RESUMEN
Using marijuana has become popular and is allowed for medical purposes in some countries. The effect of marijuana on Parkinson's disease is controversial and Medical marijuana may benefit for motor and non-motor symptoms of patients with Parkinson's disease. No research has been conducted to fully prove the benefits, risks, and uses of marijuana as a treatment for patients with Parkinson's disease. In the present study, several different approaches, including behavioral measures and the western blot method for protein level assay, were used to investigate whether exposure to marijuana affects the motor and synaptic plasticity impairment induced by 6-OHDA. Marijuana consumption significantly decreased apomorphine-induced contralateral rotation, beam travel time, beam freeze time, and catalepsy time, but significantly increased latency to fall in the rotarod test, balance time, and protein level of PSD-95 and dopamine receptor D1 in the 6-OHDA + marijuana group. These results suggest that marijuana may be helpful for motor disorders and synaptic changes in patients with Parkinson's disease.
Asunto(s)
Conducta Animal/efectos de los fármacos , Agonistas de Receptores de Cannabinoides/farmacología , Homólogo 4 de la Proteína Discs Large/efectos de los fármacos , Dronabinol/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Marihuana Medicinal/farmacología , Plasticidad Neuronal/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Adrenérgicos/farmacología , Animales , Agonistas de Receptores de Cannabinoides/administración & dosificación , Modelos Animales de Enfermedad , Dronabinol/administración & dosificación , Masculino , Marihuana Medicinal/administración & dosificación , Oxidopamina/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Extractos Vegetales , Ratas , Ratas WistarRESUMEN
Chronic pain can be recurrent or constant pain that lasts for longer than 3 months and can result in disability, suffering, and a physical disturbance. Related to the complex nature of chronic pain, treatments have a pharmacological and non-pharmacological approach. Due to the opioid epidemic, alternative therapies have been introduced, and components of the plant Cannabis Sativa, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have gained recent interest as a choice of treatment. The exact mechanism for CBD is currently unknown, but unlike the CBD's psychoactive counterpart, THC, the side effects of CBD itself have been shown to be overall much more benign. The current pharmaceutical products for the treatment of chronic pain are known as nabiximols, and they contain a ratio of THC combined with CBD, which has been promising. This review focuses on the treatment efficacy of CBD, THC: CBD-based treatments for chronic pain and adverse events with each.
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Analgésicos/administración & dosificación , Cannabidiol/administración & dosificación , Agonistas de Receptores de Cannabinoides/administración & dosificación , Dolor Crónico/tratamiento farmacológico , Dronabinol/administración & dosificación , Dolor Crónico/diagnóstico , Dolor Crónico/fisiopatología , Estudios Cruzados , Vías de Administración de Medicamentos , Combinación de Medicamentos , Quimioterapia Combinada , Humanos , Resultado del TratamientoRESUMEN
The endogenous opioid and cannabinoid receptor systems are widely distributed and co-localized throughout central and peripheral nervous system regions. A large body of preclinical evidence suggests that there are functional interactions between these two systems that may be leveraged to address various health conditions. Numerous animal studies have shown that cannabinoid agonists (e.g., delta-9-tetrahydrocannabinol [Δ9-THC]) enhance the analgesic effects of µ-opioid analgesics as evidenced by decreasing the opioid dose required for analgesia (i.e., opioid sparing) and extending the duration of the opioid analgesia. In contrast, controlled human laboratory studies and clinical trials have not demonstrated robust analgesic or opioid-sparing effects from opioid-cannabinoid combinations. Meta-analyses of the literature (clinical trials, controlled laboratory studies; some non-controlled studies/case reports) have examined the effects of cannabis/cannabinoids for pain relief in those taking a wide variety of analgesics, including prescription opioid medications. These data do not strongly support the use of cannabinoids for chronic pain nor do prospective studies demonstrate significant cannabinoid-mediated opioid-sparing effects. Preclinical studies have also suggested a role for cannabinoids for the treatment of opioid withdrawal. Controlled laboratory and clinical studies suggest that there may be a modest signal for Δ9-THC to suppress some opioid signs and symptoms but they are not completely ameliorated and there may also be concerns around safety of Δ9-THC administration in a state of heightened autonomic arousal as occurs with opioid withdrawal. Despite anecdotal and correlational reports suggesting a benefit of cannabis on reducing opioid overdose, there is no strong data supporting this contention and emerging reports have conflicting results. In summary, there is a groundswell of public advocacy supporting the use of cannabis and cannabinoids to replace opioid analgesics or to reduce opioid use; however, the extant controlled clinical data do not support the role of cannabinoids for opioid replacement or opioid-sparing effects when treating opioid use disorder or chronic pain.
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Analgésicos Opioides/administración & dosificación , Agonistas de Receptores de Cannabinoides/administración & dosificación , Dolor Crónico/tratamiento farmacológico , Dronabinol/administración & dosificación , Manejo del Dolor/métodos , Animales , Dolor Crónico/diagnóstico , Dolor Crónico/epidemiología , Ensayos Clínicos como Asunto/métodos , Humanos , Manejo del Dolor/tendencias , Estudios ProspectivosRESUMEN
Despite a growing acceptance that withdrawal symptoms can emerge following discontinuation of cannabis products, especially in high-intake chronic users, there are no Food and Drug Administration (FDA)-approved treatment options. Drug development has been hampered by difficulties studying cannabis withdrawal in laboratory animals. One preclinical approach that has been effective in studying withdrawal from drugs in several pharmacological classes is antagonist drug discrimination. The present studies were designed to examine this paradigm in squirrel monkeys treated daily with the long-acting CB1 agonist AM2389 (0.01 mg/kg) and trained to discriminate the CB1 inverse agonist/antagonist rimonabant (0.3 mg/kg) from saline. The discriminative-stimulus effects of rimonabant were both dose and time dependent and, importantly, could be reproduced by discontinuation of agonist treatment. Antagonist substitution tests with the CB1 neutral antagonists AM4113 (0.03-0.3 mg/kg), AM6527 (0.03-1.0 mg/kg), and AM6545 (0.03-1.0 mg/kg) confirmed that the rimonabant discriminative stimulus also could be reproduced by CB1 antagonists lacking inverse agonist action. Agonist substitution tests with the phytocannabinoid ∆9-tetrahydrocannabinol (0.1-1.0 mg/kg), synthetic CB1 agonists nabilone (0.01-0.1 mg/kg), AM4054 (0.01-0.03 mg/kg), K2/Spice compound JWH-018 (0.03-0.3 mg/kg), FAAH-selective inhibitors AM3506 (0.3-5.6 mg/kg), URB597 (3.0-5.6 mg/kg), and nonselective FAAH/MGL inhibitor AM4302 (3.0-10.0 mg/kg) revealed that only agonists with CB1 affinity were able to reduce the rimonabant-like discriminative stimulus effects of withholding daily agonist treatment. Although the present studies did not document physiologic disturbances associated with withdrawal, the results are consistent with the view that the cannabinoid antagonist drug discrimination paradigm provides a useful screening procedure for examining the ability of candidate medications to attenuate the interoceptive stimuli provoked by cannabis discontinuation. SIGNIFICANCE STATEMENT: Despite a growing acceptance that withdrawal symptoms can emerge following the discontinuation of cannabis products, especially in high-intake chronic users, there are no FDA-approved pharmacotherapies to assist those seeking treatment. The present studies systematically examined cannabinoid antagonist drug discrimination, a preclinical animal model that is designed to appraise the ability of candidate medications to attenuate the interoceptive effects that accompany abrupt cannabis abstinence.
Asunto(s)
Antagonistas de Receptores de Cannabinoides/uso terapéutico , Discriminación en Psicología , Modelos Animales de Enfermedad , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Animales , Benzopiranos/administración & dosificación , Benzopiranos/efectos adversos , Benzopiranos/uso terapéutico , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/efectos adversos , Agonistas de Receptores de Cannabinoides/uso terapéutico , Antagonistas de Receptores de Cannabinoides/administración & dosificación , Antagonistas de Receptores de Cannabinoides/efectos adversos , Evaluación Preclínica de Medicamentos/métodos , Sustitución de Medicamentos/métodos , Masculino , Rimonabant/administración & dosificación , Rimonabant/efectos adversos , Rimonabant/uso terapéutico , Saimiri , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB1) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB1 agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5â¯mg]; nicotine [6â¯mg]; and nicotineâ¯+â¯nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.
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Agonistas de Receptores de Cannabinoides/farmacología , Dronabinol/análogos & derivados , Potenciales Evocados Auditivos/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Estimulación Acústica/métodos , Adulto , Agonistas de Receptores de Cannabinoides/administración & dosificación , Método Doble Ciego , Dronabinol/administración & dosificación , Dronabinol/farmacología , Quimioterapia Combinada/métodos , Electroencefalografía/métodos , Electrooculografía/métodos , Lóbulo Frontal/efectos de los fármacos , Voluntarios Sanos , Humanos , Masculino , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamiento farmacológico , Lóbulo Temporal/efectos de los fármacos , Adulto JovenRESUMEN
Federal barriers and logistical challenges have hindered measurement of the real time effects from the types of cannabis products used medically by millions of patients in vivo. Between 06/06/2016 and 03/05/2018, 3,341 people completed 19,910 self- administrated cannabis sessions using the mobile device software, ReleafApp to record: type of cannabis product (dried whole natural Cannabis flower, concentrate, edible, tincture, topical), combustion method (joint, pipe, vaporization), Cannabis subspecies (C. indica and C. sativa), and major cannabinoid contents (tetrahydrocannabinol, THC; and cannabidiol, CBD), along with real-time ratings of health symptom severity levels, prior-to and immediately following administration, and reported side effects. A fixed effects panel regression approach was used to model the within-user effects of different product characteristics. Patients showed an average symptom improvement of 3.5 (SD = 2.6) on an 11-point scale across the 27 measured symptom categories. Dried flower was the most commonly used product and generally associated with greater symptom relief than other types of products. Across product characteristics, only higher THC levels were independently associated with greater symptom relief and prevalence of positive and negative side effects. In contrast, CBD potency levels were generally not associated with significant symptom changes or experienced side effects.
Asunto(s)
Cannabidiol/uso terapéutico , Agonistas de Receptores de Cannabinoides/uso terapéutico , Dronabinol/uso terapéutico , Marihuana Medicinal/uso terapéutico , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Cannabidiol/análisis , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/efectos adversos , Dronabinol/administración & dosificación , Dronabinol/efectos adversos , Humanos , Marihuana Medicinal/administración & dosificación , Marihuana Medicinal/efectos adversos , Psicotrópicos/administración & dosificación , Psicotrópicos/efectos adversos , Psicotrópicos/uso terapéutico , AutoadministraciónRESUMEN
Recently, multiple compounds have been synthesized that target the allosteric binding site(s) of CB1. These CB1 positive allosteric modulators may capture the benefits of cannabinoid receptor activation without unwanted psychoactive effects, such as sedation. For example, ZCZ011 blocks neuropathic pain, absent the catalepsy, sedation, and hypothermia caused by CB1 orthosteric modulators, including Δ9-tetrahydrocannabinol (THC). The primary goal of the present study was to evaluate the potential of ZCZ011 to attenuate somatic signs of cannabinoid withdrawal in mice. Mice were repeatedly administered THC (10â¯mg/kg, s.c.) or vehicle, and withdrawal was either precipitated using the CB1 antagonist rimonabant (3â¯mg/kg, i.p.) or elicited spontaneously via THC abstinence. ZCZ011 (≥10â¯mg/kg, i.p.) significantly attenuated somatic signs of withdrawal, including head twitches and paw tremors, but had no effect on locomotor activity or conditioned place preference. We next tested the antiulcerogenic properties of CB1 positive allosteric modulation. Mice were fasted for 22â¯h, administered ZCZ011, and gastric hemorrhages were induced with the nonsteroidal anti-inflammatory drug diclofenac sodium (100â¯mg/kg, p.o.). ZCZ011 alone had no effect on gastric ulceration, but ZCZ011 (≥10â¯mg/kg) blocked ulcer formation when combined with a subthreshold MAGL inhibitor (JZL184; 1â¯mg/kg, i.p.). Thus, CB1 positive allosteric modulation is a novel approach to treat cannabinoid dependence and gastric inflammation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Benzodioxoles/uso terapéutico , Agonistas de Receptores de Cannabinoides/farmacología , Diclofenaco/farmacología , Dronabinol/farmacología , Gastritis/inducido químicamente , Gastritis/tratamiento farmacológico , Indoles/uso terapéutico , Piperidinas/uso terapéutico , Receptor Cannabinoide CB1/metabolismo , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Tiofenos/uso terapéutico , Regulación Alostérica , Sitio Alostérico , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Benzodioxoles/farmacología , Agonistas de Receptores de Cannabinoides/administración & dosificación , Diclofenaco/administración & dosificación , Dronabinol/administración & dosificación , Quimioterapia Combinada , Indoles/farmacología , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Monoacilglicerol Lipasas/antagonistas & inhibidores , Úlcera Péptica Hemorrágica/inducido químicamente , Úlcera Péptica Hemorrágica/tratamiento farmacológico , Piperidinas/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Rimonabant/farmacología , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Tiofenos/farmacologíaRESUMEN
BACKGROUND: Cannabinoids have been used for their analgesic and euphoric effects for millennia, but recently the antipruritic effects of cannabis have been discovered. Considering the similarities between pain and itch sensations, we hypothesized that cannabinoid receptors may play a role in the antipruritic effects of cannabinoids. AIM: To analyse the role of the spinal cannabinoid receptors, CB1 and CB2, in the antipruritic effects of the cannabinoid agonist WIN 55,212-2. METHODS: Male Balb/c mice weighing 20-30 g were used. Scratching behaviour in the mice was produced by injection of serotonin 5 µg/50 µL intradermally into the nape of the neck. Scratching of the site of injection by the hind paws was video-recorded for 30 min. After testing different doses of WIN 55,212-2 [1, 3 and 10 mg/kg intraperitoneally (IP)], the effects of the CB1 receptor antagonist, AM-251 [1 µg/mouse administered intrathecally (IT)] and the CB2 receptor antagonist AM-630 (4 µg/mouse IT) on the antipruritic effects of WIN 55,212-2 were studied using a rotarod apparatus. RESULTS: WIN 55,212-2 (1, 3 or 10 mg/kg IP) dose-dependently decreased serotonin-induced scratches. The receptor antagonist CB1 partially reversed the effects of WIN 55,212-2 (P < 0.05); whereas CB2 had no statistically significant effect. WIN 55,212-2 impaired motor function only at the highest dose given (10 mg/kg, P < 0.05). CONCLUSIONS: Our findings support prior researches indicating that cannabinoids exert antipruritic effects. Moreover, our results show that the antipruritic effects of cannabinoids are partially mediated by spinal CB1 receptors.
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Benzoxazinas/uso terapéutico , Agonistas de Receptores de Cannabinoides/uso terapéutico , Morfolinas/uso terapéutico , Naftalenos/uso terapéutico , Prurito/tratamiento farmacológico , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Médula Espinal/metabolismo , Animales , Benzoxazinas/administración & dosificación , Agonistas de Receptores de Cannabinoides/administración & dosificación , Antagonistas de Receptores de Cannabinoides/farmacología , Relación Dosis-Respuesta a Droga , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Piperidinas/farmacología , Prurito/inducido químicamente , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB2/antagonistas & inhibidores , SerotoninaRESUMEN
We report the cases of two young German male patients with treatment-resistant Tourette syndrome (TS), who suffer from incapacitating stuttering-like speech disfluencies caused by vocal blocking tics and palilalia. Case 1: a 19-year old patient received medical cannabis at a dose of 1 × 0.1 g cannabis daily. Case 2: a 16-year old patient initially received dronabinol at a maximum dose of 22.4-33.6 mg daily. Both treatments provided significant symptom improvement of vocal blocking tics as well as of comorbid conditions and were well tolerated. Thus, cannabis-based medicine appears to be effective in treatment-resistant TS patients with vocal blocking tics.
Asunto(s)
Agonistas de Receptores de Cannabinoides/uso terapéutico , Dronabinol/uso terapéutico , Marihuana Medicinal/uso terapéutico , Tics/tratamiento farmacológico , Síndrome de Tourette/tratamiento farmacológico , Adolescente , Adulto , Agonistas de Receptores de Cannabinoides/administración & dosificación , Dronabinol/administración & dosificación , Humanos , Masculino , Marihuana Medicinal/administración & dosificación , Índice de Severidad de la Enfermedad , Tics/complicaciones , Tics/patología , Síndrome de Tourette/complicaciones , Síndrome de Tourette/patología , Adulto JovenRESUMEN
BACKGROUND: Cannabidiol (CBD)-based treatments for several diseases, including Tourette's syndrome, multiple sclerosis, epilepsy, movement disorders and glaucoma, are proving to be beneficial and the scientific clinical background of the drug is continuously evolving. OBJECTIVES: To investigate the short-term effect of CBD-enriched hemp oil for relieving symptoms and improving the life quality (QOL) in young girls with adverse drug effects (ADRs) following human papillomavirus (HPV) vaccine. METHODS: In this anecdotal, retrospective, "compassionate-use", observational, open-label study, 12 females (age 12-24 years) with severe somatoform and dysautonomic syndrome following HPV vaccination were given sublingual CBD-rich hemp oil drops, 25 mg/kg per day supplemented by 2-5 mg/ml CBD once a week until a maximum dose of 150 mg/ml CBD per day was reached over a 3 month period. Patients' quality of life was evaluated using the medical outcome short-form health survey questionnaire (SF-36). RESULTS: Two patients dropped out due to iatrogenic adverse events and another two patients stopped the treatment early due to lack of any improvement. SF-36 showed significant benefits in the physical component score (P < 0.02), vitality (P < 0.03) and social role functioning (P < 0.02) after the treatment. The administration of hemp oil also significantly reduced body pain according to the SF-36 assessment. No significant differences from the start of treatment to several months post-treatment were detected in role limitations due to emotional reactions (P = 0.02). CONCLUSIONS: This study demonstrated the safety and tolerability of CBD-rich hemp oil and the primary efficacy endpoint. Randomized controlled trials are warranted to characterize the safety profile and efficacy of this compound.
Asunto(s)
Cannabidiol/administración & dosificación , Vacunas contra Papillomavirus/efectos adversos , Disautonomías Primarias , Calidad de Vida , Trastornos Somatomorfos , Administración Sublingual , Adolescente , Sistema Nervioso Autónomo , Cannabidiol/efectos adversos , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/efectos adversos , Cannabis , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Monitoreo de Drogas , Femenino , Humanos , Italia , Vacunas contra Papillomavirus/administración & dosificación , Aceites de Plantas/administración & dosificación , Disautonomías Primarias/diagnóstico , Disautonomías Primarias/etiología , Disautonomías Primarias/psicología , Disautonomías Primarias/terapia , Estudios Retrospectivos , Trastornos Somatomorfos/diagnóstico , Trastornos Somatomorfos/etiología , Trastornos Somatomorfos/psicología , Trastornos Somatomorfos/terapia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a 'peripherally' restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN. METHODS: Renal function and structure, podocyte proteins and markers of both fibrosis and inflammation were studied in streptozotocin-induced diabetic mice treated for 14 weeks with vehicle, AM6545, AM1241 and AM6545-AM1241. RESULTS: Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells. CONCLUSION: 'Peripheral' CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.
Asunto(s)
Agonistas de Receptores de Cannabinoides/administración & dosificación , Antagonistas de Receptores de Cannabinoides/administración & dosificación , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Morfolinas/administración & dosificación , Pirazoles/administración & dosificación , Albuminuria/prevención & control , Animales , Antiinflamatorios/administración & dosificación , Cannabinoides/administración & dosificación , Células Cultivadas , Diabetes Mellitus Experimental/complicaciones , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Masculino , Ratones , Ratones Endogámicos C57BL , Activación Neutrófila/efectos de los fármacos , Podocitos/efectos de los fármacos , Podocitos/metabolismoRESUMEN
INTRODUCTION: The complexity of the endocannabinoid (eCB) system is becoming better understood and new drivers of eCB signaling are emerging. Modulation of the activities of the eCB system can be therapeutic in a number of diseases. Research into the eCB system has been paralleled by the development of agents that interact with cannabinoid receptors. In this regard it should be remembered that herbal cannabis contains a myriad of active ingredients, and the individual cannabinoids have quite distinct biological activities requiring independent studies. Areas covered: This article reviews the most important current data involving the eCB system in relation to human diseases, to reflect the present (based mainly on the most used prescription cannabinoid medicine, THC/CBD oromucosal spray) and potential future uses of cannabinoid-based therapy. Expert commentary: From the different therapeutic possibilities, THC/CBD oromucosal spray has been in clinical use for approximately five years in numerous countries world-wide for the management of multiple sclerosis (MS)-related moderate to severe resistant spasticity. Clinical trials have confirmed its efficacy and tolerability. Other diseases in which different cannabinoids are currently being investigated include various pain states, Alzheimer's disease, Parkinson's disease, Huntington's disease and epilepsy. The continued characterization of individual cannabinoids in different diseases remains important.
Asunto(s)
Agonistas de Receptores de Cannabinoides/administración & dosificación , Endocannabinoides/metabolismo , Extractos Vegetales/administración & dosificación , Administración Oral , Animales , Cannabidiol , Agonistas de Receptores de Cannabinoides/farmacología , Agonistas de Receptores de Cannabinoides/uso terapéutico , Dronabinol , Combinación de Medicamentos , Diseño de Fármacos , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
Several studies have shown the existence of an interaction between the endocannabinoid system and some drugs of abuse, such as opioids, nicotine, alcohol, and cocaine. For instance, the endocannabinoid system has long been known to play a role in the underlying mechanisms of drug reward and dependence. The aim of this study was to evaluate the possible existence of an interaction between the endocannabinoid system and khat after acute administration. Behavioral interactions of khat extract with cannabinoids were assessed. To this effect, mice were randomly divided into different groups (vehicle, khat extract, khat and WIN55,212-2, a cannabinoid agonist, khat extract and cannabinoid antagonists, AM251 & AM630) and their behavioral responses were evaluated in activity monitor, elevated plus maze and Y-maze tests. These tests were used to determine changes in locomotor activity, anxiety-like behavior, and working memory. Khat and WIN55,212-2 demonstrated differential responses in these tests, but co-administration of these agents invariably increased the measured parameters, which were reversed by the cannabinoid receptor antagonists used. The data collectively indicate that there is an interaction between khat and the endocannabinoid system, which most likely involves the cannabinoid receptors or a common mechanism separately activated by the two agents.
Asunto(s)
Conducta Animal/efectos de los fármacos , Agonistas de Receptores de Cannabinoides/administración & dosificación , Catha , Endocannabinoides/fisiología , Extractos Vegetales/administración & dosificación , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Animales , Ansiedad , Benzoxazinas/administración & dosificación , Indoles/administración & dosificación , Locomoción/efectos de los fármacos , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Piperidinas/administración & dosificación , Pirazoles/administración & dosificaciónRESUMEN
Cannabis use has been increasingly accepted legally and in public opinion. However, cannabis has the potential to produce adverse physical and mental health effects, and cannabis use disorder (CUD) occurs in a substantial percentage of both occasional and daily cannabis users. Many people have difficulty discontinuing use despite receiving treatment. Therefore, it would be beneficial to develop safe and effective medications for treating CUD. To achieve this, methods have been developed for screening and evaluating potential medications using animal models and controlled experimental protocols in human volunteers. In this chapter, we describe: (1) animal models available for assessing the effect of potential medications on specific aspects of CUD, (2) the main findings obtained so far with these animal models, (3) the approaches used to assess potential medications in humans in laboratory experiments and clinical trials, and (4) the effectiveness of several potential pharmacotherapies on particular aspects of CUD modeled in these human studies.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Abuso de Marihuana/tratamiento farmacológico , Animales , Agonistas de Receptores de Cannabinoides/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Dronabinol/administración & dosificación , Humanos , AutoadministraciónRESUMEN
IMPORTANCE: There are no medications approved for treating cannabis dependence or withdrawal. The cannabis extract nabiximols (Sativex), developed as a multiple sclerosis treatment, offers a potential agonist medication for cannabis withdrawal. OBJECTIVE: To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal. DESIGN, SETTING, AND PARTICIPANTS: A 2-site, double-blind randomized clinical inpatient trial with a 28-day follow-up was conducted in New South Wales, Australia. Participants included 51 DSM-IV-TR cannabis-dependent treatment seekers. INTERVENTIONS: A 6-day regimen of nabiximols (maximum daily dose, 86.4 mg of Δ9-tetrahydrocannabinol and 80 mg of cannabidiol) or placebo with standardized psychosocial interventions during a 9-day admission. MAIN OUTCOMES AND MEASURES: Severity of cannabis withdrawal and cravings (Cannabis Withdrawal Scale), retention in withdrawal treatment, and adverse events. Secondary outcomes include postwithdrawal cannabis use, health outcomes, and psychosocial outcomes. RESULTS: Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal relative to placebo (F8,377.97 = 2.39; P = .01), including effects on withdrawal-related irritability, depression, and cannabis cravings. Nabiximols had a more limited, but still positive, therapeutic benefit on sleep disturbance, anxiety, appetite loss, physical symptoms, and restlessness. Nabiximols patients remained in treatment longer during medication use (unadjusted hazard ratio, 3.66 [95% CI, 1.18-11.37]; P = .02), with 2.84 the number needed to treat to achieve successful retention in treatment. Participants could not reliably differentiate between nabiximols and placebo treatment (χ21 = 0.79; P = .67), and those receiving nabiximols did not report greater intoxication (F1,6 = 0.22; P = .97). The number (F1,50 = 0.3; P = .59) and severity (F1,50 = 2.69; P = .10) of adverse events did not differ significantly between groups. Both groups showed reduced cannabis use at follow-up, with no advantage of nabiximols over placebo for self-reported cannabis use (F1,48 = 0.29; P = .75), cannabis-related problems (F1,49 = 2.33; P = .14), or cannabis dependence (F1,50 < 0.01; P = .89). CONCLUSIONS AND RELEVANCE: In a treatment-seeking cohort, nabiximols attenuated cannabis withdrawal symptoms and improved patient retention in treatment. However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use following medication cessation. The data support further evaluation of nabiximols for management of cannabis dependence and withdrawal in treatment-seeking populations. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12611000398909.
Asunto(s)
Cannabidiol/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Dronabinol/farmacología , Abuso de Marihuana/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Adulto , Australia , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/efectos adversos , Terapia Combinada , Método Doble Ciego , Dronabinol/administración & dosificación , Dronabinol/efectos adversos , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Efecto Placebo , Placebos , Psicoterapia/métodos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The regulation of glucose, lipid metabolism and immunoreactivities of insulin and glucagon peptides by delta-9-tetrahydrocannabinol (Δ(9)-THC) in diabetes were examined in an experimental rat model. Male Sprague-Dawley rats were divided into four groups: (1) control, (2) Δ(9)-THC treated, (3) diabetic, and (4) diabetic+Δ(9)-THC. The type 2 diabetic rat model was established by intraperitoneal (i.p.) injection of nicotinamide (85 mg/kg body weight) followed after 15 min by i.p. injection of streptozotocin (STZ) at 65 mg/kg of body weight. Δ(9)-THC and Δ(9)-THC treated diabetic groups received 3mg/kg/day of Δ(9)-THC for 7 days. The immunolocalization of insulin and glucagon peptides was investigated in the pancreas using a streptavidin-biotin-peroxidase technique. High density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), very low density lipoprotein cholesterol (VLDL), triglycerides (TG), total cholesterol (TC) and total protein (TP) levels were measured in serum. Total islet area percent of insulin immunoreactive cells slightly changed in diabetic+Δ(9)-THC rats compared to diabetic animals. However, the area percent of glucagon immunoreactive cells showed a decrease in diabetic+Δ(9)-THC rats compared to that of diabetic animals alone. Serum TC, HDL and LDL levels of diabetes+Δ(9)-THC group showed a decrease compared to the diabetic group. These results indicate that Δ(9)-THC may serve a protective role against hyperlipidemia and hyperglycemia in diabetic rats.
Asunto(s)
Agonistas de Receptores de Cannabinoides/administración & dosificación , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dronabinol/administración & dosificación , Animales , Glucemia , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Tipo 2/sangre , Evaluación Preclínica de Medicamentos , Glucagón/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Metabolismo de los Lípidos/efectos de los fármacos , Lipoproteínas/sangre , Masculino , Ratas Sprague-DawleyRESUMEN
The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB2). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB2 is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, we have investigated the analgesic effects of BCP in animal models of inflammatory and neuropathic pain. We demonstrate that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB2 receptor-dependent manner, while it had no effect on acute (early phase) responses. In a neuropathic pain model the chronic oral administration of BCP attenuated thermal hyperalgesia and mechanical allodynia, and reduced spinal neuroinflammation. Importantly, we found no signs of tolerance to the anti-hyperalgesic effects of BCP after prolonged treatment. Oral BCP was more effective than the subcutaneously injected synthetic CB2 agonist JWH-133. Thus, the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Agonistas de Receptores de Cannabinoides/uso terapéutico , Modelos Animales de Enfermedad , Neuralgia/tratamiento farmacológico , Receptor Cannabinoide CB2/agonistas , Neuropatía Ciática/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Conducta Animal/efectos de los fármacos , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inmunología , Hiperalgesia/metabolismo , Masculino , Ratones , Ratones Congénicos , Actividad Motora/efectos de los fármacos , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuralgia/inmunología , Neuralgia/metabolismo , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/metabolismo , Dimensión del Dolor , Fitoquímicos/administración & dosificación , Fitoquímicos/efectos adversos , Fitoquímicos/uso terapéutico , Sesquiterpenos Policíclicos , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Nervio Ciático/efectos de los fármacos , Nervio Ciático/inmunología , Nervio Ciático/metabolismo , Neuropatía Ciática/inmunología , Neuropatía Ciática/metabolismo , Sesquiterpenos/administración & dosificación , Sesquiterpenos/efectos adversos , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/metabolismoRESUMEN
Drugs that modulate the endocannabinoid system and endocannabinoids typically play an anticonvulsant role although some proconvulsant effects have been reported both in humans and animal models. Moreover, no evidence for a role of the cannabinoid system in human absence epilepsy has been found although limited evidence of efficacy in relevant experimental animal models has been documented. This study aims to characterize the role of cannabinoids in specific areas of the cortico-thalamic network involved in oscillations that underlie seizures in a genetic animal model of absence epilepsy, the WAG/Rij rat. We assessed the effects of focal injection of the endogenous cannabinoid, anandamide (AEA), a non-selective CB receptor agonist (WIN55,212) and a selective CB1 receptor antagonist/inverse agonist (SR141716A) into thalamic nuclei and primary somatosensory cortex (S1po) of the cortico-thalamic network. AEA and WIN both reduced absence seizures independently from the brain focal site of infusion while, conversely, rimonabant increased absence seizures but only when focally administered to the ventroposteromedial thalamic nucleus (VPM). These results, together with previous reports, support therapeutic potential for endocannabinoid system modulators in absence epilepsy and highlight that attenuated endocannabinergic function may contribute to the generation and maintenance of seizures. Furthermore, the entire cortico-thalamic network responds to cannabinoid treatment, indicating that in all areas considered, CB receptor activation inhibits the pathological synchronization that subserves absence seizures. In conclusion, our result might be useful for the identification of future drug therapies in absence epilepsy.
Asunto(s)
Anticonvulsivantes , Agonistas de Receptores de Cannabinoides/farmacología , Corteza Cerebral/efectos de los fármacos , Epilepsia Tipo Ausencia/genética , Epilepsia Tipo Ausencia/prevención & control , Vías Nerviosas/efectos de los fármacos , Receptor Cannabinoide CB1/agonistas , Tálamo/efectos de los fármacos , Animales , Ácidos Araquidónicos/farmacología , Benzoxazinas/farmacología , Agonistas de Receptores de Cannabinoides/administración & dosificación , Electroencefalografía/efectos de los fármacos , Endocannabinoides/farmacología , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Inyecciones Intraventriculares , Masculino , Morfolinas/farmacología , Naftalenos/farmacología , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Pirazoles/farmacología , Ratas , Rimonabant , Convulsiones/fisiopatología , Corteza Somatosensorial/fisiologíaRESUMEN
The aim of the present study was to investigate the effects of AZD1940, a novel peripherally acting cannabinoid CB(1) /CB(2) receptor agonist, on capsaicin-induced pain and hyperalgesia, as well as on biomarkers of cannabinoid central nervous system (CNS) effects. The present study was a randomized, double-blind, placebo-controlled, four-sequence, two-period, cross-over study in 44 male healthy volunteers aged 20-45 years. The effects of two single oral doses of AZD1940 (400 and 800 µg) were compared with placebo. Pain intensity after intradermal capsaicin injections in the forearm was assessed on a continuous visual analogue scale (VAS; 0-100 mm). Primary and secondary hyperalgesia induced by application of capsaicin cream on the calf were assessed by measuring heat pain thresholds and the area of mechanical allodynia, respectively. The CNS effects were assessed at baseline and up to 24 h after dosing using a visual analogue mood scales (VAMS) for feeling 'stimulated', 'high', 'anxious', 'sedated' or 'down'. AZD1940 did not significantly attenuate ongoing pain or primary or secondary hyperalgesia compared with placebo. Mild CNS effects for AZD1940were observed on the VAMS for 'high' and 'sedated'. Dose-dependent mild-to-moderate CNS-related and gastrointestinal adverse events were reported following treatment with AZD1940. No evidence of analgesic efficacy was found for a peripherally acting CB(1)/CB(2) receptor agonist in the human capsaicin pain model. The emergence of mild dose-dependent CNS effects suggests that the dose range predicted from preclinical data had been attained.
Asunto(s)
Analgésicos/uso terapéutico , Bencimidazoles/uso terapéutico , Agonistas de Receptores de Cannabinoides/uso terapéutico , Capsaicina/administración & dosificación , Hiperalgesia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Psicotrópicos/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Analgésicos/administración & dosificación , Analgésicos/efectos adversos , Analgésicos/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/efectos adversos , Agonistas de Receptores de Cannabinoides/farmacocinética , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Psicotrópicos/administración & dosificación , Psicotrópicos/efectos adversos , Psicotrópicos/farmacocinética , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
RATIONALE: Chronic cannabis use can induce psychotic states that resemble schizophrenia. Yet, schizophrenic patients often smoke cannabis as a form of self-medication to counter the aversive symptoms of schizophrenia. We recently demonstrated an ameliorating effect of cannabinoid self-administration (SA) on negative and cognitive schizophrenia-like symptoms induced experimentally by the non-competitive N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Whether cannabinoid SA alleviates or exacerbates schizophrenia-like positive symptoms is still unclear. OBJECTIVES: This follow-up study aimed to evaluate the effect of self-administered cannabinoid on PCP-induced schizotypic positive symptoms in adult rats. METHODS: Male rats were trained to self-administer either the cannabinoid CB1 receptor agonist WIN 55,212-2 (WIN; 12.5 µg/kg/infusion) or its vehicle (Veh) intravenously. The effects of acute and chronic intermittent intraperitoneal administration of PCP (2.5 mg/kg) on motor parameters were then tested in Veh-SA and WIN-SA. RESULTS: Cannabinoid SA significantly attenuated the psychotomimetic effects of PCP exposure observed in control rats. Following acute PCP administration, WIN-SA animals displayed more frequent rearing and lower anxiety-like profile than Veh-SA rats. WIN-SA rats also exhibited lower behavioural sensitisation to chronic PCP treatment as demonstrated by reduced hyperlocomotion in response to an acute PCP challenge. In addition, parallel experiments performed in experimenter-administered rats that received WIN at comparable SA doses confirmed the ameliorating effects of cannabinoid exposure on PCP-induced schizotypic behaviours, indicating that motivational effects were not responsible for the ameliorative effects of cannabinoids. CONCLUSIONS: Our results indicate that cannabis may exert protective effects on positive schizotypic symptoms in adult animals such as hypermotility and anxiety state.