an auxiliary compound to reduce the number of patients suffering from ophthalmic diseases. Despite presented in the literature effects of the endocannabinoid system in the eye, none of the current ECS reviews presented a comprehensive description of the endocannabinoid system, its compounds, and, subsequently ophthalmic disorders. Thus, the aim of this review was to summarize all the major data, including the most up-to-date research, concerning a correlation between the endocannabinoid system and the major ophthalmic pathologies.
Background
Cannabinoid-based medicines (CBMs) are being used widely in older people. However, information on the incidence of adverse events (AEs) is limited.
Objective
To quantify the incidence rate difference (IRD) of AEs in middle aged and older adults of age ≥50 years receiving CBMs and also examine associations with weekly doses.
Design
Systematic review and meta-analysis.
Data sources
MEDLINE, PubMed, EMBASE, CINAHL, PsychInfo, Cochrane Library and ClinicalTrials.gov (1st Jan 1990–12th June 2023).
Methods
We included randomised clinical trials (RCTs) using CBMs with mean participant age ≥50 years for medicinal purposes for all clinical indications. Paired reviewers independently screened studies, extracted data and appraised risk of bias. We estimated pooled effect-sizes IRD under the random-effects model.
Results
Data from 58 RCTs (37 moderate-high quality studies, pooled n = 6611, mean age range 50–87 years, 50% male, n = 3450 receiving CBMs) showed that compared with controls, the incidence of all-cause and treatment-related AEs attributable to delta-9-tetrahydrocannabinol (THC)-containing CBMs were: THC alone [IRD:18.83(95% Confidence Interval [CI], 1.47–55.79) and 16.35(95% CI, 1.25–48.56)] respectively; THC:cannabidiol (CBD) combination [IRD:19.37(95% CI, 4.24–45.47) and 11.36(95% CI, 2.55–26.48)] respectively. IRDs of serious AEs, withdrawals and deaths were not significantly greater for CBMs containing THC with or without CBD. THC dose-dependently increased the incidence of dry mouth, dizziness/lightheadedness, mobility/balance/coordination difficulties, dissociative/thinking/perception problems and somnolence/drowsiness. The interaction of weekly THC:CBD doses played a role in mostly neurological, psychiatric and cardiac side-effects.
Conclusions
Although CBMs in general are safe and acceptable in middle aged and older adults, one needs to be mindful of certain common dose-dependent side-effects of THC-containing CBMs.
Alternative and complementary medicine consists of a variety of medical
practices, therapies and treatments outside of Western medicine. Such
practices are often derived from traditional, cultural or holistic approaches
to health and healing. Examples include herbal medicine, acupuncture, dry needling,
kinesiological taping, chiropractic care, homeopathy and mind-body therapies. Alternative medicine generally emphasises the combined healing of the mind, body and
spirit to improve overall health, well-being and capacity for work. The therapies are
personalised according to the individual’s lifestyle, diet, emotional state and health
history. Most alternative medicine practices focus on preventing and maintaining
health rather than treating disease, which can improve long-term health outcomes
and reduce dependence on conventional medical interventions. Furthermore, when
alternative medicine is used in combination with conventional medicine, it can increase treatment efficacy and alleviate side effects. Alternative and complementary
therapies have been used for centuries and have a long history in various cultural
traditions. Such practices express respect for various healing modalities and cultural
heritage. Many alternative therapies may be more affordable and accessible than
conventional treatments, particularly in areas with limited access to health services.
Alternative medicine encourages patients to take an active role in their health
and healing processes, which increases a sense of empowerment and self-care in
individuals. Nevertheless, the effectiveness and safety of some alternative therapies
may be less well documented compared to conventional treatments.
Music-assisted physiotherapy is a treatment method applied by using music
in a structured way in physiotherapy processes. The therapy helps patients’
recovery processes in many areas such as improving motor skills, muscle
relaxation, pain management and psychological support. Especially thanks to the
effect of rhythm on the regulation of motor movements, it provides significant
benefits in neurological diseases (such as Parkinson’s disease, rehabilitation after
stroke). Music helps to relax muscles, reduce pain perception and increase patients’
motivation. In addition, music has a psychologically relaxing effect, making physiotherapy sessions more efficient and bearable. As an important complementary
method in the treatment of neurological and orthopedic problems, music therapy
can be applied in two different ways: active and passive. While active music therapy
involves the participation of patients in the music-making process, in passive therapy
the patient relaxes by listening to the music. Neuroplasticity plays a vital role as
music-based rehabilitation promotes recovery by engaging multiple cognitive and
motor systems (Fujioka et al., 2018). Integration of rhythmic auditory cues such as
music into rehabilitation can enhance task training, making it more enjoyable and
effective for self-management (van Wijck et al., 2012). Qualitative studies reveal
that participants in music-based rehabilitation programs report positive emotional
and social benefits and improved their overall quality of life (Pohl et al., 2018).
Research shows that music can contribute to physical, psychological and cognitive
healing.
Objective
To determine the chronic effects of oral cannabidiol (CBD) use on tear production, intraocular pressure (IOP), and concentration of CBD in tears of healthy dogs.
Animals Studied
Eighteen healthy research Beagles.
Procedures
This was a masked, placebo‐controlled, randomized prospective study. Eighteen dogs were randomly assigned to three groups (six dogs per group) based on daily dosage of oral MCT oil (placebo), CBD 5 mg/kg, and CBD 10 mg/kg. Schirmer tear test (STT‐1) and IOP were measured twice daily (7 am and 7 pm) every 4 weeks for 36 weeks. Week 36 tears were collected and analyzed for CBD concentrations (ng/mL) using liquid chromatography/mass spectrometry. A mixed linear model was used as the statistical method and p ‐value <.05 was considered significant.
Results
No significant differences were found between placebo vs. 5 mg/kg vs. 10 mg/kg for STT‐1 or IOP (AM and PM). CBD was detected in 10 out of 11 (91%) viable tear samples receiving 5 mg/kg or 10 mg/kg dosages. One sample in the 5 mg/kg group had inadequate tear volume for analysis. The CBD concentration in tears was at or below the lower limit of quantification in placebo group, 4.12–11.2 ng/mL for the 5 mg/kg group, and 6.22–152 ng/mL for the 10 mg/kg group.
Conclusions
Long‐term administration of oral CBD in healthy research beagles demonstrates a favorable safety profile regarding ocular tolerability. Oral CBD administration does not appear to affect tear production or IOP over a 36‐week period. This is the first canine study positively identifying concentrations of CBD in tears following oral administration.
Is Cannabis a boon or bane? Cannabis sativa has long been a versatile crop for fiber extraction (industrial hemp), traditional Chinese medicine (hemp seeds), and recreational drugs (marijuana). Cannabis faced global prohibition in the 20th century because of the psychoactive properties of ∆9-tetrahydrocannabinol; however, recently, the perspective has changed with the recognition of additional therapeutic values, particularly the pharmacological potential of cannabidiol. A comprehensive understanding of underlying mechanism of cannabinoid biosynthesis is necessary to cultivate and promote globally the medicinal application of Cannabis resources. Here, we comprehensively review the historical usage of Cannabis, biosynthesis of trichome-specific cannabinoids, regulatory network of trichome development, and synthetic biology of cannabinoids. This review provides valuable insights into the efficient biosynthesis and green production of cannabinoids, and the development and utilization of novel Cannabis varieties.
Marijuana is one type of narcotics that is prohibited in Indonesia, as defined in Appendix I of Law Number 35 of 2009 concerning Narcotics. Marijuana is classified as a class I narcotic that cannot be used for medical purposes. Although it is illegal in Indonesia, some people use it as a medical substance to treat their illnesses. This research was conducted using the normative juridical method. According to the research findings, some Indonesians currently believe that marijuana is a dangerous plant that can cause temporary pleasure and addiction. On the other hand, there are also those who argue that cannabis can provide a sense of relaxation, pleasure, and happiness, as well as flow inspiration, drive away fatigue, boredom, even depression and stress. Another common misconception is that cannabis is a powerful medicine capable of alleviating various types of pain and slowing the spread of deadly diseases. Given that many other countries have legalized cannabis for medical purposes, the Appendix to Law Number 35 of 2009 must be revised by removing the cannabis plant, all plants of the cannabis genus, and all parts of the plant including seeds, fruit, straw, processed cannabis plants or parts of cannabis plants including cannabis and cannabis resin, and reclassifying them as class II narcotics so that they can be used as medical materials. Ganja merupakan salah satu jenis narkotika yang dilarang di Indonesia, sebagaimana didefinisikan dalam Lampran I Undang-Undang Nomor 35 Tahun 2009 tentang Narkotika. Ganja diklasifikasikan sebagai narkotika golongan I yang tidak dapat digunakan untuk tujuan medis. Meskipun ilegal di Indonesia, beberapa orang menggunakannya sebagai bahan medis untuk mengobati penyakit mereka. Penelitian ini dilakukan dengan menggunakan metode yuridis normatif. Menurut temuan penelitian, sebagian masyarakat Indonesia saat ini percaya bahwa ganja adalah tanaman berbahaya yang dapat menyebabkan kenikmatan sementara dan kecanduan. Di sisi lain, ada juga yang berpendapat bahwa ganja dapat memberikan rasa rileks, senang, dan bahagia, serta mengalirkan inspirasi, mengusir penat, bosan, bahkan depresi dan stres. Kesalahpahaman umum lainnya adalah bahwa ganja adalah obat yang ampuh yang mampu meringankan berbagai jenis rasa sakit dan memperlambat penyebaran penyakit mematikan. Mengingat banyak negara lain yang telah melegalkan ganja untuk kepentingan medis, maka Lampiran Undang-Undang Nomor 35 Tahun 2009 harus direvisi dengan menghapus tanaman ganja, semua tanaman genus ganja, dan semua bagian tanaman termasuk biji, buah, jerami, tanaman ganja yang telah diolah atau bagian tanaman ganja termasuk resin ganja dan ganja, serta mengklasifikasikannya kembali sebagai narkotika golongan II agar dapat digunakan sebagai bahan medis.
Glaucoma is characterized by a continuous loss of retinal ganglion cells. The cause of glaucoma is associated with an increase in intraocular pressure (IOP), but the underlying pathophysiology is diverse and, in most cases, unknown. There is an indisputable unmet need to identify new pathways involved in glaucoma pathogenesis. Increasing evidence suggests that bioactive lipids may be critical in the development and progression of glaucoma. Preclinical and clinical bioactive lipid targets exist and are being developed. In this review, we aim to shed light on the potential of bioactive lipids for the prevention, diagnosis, prognosis, and treatment of glaucoma by asking the question "is fat the future for saving sight".
Transtorno do Espectro do Autismo | Trauma na Infância | Adição
Transtorno Do Estresse Pós-Traumático (TEPT) | Depressão | Esquizofrenia |Epilepsia
Dor Crônica | Zumbido | Estado Vegetativo e Outros Distúrbios de Consciência
Demência Do Tipo Alzheimer | Doença De Parkinson
Aspectos Neuropsiquiátricos Da Infecção Pelo HIV
Cannabis Sativa e Seus Derivados Naturais e Sintéticos: uso Terapêutico e Recreativo
Elisabete Castelon
Transtorno do Espectro do Autismo | Trauma na Infância | Adição
Transtorno Do Estresse Pós-Traumático (TEPT) | Depressão | Esquizofrenia |Epilepsia
Dor Crônica | Zumbido | Estado Vegetativo e Outros Distúrbios de Consciência
Demência Do Tipo Alzheimer | Doença De Parkinson
Aspectos Neuropsiquiátricos Da Infecção Pelo HIV
Cannabis Sativa e Seus Derivados Naturais e Sintéticos: uso Terapêutico e Recreativo
Cannabidiol (CBD) is the major non-psychoactive and most widely studied of the cannabinoid constituents and has great therapeutic potential in a variety of diseases. However, contradictory reports in the literature with respect to CBD’s effect on intraocular pressure (IOP) have raised concerns and halted research exploring its use in ocular therapeutics. Therefore, the current investigation aimed to further evaluate CBD’s impact on the IOP in the rabbit model. CBD nanoemulsions, containing Carbopol® 940 NF as a mucoadhesive agent (CBD-NEC), were prepared using hot-homogenization followed by probe sonication. The stability of the formulations post-moist-heat sterilization, in terms of physical and chemical characteristics, was studied for three different storage conditions. The effect of the formulation on the intraocular pressure (IOP) profile in normotensive Dutch Belted male rabbits was then examined. The lead CBD-NEC formulation (1% w/v CBD) exhibited a globule size of 259 ± 2.0 nm, 0.27 ± 0.01 PDI, and 23.2 ± 0.4 cP viscosity, and was physically and chemically stable for one month (last time point tested) at 4 °C, 25 °C, and 40 °C. CBD-NEC significantly lowered the IOP in the treated eyes for up to 360 min, with a peak drop in IOP of 4.5 mmHg observed at the 150 min time point, post-topical application. The IOP of the contralateral eye (untreated) was also observed to be lowered significantly, but the effect lasted up to the 180 min time point only. Overall, topically administered CBD, formulated in a mucoadhesive nanoemulsion formulation, reduced the IOP in the animal model studied. The results support further exploration of CBD as a therapeutic option for various inflammation-based ocular diseases.
Cette revue de la littérature est consacrée aux travaux montrant l’intérêt potentiel des cannabinoïdes et en particulier du CBD dans le traitement de la pression oculaire et du glaucome, même si des études complémentaires sont attendues. Le premier collyre à base de cannabis contre le glaucome a été mis sur le marché en Jamaïque.
Neuropathic pain is experienced due to injury to the nerves, underlying disease conditions or toxicity induced by chemotherapeutics. Multiple factors can contribute to neuropathic pain such as central nervous system (CNS)-related autoimmune and metabolic disorders, nerve injury, multiple sclerosis and diabetes. Hence, development of pharmacological interventions to reduce the drawbacks of existing chemotherapeutics and counter neuropathic pain is an urgent unmet clinical need. Cannabinoid treatment has been reported to be beneficial for several disease conditions including neuropathic pain. Cannabinoids act by inhibiting the release of neurotransmitters from presynaptic nerve endings, modulating the excitation of postsynaptic neurons, activating descending inhibitory pain pathways, reducing neural inflammation and oxidative stress and also correcting autophagy defects. This review provides insights on the various preclinical and clinical therapeutic applications of cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) in various diseases and the ongoing clinical trials for the treatment of chronic and acute pain with cannabinoids. Pharmacological and genetic experimental strategies have well demonstrated the potential neuroprotective effects of cannabinoids and also elaborated their mechanism of action for the therapy of neuropathic pain.
Background:
There is a growing interest in the use of cannabis (and its extracts), as well as CBD oil (hemp extracts containing cannabidiol), for therapeutic purposes. While there is reason to believe that cannabinoids may be efficacious for a number of different diseases and syndromes, there exist limited objective data supporting the use of crude materials (CBD oil, cannabis extracts, and/or cannabis itself).
Summary:
In the present review, we examined data for pure cannabinoid compounds (dronabinol, nabilone, and CBD), as well as partially purified medicinal cannabis extracts (nabiximols), to provide guidance on the potential therapeutic uses of high-THC cannabis and CBD oil. In general, data support a role for cannabis/cannabinoids in pain, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting. Given the biological activities of the cannabinoids, there may be utility in treatment of central nervous system disorders (such as neurodegenerative diseases, PTSD, and addiction) or for the treatment of cancer. However, those data are much less compelling. Key Message: On balance, there are reasons to support the potential use of medical cannabis and cannabis extract (Δ9-THC-dominant or CBD-dominant), but much more careful research is required.
Cannabidiol (CBD) products have gained popularity among horse owners despite limited evidence regarding pharmacokinetics. The purpose of this study was to describe the pharmacokinetic profile of multiple doses of an orally administered cannabidiol product formulated specifically for horses. A randomized 2-way crossover design was used. Seven horses received 0.35 or 2.0 mg/kg CBD per os every 24h for 7 total doses, separated by a 2-week washout. Plasma CBD and delta-9-tetrahydrocannabinol (THC) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) daily through day 10, then on day 14 after beginning CBD administration. On the final day of CDB administration, plasma CBD and THC were quantified at multiple times. After administration of 0.35 mg/kg of CDB, the Cmax of CBD was 6.6 ± 2.1 ng/mL while Tmax was 1.8 ± 1.2 h, whereas the Cmax for THC was 0.7 ± 0.6 ng/mL with a Tmax of 2.5 ± 1 h. After administration of 2.0 mg/kg of CBD, the Cmax of CBD was 51 ± 14 ng/mL with a mean Tmax of 2.4 ± 1.1 h and terminal phase half-life of 10.4 ± 6 h, whereas the Cmax of THC was 7.5 ± 2.2 ng/mL with a Tmax of 2.9 ± 1.1 h. Oral administration of a cannabidiol product at 0.35 mg/kg or 2.0 mg/kg once daily for 7 days was well-tolerated. Based on plasma CBD levels obtained, dose escalation trials in the horse evaluating clinical efficacy at higher mg/kg dose rates are indicated.
Objectives
Glaucoma is characterized by progressive damage of the retinal ganglion cells (RGC), resulting in irreversible vision loss. Cannabinoids (CBs) ameliorate several factors that contribute to the progression of glaucoma, including increased intraocular pressure (IOP), degeneration of RGC and optical nerve (ON) damage. However, a direct correlation of specific CBs with the molecular events pertaining to glaucoma pathology is not well established. Therefore, this study aims to evaluate the role of cannabinol (CBN) on RGC protection, modulation of IOP, and its effects on the level of extracellular matrix (ECM) proteins using both in vitro and in vivo models of glaucoma.
Methods and results
When exposed to elevated hydrostatic pressure, CBN, in a dose-dependent manner, protected differentiated mouse 661W retinal ganglion precursor-like cells from pressure-induced toxicity. In human trabecular meshwork cells (hTM), CBN attenuated changes in the ECM proteins, including fibronectin and α-smooth muscle actin (α-SMA), as well as mitogen-activated protein kinases (phospho-ERK1/2) in the presence or absence of transforming growth factor-beta 2 (TGF-β2) induced stress. Ocular pharmacokinetic parameters were evaluated post-intravitreal (IVT) CBN delivery in vivo. Furthermore, we demonstrated that IVT-administered CBN improved pattern electroretinogram (pERG) amplitudes and reduced IOP in a rat episcleral vein laser photocoagulation model of glaucoma.
Conclusion
CBN promotes neuroprotection, abrogates changes in ECM protein, and normalizes the IOP levels in the eye. Therefore, our observations in the present study indicate a therapeutic potential for CBN in the treatment of glaucoma.
Prcis:
With expanding legality of medical marijuana (MMJ) in the United States, it is important for ophthalmologists to have greater understanding of the implications of MMJ and glaucoma treatment and how it can impact their patients.
Purpose:
Previous work has demonstrated that inhaled tetrahydrocannabinol can lower intraocular pressure. The stance of the American Glaucoma Society (AGS) is that MMJ is not an acceptable treatment for glaucoma. The purpose of this study is to evaluate the glaucoma specialists' perceptions and attitudes toward the use of MMJ for glaucoma.
Methods:
An electronic survey was sent to members of the AGS which addressed attitudes and perceptions on the use of MMJ in the management of glaucoma. Study questions included practitioner demographics, previous experiences with patients discussing the topic, prescribing patterns, and knowledge regarding the use of MMJ for the treatment of glaucoma.
Results:
Thirty-seven percent of respondents reported having patients who cited using MMJ for their glaucoma, and 38% of respondents were asked about MMJ by their patients at least once per week. Fifty-five percent of respondents had patients who asked them for MMJ prescriptions. When asked if they felt if there was a possible role for marijuana in the management of glaucoma patients, 27% of survey takers responded yes. Fourteen percent of survey respondents kept information on MMJ in their office. Finally, 76% of participants responded they would be interested in additional education on the topic.
Conclusions:
Over 25% of the glaucoma specialists responded that MMJ had a role in the treatment of glaucoma, despite the recommendation of the professional society. This group was least likely to have received education on the topic. Given the expanding legality and curiosity of patients with regards to marijuana in the United States, it is important for ophthalmologists to have a greater understanding of the implications of marijuana in glaucoma.
To the Editor We wish to discuss the effects of CBD and THC on visual function, which may influence driving but may not be detected by road-tracking tests as performed in the article by Dr Arkell and colleagues.¹ A double-blind study reported that 15 mg of THC produced transient color discrimination impairment in the blue and red to yellow region of the color circle, while 8 mg of THC and placebo did not impair color discrimination ability.² This transient color perception impairment may impair the development of numerous adaptations that individuals with congenital color defects use, such as memorization of the order of traffic signals. Another double-blind study found that 15 mg of THC impaired visual working memory, which may be associated with decreased task performance monitoring and increased mind wandering.³ Although there are several studies examining the effects of THC on vision, few studies have addressed CBD or compared THC with CBD in their effects on the human visual system. Only 1 double-blind study reported that a 5-mg sublingual dose of THC reduced intraocular pressure, while a 40-mg sublingual dose of CBD increased intraocular pressure.⁴ Future studies are warranted to examine the effects of CBD on the visual system.
In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma.
. 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].
Cannabinoid receptor agonists act presynaptically to inhibit the release of glutamate. Because other drugs with this action are known to reduce excitotoxicity, we tested several cannabimimetics in a model of synaptically mediated neuronal death. Reduction of the extracellular Mg2+ concentration to 0.1 mM evoked a repetitive pattern of intracellular Ca2+ concentration ([Ca2+]i) spiking that, when maintained for 24 hr, resulted in significant neuronal death. The [Ca2+]i spiking and cell death in this model result from excessive activation of N-methyl-D-aspartate receptors, as indicated by the inhibition of both [Ca2+]i spiking and neuronal death by the N-methyl-D-aspartate receptor antagonist CGS19755 (10 microM). The cannabimimetic drug Win55212-2 (100 nM) completely blocked [Ca2+]i spiking and prevented neuronal death induced by low extracellular Mg2+ concentrations. These effects on [Ca2+]i spiking and viability were stereoselective and were prevented by the CB1 receptor antagonist SR141716 (100 nM). The partial agonist CP55940 (100 nM) also afforded significant protection from excitotoxicity. Cannabimimetic drugs did not protect cells from the direct application of glutamate (30 microM). These data suggest that cannabimimetic drugs may slow the progression of neurodegenerative diseases.
To determine the presence and distribution of CB1 cannabinoid receptors within the human eye.
A subtype-specific affinity-purified polyclonal antibody to the cannabinoid CB1 receptor was used to determine CB1 localization. Postmortem human eyes were fixed in methacarn and embedded in paraffin. Sagittal sections were mounted on slides and immunostained using antibodies to the CB1 receptor. Antibody binding was detected either by using peroxidase conjugated secondary antibodies and developing with diaminobenzidine or by using fluorescent secondary antibodies.
Strong CB1 receptor labeling was detected in the ciliary epithelium, the corneal epithelium, and endothelium of the anterior human eye. Strong-to-moderate levels of CB1 staining were found in the trabecular meshwork and Schlemm's canal. Moderate labeling was detected in the ciliary muscle and in the blood vessels of the ciliary body. Moderate-to-light labeling also was detected in the sphincter papillae of the anterior human eye. Staining for CB1 receptors also was detected in human retina. The two synaptic layers of the retina and the inner and outer plexiform layers, were both moderately stained for CB1. In addition, moderate labeling was detected in the inner nuclear layer, and the ganglion cell layer. Strong labeling was detected in the outer segments of photoreceptors. No staining was observed in the corneal stroma or in the choroid.
The wide distribution of cannabinoid CB1 receptors in both the anterior eye and the retina of humans suggests that cannabinoids influence several different physiological functions in the human eye.
Objectives: To determine whether plant-derived cannabis medicinal extracts (CME) can alleviate neurogenic symptoms unresponsive to standard treatment, and to quantify adverse effects.
Design: A consecutive series of double-blind, randomized, placebo-controlled single-patient cross-over trials with two-week treatment periods.
Setting: Patients attended as outpatients, but took the CME at home.
Subjects: Twenty-four patients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1).
Intervention: 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.
Results: 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.
Conclusions: 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.
The potential activity of cannabidiol, a non-psychoactive constituent of marijuana, in preventing damage caused by cerebral ischemia was studied. Cannabidiol (1.25-20 mg/kg) was given 5 min after 10 min bilateral carotid occlusion in freely-moving awake gerbils. Seven days after ischemia, it antagonized the electroencephalographic flattening of total spectral power, with a dose-dependent bell-shaped curve; the neuroprotective effect was greatest with 5 mg/kg. One day after ischemia cannabidiol completely antagonized ischemia-induced hyperlocomotion, at all doses. Rectal temperature did not change during the first hour after occlusion. Histological examination showed complete survival of CA1 neurons in cannabidiol-treated gerbils. These findings suggest a potential therapeutic role of cannabidiol in cerebral ischemia, though the clear mechanism of action remains to be elucidated.
Glaucoma is one of the leading causes of blindness in the world. In spite of the diverse therapeutic possibilities, new and better treatments for glaucoma are highly desirable. Cannabinoids effectively lower the intraocular pressure (IOP) and have neuroprotective actions. Thus, they could potentially be useful in the treatment of glaucoma. The purpose of this article is to provide the reader with an overview of the latest achievements in research into the potential use of cannabinoids for glaucoma.
Seventeen nonsmokers with heterogeneous glaucomas were tested with synthetic oral Δ9-THC in single-dose administrations. The intraocular pressure was decreased 7.8 ± 1.7 mm Hg after 5 hours in the 7 subjects tested with higher doses. These 7 subjects who received the higher doses (>20 mg) manifested severe alterations in sensorium including depersonalization, acute panic reactions, and paranoiac feelings. No significant differences in intraocular and blood pressures occurred after 5 or 10 mg Δ9-THC, though 1 subject who became severely hypotensive after 5 mg Δ9-THC is described.
To the Editor.—
It is accepted widely that the physiologic effects of smoking marihuana are not well known, despite an acknowledged high incidence of usage. Even the President of the United States has called for a major effort to study drug effects in a scientific manner. In an attempt to investigate the effects of marihuana smoking upon the human visual system, complete ocular examinations were performed in a group of youthful subjects, before and one hour after smoking. Selection of subjects, medical and other safeguards utilized, and details of the protocol will be presented in a later publication.The purpose of this letter is to present preliminary data concerning the most impressive change observed so far, namely, a substantial decrease in intraocular pressure observed in a large percentage of subjects. Applanation tonometry was performed by the same experienced examiner, using the same tonometer for each pair of observations. Marihuana was
Primary objectives of this study were to assess the pharmacokinetic characteristics of CBME when administered sublingually in different ratios, to determine if the pharmacokinetic profiles of THC and its metabolite 11-hydroxy-THC are different when administered sublingually in different formulations, and to characterise the pharmacokinetic profile of CBD when administered with THC in equal amounts. Secondary objectives were to determine if there was a correlation between intoxication levels and plasma concentrations of THC and/or its metabolite 11-hydroxy-THC, and to assess safety and tolerability of CBME when administered sublingually.Methodology employed a double-blind, randomised, three-way crossover study of placebo, High THC and CBD:THC administered sublingually as a liquid spray. Twenty-four subjects were planned, dosed, completed the study and were analysed.Test products were Δ-tetrahydrocannabinol (THC, formulated as 25 mg THC per ml) with or without cannabidiol (CBD) (formulated as 25 mg CBD + 25 mg THC per ml) formulated in ethanol (Eth):propylene glycol (PG) with peppermint (ppmt) flavouring or matching placebo, administered with a 100 μl pump. Each subject received one single dose of 10 mg THC and one single dose of 10 mg CBD + 10 mg THC plus a single dose of placebo in a randomised manner on three separate occasions. The washout period was six days between each dose. Placebo was Eth:PG in a 50:50 ratio with ppmt flavouring, administered with a 100 μl actuator pump.Mean plasma concentrations show that following administration of both High THC and CBD:THC formulations CBD and or THC was detectable in plasma in measurable concentrations 15–30 minutes after dosing, although individual subjects showed quite wide variability, 15 to 135 minutes, to appearance measurable concentrations. At all time points up to 180 minutes after dosing mean concentrations of THC were greater following the High THC formulation than CBD:THC. Concentrations of THC were also greater than corresponding concentrations of CBD following the CBD:THC treatment.There were no statistically significant differences in mean Cmax, t1/2, AUC0-t and AUC0-∞of both THC and 11-hydroxy-THC between the High THC and CBD:THC formulations. THC Tmax was statistically significantly later following CBD:THC than High THC (p = 0.014) and this was the only statistically significant difference in pharmacokinetic parameters between the treatments. The AUC values (AUC0-t and AUC0-∞) for THC show an approximate 8 to 10-fold difference between the lowest and highest subject values while the difference for CBD was approximately 3.5 to 4-fold. Differences in Cmax were 20 to 30 fold for THC and approximately 14-fold for CBD. Intra-subject differences in values for THC between treatments were smaller though differences in Cmax of up to 5-fold and 3-fold in AUC (AUC0-t and AUC0-∞) were observed. Other than a single isolated significant difference in Tmax there were no significant differences in pharmacokinetic parameters between the CBD:THC and High THC formulations. The bioavailability of THC appears to be greater than that of CBD.Mean intoxication scores on both CBME treatments were very low throughout the observation period. The majority of subjects scored zero for the majority of assessment points and there were few scores greater than three on the Box Scale 11 (BS-11). Recorded intoxication scores do not seem to show a direct relationship to plasma concentrations of THC and/or 11-hydroxy-THC either within or between subjects. The time of intoxication scores in individual subjects do not seem to relate consistently with the timing of increases in plasma concentrations or maximal concentrations of THC or 11-hydroxy-THC. Neither is there an apparent relationship between subjects reporting intoxication and those with the highest plasma levels of THC or 11-hydroxy-THC.No subjects withdrew from the study as a result of adverse events and both active and the placebo test treatments were well tolerated. The treatment with the least number of treatment related adverse events was placebo. High THC and CBD:THC had a greater number of subjects who experienced intoxication type adverse events and application site type reactions. The most common overall adverse event experienced was throat irritation, followed by dizziness, somnolence, oral paraesthesia and then headache. All the events were mild and only two events needed any treatment. There were no clinically significant changes from baseline for haematology, biochemistry, vital signs or ECGs.There was wide inter- and intra-subject variability in pharmacokinetic parameters with up to 10-fold differences in THC AUC between subjects and even greater differences in Cmax. Results suggest that there are no overall statistically significant differences between the pharmacokinetic parameters of High THC and CBD:THC other than a delay in Tmax. Considering the wide inter- and intra-subject variability in pharmacokinetic parameters including Tmax this is unlikely to be clinically important in a medication that is self titrated by the patient.
The present study attempts to indirectly determine if a neuronal cannabinoid (CB1) receptor mediates the intraocular pressure (IOP) reduction effects of arachidonoyl ethanolamide (AEA), its R-alpha-isopropyl analog, and the non-classical cannabinoid, CP-55,940. A series of these cannabinoids were dissolved in an aqueous 10–20% 2-hydroxypropyl-beta-cyclodextrin (2-HP-β-CD) solution (containing 3% polyvinyl alcohol) and administered (25–62.5 μg) unilaterally to normotensive rabbit eyes. This was repeated on animals pre-treated with a subcutaneous injection (2.5 mg/kg) of the highly specific CB1 receptor antagonist, SR 141716A, dissolved in an aqueous 42% 2-HP-β-CD solution. AEA, its R-alpha-isopropyl analog, and CP-55,940 reduced IOP upon topical application to a greater degree than was detected in the untreated eye. This reduction was eliminated for the latter two compounds by subcutaneous (s.c.) pretreatment of the rabbits with the CB1 receptor antagonist, but the IOP properties of AEA remained unchanged. SR 141716A administered alone (s.c.), elevated the IOP of both eyes. A CB1 receptor seems involved in the IOP reduction induced by either R-alpha-isopropyl anandamide or CP-55,940. However, AEA apparently functions through a different mechanism.
Systemic administration of cannabinoids decreases intraocular pressure (IOP). To determine whether the mechanism of action originates in the central nervous system, we administered various cannabinoids into the cerebral ventricles of conscious New Zealand albino rabbits. When delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol, cannabinol, and cannabidiol were given intravenously, only delta 9-THC produced dose-dependent ocular hypotension and miosis. Bolus administration into the cerebral ventricles or ventriculocisternal perfusion of delta 9-THC did not change IOP or pupil size. In urethane-anesthetized rabbits, IOP and blood pressure were lowered by intravenous administration of delta 9-THC but not by bolus cerebral administration. These observations indicate that the action of cannabinoids on IOP does not originate in the central nervous system. Alteration of blood pressure may be involved in the mechanism of ocular hypotension induced by delta 9-THC.
delta 9-Tetrahydrocannabinol (THC) or vehicle alone was applied topically to one eye of normal paid volunteers. Ocular and systemic toxic effects and intraocular responses were measured in different series. Toxicity was limited to minor conjunctival injection that was of short (less than 60 minutes) duration and occurred with both drug and vehicle alone. Subjective responses indicated a sensation of minor burning and/or tearing. No fall in intraocular pressure was found. A small (1 mm) but significant mydriasis occurred in both the treated eye and untreated eye and was not drug related. Single-drop administration of delta 9-THC did not, therefore, cause any significant ocular irritation or reduce IOP.
Twenty-eight male volunteers were given either 1% delta 9-tetrahydrocannabinol (delta 9-THC) or vehicle alone (light mineral oil). They used the medication four times per day for one week. Five volunteers, four of which used vehicle alone, discontinued the study because of burning sensation and lid swelling. In the 23 volunteers who completed the study, there was no difference in intraocular pressure between eyes treated with 1% delta 9-THC and controls.
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.
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.
HU-211 is a novel synthetic analog of tetrahydrocannabinol that was recently shown in animal models to be nonpsychotropic. In this study we show that HU-211 can potentially be used as a neuroprotective compound in the CNS. Using a calibrated crush injury of adult rat optic nerve, we show that HU-211 can reduce injury-induced metabolic and electrophysiological deficits. Energy metabolism was monitored by measuring the intramitochondrial nicotine-amine adenine dinucleotide redox state hourly for 6 h after injury and treatment. Electrophysiological activity was assessed by compound action potential and visual evoked potential response. Beneficial effects were dose-dependent, being optimal at 7 mg/kg, administered intraperitoneally. The time window during which treatment was effective was found to be from the time of injury for at least 5 h, with treatment most effective at the time of injury. These results strongly suggest that HU-211, given immediately after CNS injury at the optimal dosage, may possess neuroprotective activities.
We used RT-PCR to measure relative differences in cannabinoid receptor (CB) mRNAs in the rat eye, comparing CB1 or CB2 transcripts to that of the normalizing reference gene beta2 microglobulin (beta2m). Significantly higher levels of CB1 mRNA levels were found in the ciliary body (0.84+/-0.05% of beta2m) than in the iris, (0.34+/-0.04% of beta2m), retina (0.07+/-0.005% of beta2m) and choroid (0.06+/-0.005% of beta2m). CB2 mRNA was undetectable. This expression pattern supports a specific role for the CB1 receptor in controlling intraocular pressure, helping to explain the antiglaucoma property of cannabinoids.
Retinal ganglion cell death is the final common pathway of virtually all diseases of the optic nerve, including glaucomatous optic neuropathy. In recent years it has been shown that retinal ganglion cells die after axonal injury via a programmed cell death process called apoptosis. The dynamics of retinal ganglion cell death reflect the timing and degree of the axonal injury, rather than its nature. For example, whether mediated by ischemia (corresponding to abnormalities of peripapillary circulation) or compression (e.g., changes in retrograde transport caused by increased intraocular pressure), the end result is a series of changes at the level of the axon, which subsequently affect the retinal ganglion cell body. Our studies on neuroprotection of retinal ganglion cells have focused on general mechanisms applicable to axonal injuries. By dissecting the pathways by which retinal ganglion cells die in these situations, strategies for protection may become manifest. We and others have found that production of certain reactive oxygen species is a necessary step for neuronal death after neurotrophin deprivation. In response, cells invoke compensatory mechanisms to maintain survival in the face of this attack. We have studied the transcriptional regulation of one candidate compensatory gene and discuss it as a model for gene-based approaches to neuroprotective therapy for glaucomatous optic neuropathy. By approaching the problem of therapy from this point of view, it may become possible to prevent irreversible glaucomatous optic nerve changes by inducing endogenous cell-rescue mechanisms and, thus, with the retinal ganglion cells' own defense mechanisms, to prevent its death.
It is known that marijuana smoking and administration of natural cannabinoids reduce intraocular pressure. However, it has not been established whether the intraocular pressure-lowering effects of cannabinoids are mediated by cannabinoid receptors. Aminoalkylindoles are a new class of cannabimimetics with structures entirely different from those of natural cannabinoids. WIN55212-2, a prototypic aminoalkylindole, has been shown to bind cannabinoid receptors and to exhibit cannabinoid-like activities. The objective of this study was to determine whether aminoalkylindoles lower intraocular pressure and whether the effects of aminoalkylindoles are mediated by ocular cannabinoid receptors. The intraocular pressure of New Zealand White rabbits was measured with the use of applanation pneumatonography. After the measurement of baseline intraocular pressure, drugs were applied topically and the intraocular pressure was monitored. The topical application of WIN55212-2 significantly reduced intraocular pressure in the treated eyes. The intraocular pressure-lowering effects of WIN55212-2 were time and dose dependent, and the maximal reduction was 4.7 +/- 0.5 mm Hg at a dose of 100 microg. In contrast to treated eyes, the intraocular pressure on the contralateral eyes was not significantly affected. The topical application of WIN55212-3, the enantiomer of WIN55212-2, had no effect on intraocular pressure. Furthermore, the intraocular pressure-lowering effects of WIN55212-2 were significantly reduced by topically administered SR141716A, a selective antagonist for the CB1 cannabinoid receptor. The dose-response curve of WIN55212-2 is shifted parallel to the right by SR141716A. These data demonstrate that like natural cannabinoids, WIN55212-2 also reduces intraocular pressure, and the effects of WIN55212-2 are mediated at least in part by the CB1 cannabinoid receptors in the eye.
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.
Cannabinoids protect cortical neurons from ischemic injury by interacting with CB1 receptors. Because a variety of neuroprotective genes are induced in cerebral ischemia, we examined the effect of experimental stroke, produced by 20 minutes of middle cerebral artery occlusion in rats, on CB1 receptor expression. Western blotting and immunohistochemistry showed that CB1 expression on neurons was increased in the arterial boundary zone of the cortical mantle, beginning by 2 hours and persisting for 72 hours or more after ischemia These findings are consistent with a neuroprotective role for endogenous cannabinoid signaling pathways and with a potential therapeutic role in stroke for drugs that activate CB1 receptors.
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Assess therapeutic profile of cannabis and cannabinoids.
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Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.
The search for new ocular hypotensive agents represents a frontier of current eye research because blindness due to optic neuropathy occurs insidiously in 10% of all patients affected by glaucoma. Cannabinoids have been proposed to lower intraocular pressure by either central or peripheral effects but a specific mechanism for this action has never been elucidated. We recently demonstrated the presence of the central cannabinoid receptor (CB(1)) mRNA and protein in the human ciliary body. In the present study we show that the synthetic CB(1) receptor agonist, WIN 55212--2, applied topically at doses of 25 or 50 microg (n = 8), decreases the intraocular pressure of human glaucoma resistant to conventional therapies within the first 30 min (15 +/- 0.5% and 23 +/- 0.9%, respectively). A maximal reduction of 20 +/- 0.7% and 31 +/- 0.6%, respectively, is reached in the first 60 min. These data confirm that CB(1) receptors have direct involvement in the regulation of human intraocular pressure, and suggest that, among various classes of promising antiglaucoma agents, synthetic CB(1) receptor agonists should deserve further research and clinical development.
Mounting in vitro and in vivo data suggest that the endocannabinoids anandamide and 2-arachidonoyl glycerol, as well as some plant and synthetic cannabinoids, have neuroprotective effects following brain injury. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission and reduce the production of tumour necrosis factor-alpha and reactive oxygen intermediates, which are factors in causing neuronal damage. The formation of the endocannabinoids anandamide and 2-arachidonoyl glycerol is strongly enhanced after brain injury, and there is evidence that these compounds reduce the secondary damage incurred. Some plant and synthetic cannabinoids, which do not bind to the cannabinoid receptors, have also been shown to be neuroprotective, possibly through their direct effect on the excitatory glutamate system and/or as antioxidants.
Neuroprotective effects have been described for many cannabinoids in several neurotoxicity models. However, the exact mechanisms have not been clearly understood yet. In the present study, antioxidant neuroprotective effects of cannabinoids and the involvement of the cannabinoid receptor 1 (CB1) were analysed in detail employing cell-free biochemical assays and cultured cells. As it was reported for oestrogens that the phenolic group is a lead structure for antioxidant neuroprotective effects, eight compounds were classified into three groups. Group A: phenolic compounds that do not bind to CB1. Group B: non-phenolic compounds that bind to CB1. Group C: phenolic compounds that bind to CB1. In the biochemical assays employed, a requirement of the phenolic lead structure for antioxidant activity was shown. The effects paralleled the protective potential of group A and C compounds against oxidative neuronal cell death using the mouse hippocampal HT22 cell line and rat primary cerebellar cell cultures. To elucidate the role of CB1 in neuroprotection, we established stably transfected HT22 cells containing CB1 and compared the protective potential of cannabinoids with that observed in the control transfected HT22 cell line. Furthermore, oxidative stress experiments were performed in cultured cerebellar granule cells, which were derived either from CB1 knock-out mice or from control wild-type littermates. The results strongly suggest that CB1 is not involved in the cellular antioxidant neuroprotective effects of cannabinoids.
The leading cause of irreversible blindness is glaucoma, a disease normally characterized by the development of ocular hypertension and consequent damage to the optic nerve at its point of retinal attachment. This results in a narrowing of the visual field, and eventually results in blindness. A number of drugs are available to lower intraocular pressure (IOP), but, occasionally, they are ineffective or have intolerable side-effects for some patients and can lose efficacy with chronic administration. The smoking of marijuana has decreased IOP in glaucoma patients. Cannabinoid drugs, therefore, are thought to have significant potential for pharmaceutical development. However, as the mechanism surrounding their effect on IOP initially was thought to involve the CNS, issues of psychoactivity hindered progress. The discovery of ocular cannabinoid receptors implied an explanation for the induction of hypotension by topical cannabinoid applications, and has stimulated a new phase of ophthalmic cannabinoid research. Featured within these investigations is the possibility that at least some cannabinoids may ameliorate optic neuronal damage through suppression of N-methyl-D-aspartate receptor hyperexcitability, stimulation of neural microcirculation, and the suppression of both apoptosis and damaging free radical reactions, among other mechanisms. Separation of therapeutic actions from side-effects now seems possible through a diverse array of novel chemical, pharmacological, and formulation strategies.
To evaluate the effects of WIN 55212-2, a cannabinoid receptor agonist, on intraocular pressure and aqueous humor dynamics in normal monkeys and monkeys with glaucoma.
Intraocular pressure was measured prior to and up to 6 hours after the topical administration of WIN 55212-2 to 1 eye of 5 normal monkeys and to the glaucomatous eye of 8 monkeys with unilateral laser-induced glaucoma. Tonographic outflow facility and fluorophotometric flow rates of aqueous humor were measured in 6 normal monkeys before and after treatment.
In normal monkeys, a single dose of WIN 55212-2 reduced intraocular pressure for 4, 5, or 6 hours, with a maximum reduction of 1.4 +/- 0.4 (mean +/- SEM) mm Hg, 2.9 +/- 0.4 mm Hg, and 3.4 +/- 0.6 mm Hg following the 0.07%, 0.2%, and 0.5% concentrations, respectively (P =.08). In 8 glaucomatous monkey eyes, the ocular hypotensive effect was maintained for 5 days with twice-daily administration of 0.5% WIN 55212-2. Outflow facility was unchanged (P =.34) and aqueous humor flow was decreased by 18% (P =.04) in the treated eyes compared with vehicle-treated contralateral control eyes in normal monkeys.
WIN 55212-2, a cannabinoid agonist at the CB(1) receptor, reduces intraocular pressure in both normal and glaucomatous monkey eyes. A decrease of aqueous flow appears to account for the intraocular pressure reduction in normal monkey eyes.
Cannabinoid agonists at the CB(1) receptor, a new class of antiglaucoma agents that is different from currently used clinical drugs, may have clinical potential.
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