RESUMEN
Importance: Safe and effective nonhormonal treatments for menopausal vasomotor symptoms (VMS) are needed. Objective: To evaluate the efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist, for the treatment of moderate to severe menopausal vasomotor symptoms. Design, Setting, and Participants: Two randomized double-blind phase 3 trials (OASIS 1 and 2) included postmenopausal participants aged 40 to 65 years experiencing moderate to severe vasomotor symptoms (OASIS 1: 77 sites in the US, Europe, and Israel from August 27, 2021, to November 27, 2023, and OASIS 2: 77 sites in the US, Canada, and Europe from October 29, 2021, to October 10, 2023). Intervention: Once daily oral elinzanetant, 120 mg, for 26 weeks or matching placebo for 12 weeks followed by elinzanetant, 120 mg, for 14 weeks. Main Outcomes and Measures: Primary end points included mean change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12, measured by the electronic hot flash daily diary. Secondary end points included Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality of Life questionnaire total score from baseline to week 12. Results: Eligible participants (mean [SD] age, OASIS 1: 54.6 [4.9] years; OASIS 2: 54.6 [4.8] years) were randomized to elinzanetant (OASIS 1: n = 199; OASIS 2: n = 200) or placebo (OASIS 1: n = 197; OASIS 2: n = 200). A total of 309 (78.0%) and 324 (81.0%) completed OASIS 1 and 2, respectively. For the elinzanetant and placebo groups, the baseline mean (SD) VMS per 24 hours were 13.4 (6.6) vs 14.3 (13.9) (OASIS 1) and 14.7 (11.1) v 16.2 (11.2) (OASIS 2). Baseline VMS severity was 2.6 (0.2) vs 2.5 (0.2) (OASIS 1) and 2.5 (0.2) vs 2.5 (0.2) (OASIS 2). Elinzanetant significantly reduced VMS frequency at week 4 (OASIS 1: -3.3 [95% CI, -4.5 to -2.1], P < .001; OASIS 2: -3.0 [95% CI, -4.4 to -1.7], P < .001) and at week 12 (OASIS 1: -3.2 [95% CI, -4.8 to -1.6], P < .001; OASIS 2: -3.2 [95% CI, -4.6 to -1.9], P < .001). Elinzanetant also improved VMS severity at week 4 (OASIS 1: -0.3 [95% CI, -0.4 to -0.2], P < .001; OASIS 2: -0.2 [95 CI, -0.3 to -0.1], P < .001) and week 12 (OASIS 1: -0.4 [95% CI, -0.5 to -0.3], P < .001; OASIS 2: -0.3 [95% CI, -0.4 to -0.1], P < .001). Elinzanetant improved sleep disturbances and menopause-related quality of life at week 12, and the safety profile was favorable. Conclusions and Relevance: Elinzanetant was well tolerated and efficacious for moderate to severe menopausal VMS. Trial Registration: ClinicalTrials.gov Identifier: OASIS 1: NCT05042362, OASIS 2: NCT05099159.
RESUMEN
OBJECTIVE: Elinzanetant is a selective neurokinin-1,3 receptor antagonist in development for the treatment of vasomotor symptoms (VMS) associated with menopause. The pivotal, double-blind, randomized, placebo-controlled phase 3 studies Overall Assessment of efficacy and Safety of elinzanetant In patients with vasomotor Symptoms (OASIS) 1 and 2 will assess the efficacy and safety of elinzanetant in women with VMS. METHODS: The OASIS 1 and 2 pivotal studies are designed in accordance with regulatory guidance. Postmenopausal women with moderate/severe VMS are randomized to receive 120 mg elinzanetant or placebo once daily for 12 weeks, followed by a 14-week active treatment extension. Primary endpoints are the mean change in frequency and severity of moderate/severe VMS from baseline to weeks 4 and 12. Key secondary endpoints will assess the onset of action and effects on sleep disturbance and menopause-related quality of life. Primary and key secondary endpoints will be analyzed using a mixed model with repeated measures. Feedback from postmenopausal women with VMS was used during protocol development. RESULTS: Women confirmed the relevance of endpoints that assess the impact of VMS, sleep disturbance, and mood changes, and the need for new nonhormone treatments. Educational materials around study design, conduct and expected assessments and procedures were developed based on questions and concerns raised by women. CONCLUSIONS: The OASIS 1 and 2 pivotal phase 3 studies will enable assessment of the efficacy and safety of elinzanetant as a treatment for VMS, together with its effect on sleep disturbances, depressive symptoms, and menopause-related quality of life. Feedback from postmenopausal women with VMS was used to maximize patient centricity in the trials.
Asunto(s)
Sofocos , Menopausia , Calidad de Vida , Adulto , Femenino , Humanos , Persona de Mediana Edad , Método Doble Ciego , Sofocos/tratamiento farmacológico , Menopausia/efectos de los fármacos , Posmenopausia , Resultado del TratamientoRESUMEN
OBJECTIVE: Neurokinin (NK)-3 and NK-1 receptors have been implicated in the etiology of vasomotor symptoms (VMS) and sleep disturbances associated with menopause. This phase 2b, adaptive, dose-range finding study aimed to assess the efficacy and safety of multiple doses of elinzanetant (NT-814), a selective NK-1,3 receptor antagonist, in women experiencing VMS associated with menopause, and investigate the impact of elinzanetant on sleep and quality of life. METHODS: Postmenopausal women aged 40 to 65 years who experienced seven or more moderate-to-severe VMS per day were randomized to receive elinzanetant 40, 80, 120, or 160 mg or placebo once daily using an adaptive design algorithm. Coprimary endpoints were reduction in mean frequency and severity of moderate-to-severe VMS at weeks 4 and 12. Secondary endpoints included patient-reported assessments of sleep and quality of life. RESULTS: Elinzanetant 120 mg and 160 mg achieved reductions in VMS frequency versus placebo from week 1 throughout 12 weeks of treatment. Least square mean reductions were statistically significant versus placebo at both primary endpoint time points for elinzanetant 120 mg (week 4: -3.93 [SE, 1.02], P < 0.001; week 12: -2.95 [1.15], P = 0.01) and at week 4 for elinzanetant 160 mg (-2.63 [1.03]; P = 0.01). Both doses also led to clinically meaningful improvements in measures of sleep and quality of life. All doses of elinzanetant were well tolerated. CONCLUSIONS: Elinzanetant is an effective and well-tolerated nonhormone treatment option for postmenopausal women with VMS and associated sleep disturbance. Elinzanetant also improves quality of life in women with VMS.
Asunto(s)
Sofocos , Calidad de Vida , Femenino , Humanos , Sofocos/tratamiento farmacológico , Resultado del Tratamiento , Menopausia , Sueño , Método Doble CiegoRESUMEN
AIM: Cannabinoid receptor type 1 (CB1 ) antagonists have been developed for the treatment of obesity and associated risk factors. Surinabant is a high affinity CB1 antagonist in vitro. The aim of this study was to assess the magnitude of inhibition by surinabant of CNS effects and heart rate induced by Δ(9) -tetrahydrocannabinol (THC) in humans. METHODS: This was a double-blind, placebo-controlled, randomized, four period six sequence crossover study. Thirty healthy young male occasional cannabis users (<1 per week) were included. A single oral dose of surinabant (5, 20 or 60 mg) or placebo was administered followed 1.5 h later by four intrapulmonary THC doses (2, 4, 6 and 6 mg) or vehicle, administered at 1 h intervals. The wash-out period was 14-21 days. Subjective and objective pharmacodynamic (PD) measurements were performed. A population PK-PD model for THC and surinabant quantified PK and PD effects. RESULTS: Surinabant 20 and 60 mg inhibited all THC-induced PD effects in a similar range for both doses with inhibition ratios ranging from 68.3% (95% CI = 32.5, 104.2; heart rate) to 91.1% (95% CI = 30.3, 151.8; body sway). IC50 ranged from 22.0 ng ml(-1) [relative standard error (RSE) = 45.2%; body sway] to 58.8 ng ml(-1) (RSE = 44.2%; internal perception). Surinabant 5 mg demonstrated no significant effects. CONCLUSIONS: The dose-related inhibition by surinabant, without any effect of its own, suggests that this compound behaves as a CB1 receptor antagonist in humans at these concentrations. A single surinabant dose between 5 to 20 mg and above was able to antagonize THC-induced effects in humans.
Asunto(s)
Antagonistas de Receptores de Cannabinoides/farmacología , Dronabinol/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Adolescente , Adulto , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/administración & dosificación , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Dronabinol/administración & dosificación , Humanos , Masculino , Modelos Biológicos , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Receptor Cannabinoide CB1/antagonistas & inhibidores , Adulto JovenRESUMEN
RATIONALE: Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. OBJECTIVES: The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist Δ(9)-tetrahydrocannabinol (THC) on reward-related brain activity. METHODS: Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with administration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded ("reward trial") or not ("neutral trial"). RESULTS: Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. CONCLUSIONS: These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction.
Asunto(s)
Moduladores de Receptores de Cannabinoides/metabolismo , Dronabinol/farmacología , Endocannabinoides , Imagen por Resonancia Magnética/métodos , Recompensa , Adolescente , Adulto , Anticipación Psicológica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estudios Cruzados , Retroalimentación Fisiológica , Humanos , Masculino , Tiempo de Reacción , Adulto JovenRESUMEN
Deficits in memory function are an incapacitating aspect of various psychiatric and neurological disorders. Animal studies have recently provided strong evidence for involvement of the endocannabinoid (eCB) system in memory function. Neuropsychological studies in humans have shown less convincing evidence but suggest that administration of cannabinoid substances affects encoding rather than recall of information. In this study, we examined the effects of perturbation of the eCB system on memory function during both encoding and recall. We performed a pharmacological MRI study with a placebo-controlled, crossover design, investigating the effects of Δ9-tetrahydrocannabinol (THC) inhalation on associative memory-related brain function in 13 healthy volunteers. Performance and brain activation during associative memory were assessed using a pictorial memory task, consisting of separate encoding and recall conditions. Administration of THC caused reductions in activity during encoding in the right insula, the right inferior frontal gyrus, and the left middle occipital gyrus and a network-wide increase in activity during recall, which was most prominent in bilateral cuneus and precuneus. THC administration did not affect task performance, but while during placebo recall activity significantly explained variance in performance, this effect disappeared after THC. These findings suggest eCB involvement in encoding of pictorial information. Increased precuneus activity could reflect impaired recall function, but the absence of THC effects on task performance suggests a compensatory mechanism. These results further emphasize the eCB system as a potential novel target for treatment of memory disorders and a promising target for development of new therapies to reduce memory deficits in humans.
Asunto(s)
Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Dronabinol/administración & dosificación , Imagen por Resonancia Magnética , Memoria a Corto Plazo/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Psicotrópicos/administración & dosificación , Administración por Inhalación , Adolescente , Adulto , Mapeo Encefálico , Estudios Cruzados , Método Doble Ciego , Dronabinol/sangre , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Pruebas Neuropsicológicas , Oxígeno , Dimensión del Dolor , Adulto JovenRESUMEN
The Nateglinide and Valsartan Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is exploring two pharmacological strategies (nateglinide and valsartan, both alone and in combination) in the prevention of overt diabetes mellitus (DM) and the reduction of cardiovascular disease (CVD) in subjects at high risk for these events. In this analysis, we provide baseline characteristics of the randomized NAVIGATOR study population and contrast them with those from other trials of DM prevention. Key eligibility criteria include impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), a history of CVD (in patients aged > or =50 years), and > or =1 cardiovascular risk factor (in patients aged > or =55 years). Baseline demographic characteristics, laboratory findings, cardiovascular risk factors, CVD history, and medication use are described and compared with other trials of DM prevention. The full analysis set of subjects (N = 9306) showed a clustering of risk factors consistent with the metabolic syndrome: high rates of hypertension (77.5%), dyslipidemia (44.7%), increased waist circumference (101.0 cm), and high body mass index (BMI) (47.5% with BMI > or =30 kg/m(2)). A minority of patients had a history of CVD (24.3%); of these, 11.7% had a history of myocardial infarction and most of the remainder had evidence of coronary artery disease. Subjects also had elevated blood pressure (BP) (predominantly systolic) (139.7/82.6 mm Hg), increased serum low-density lipoproteins cholesterol levels (3.27 mmol/L), and borderline elevation of triglyceride levels (1.97 mmol/L). Demographic data, BP, and lipid profiles in NAVIGATOR were similar to those of previous DM prevention trials, which were also based largely on meeting criteria for IGT. Medication use at baseline among NAVIGATOR subjects, which frequently included aspirin, beta-blockers, calcium channel blockers, diuretics, and lipid-lowering agents, reflects enhanced CVD risk. However, little prescribing of renin-angiotensin-aldosterone system blockers was observed, likely due to protocol exclusion criteria. In conclusion, the NAVIGATOR study comprises prediabetic subjects who typically have concurrent BP and metabolic disturbances and an enhanced risk of CVD, and are thus at higher risk for cardiovascular events than subjects in previous DM prevention trials.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Ciclohexanos/uso terapéutico , Diabetes Mellitus/prevención & control , Intolerancia a la Glucosa/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Fenilalanina/análogos & derivados , Estado Prediabético/tratamiento farmacológico , Tetrazoles/uso terapéutico , Valina/análogos & derivados , Anciano , Glucemia/metabolismo , Presión Sanguínea , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus/sangre , Diabetes Mellitus/etiología , Diabetes Mellitus/fisiopatología , Femenino , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Nateglinida , Selección de Paciente , Fenilalanina/uso terapéutico , Estado Prediabético/sangre , Estado Prediabético/fisiopatología , Proyectos de Investigación , Medición de Riesgo , Factores de Riesgo , Valina/uso terapéutico , ValsartánRESUMEN
An ideal drug for outpatient treatments under conscious sedation would have both sedative and analgesic properties. CB1/CB2 agonists are expected to have sedative, amnestic, analgesic and anti-emetic properties. The main objective of this first study in humans was to assess the sedative properties of intravenous Org 26828. In addition, pharmacokinetics, amnestic properties, postural stability, and behavioural and cardiovascular effects were studied. Midazolam intravenous 0.1 mg/kg and placebo were used as controls. The pharmacokinetic parameters (Cmax and AUC0-inf) of the main metabolite Org 26761 were proportional to dose. No effects were observed after doses up to 0.3 µg/kg of Org 26828. Dose-related effects were observed at higher doses. Although subjects reported subjective sedation after administration of Org 26828 at 3 and 6 µg/kg, the observed sedation was considerably less than after midazolam. Doses higher than the maximum tolerated dose of 1 µg/kg of Org 26828 caused unpleasant central nervous system effects (anxiety, paranoia, hallucinations). Therefore, Org 26828 is not suitable for providing sedation for outpatient surgical procedures.
Asunto(s)
Sedación Consciente , Dronabinol/análogos & derivados , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/farmacocinética , Midazolam/farmacología , Midazolam/farmacocinética , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/efectos de los fármacos , Adulto , Procedimientos Quirúrgicos Ambulatorios , Relación Dosis-Respuesta a Droga , Dronabinol/efectos adversos , Dronabinol/sangre , Dronabinol/farmacocinética , Dronabinol/farmacología , Humanos , Hipnóticos y Sedantes/efectos adversos , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Adulto JovenRESUMEN
AIM: In determining the acute effects of alcohol, it is helpful if alcohol concentrations are maintained at stable levels, to facilitate the interpretation of the results. Recently, an alcohol clamping method was developed that resulted in stable alcohol concentrations for hours. The aim of this study was to test a range of central nervous system (CNS) effects under pseudo-steady-state conditions. METHODS: To achieve a pseudo-steady state of 0.6 g l(-1), breath alcohol concentrations (BrAC) were frequently measured and fed back into a spreadsheet-based program to guide intravenous dosing. CNS effects were frequently measured throughout the clamp. RESULTS: The clamping paradigm resulted in a pseudo-steady-state BrAC of 0.61 g l(-1) (coefficient of variation 6.2%). A plateau was maintained from 25 to 300 min and caused significant effects on smooth pursuit eye movements [-9.7%, 95% confidence interval (CI) -12.4, -7.1], adaptive tracking (-3.4%, 95% CI -4.5, -2.2), visual analogue scale (VAS) alertness (-13 mm, 95% CI -20, -6), VAS alcohol effects (16 mm, 95% CI 7, 25) and body sway (21.3%, 95% CI 1.8, 45). Some effects (like smooth pursuit eye movements) closely followed the relatively stable alcohol concentrations, whereas others (such as body sway and VAS alcohol effects) fluctuated during the plateau phase. CONCLUSIONS: Most CNS effects of alcohol showed a trend to change over time, despite stable concentrations. Other variables remained stable under pseudo-steady-state conditions. The intravenous clamping method provides precise control over BrAC levels and allows frequent repetition of different CNS measurements. These features make this technique eminently suitable to study the complex pharmacodynamic effects of acute alcohol administration.
Asunto(s)
Depresores del Sistema Nervioso Central/efectos adversos , Etanol/farmacología , Adolescente , Adulto , Área Bajo la Curva , Pruebas Respiratorias/métodos , Depresores del Sistema Nervioso Central/administración & dosificación , Constricción , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Etanol/administración & dosificación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Adulto JovenRESUMEN
An increasing number of novel therapeutic agents are targeted at cannabinoid receptors. Drug development programmes of new cannabinoid drugs may be facilitated by the identification of useful biomarkers. This systemic literature review aims to assess the usefulness of direct biomarkers for the effects of cannabis and tetrahydrocannabinol (THC) in healthy volunteers. One hundred and sixty-five useful articles were found that investigated the acute effects of cannabis or THC on the central nervous system (CNS) and heart rate in healthy volunteers. Three hundred and eighteen tests (or test variants) were grouped in test clusters and functional domains, to allow their evaluation as a useful biomarker and to study their dose-response effects. Cannabis/THC affected a wide range of CNS domains. In addition to heart rate, subjective effects were the most reliable biomarkers, showing significant responses to cannabis in almost all studies. Some CNS domains showed indications of depression at lower and stimulation at higher doses. Subjective effects and heart rate are currently the most reliable biomarkers to study the effect of cannabis. Cannabis affects most CNS domains, but too many different CNS tests are used to quantify the drug-response relationships reliably. Test standardization, particularly in motor and memory domains, may reveal additional biomarkers.
Asunto(s)
Cannabinoides/farmacología , Cannabis , Dronabinol/farmacología , Administración por Inhalación , Adolescente , Adulto , Cannabinoides/administración & dosificación , Relación Dosis-Respuesta a Droga , Dronabinol/administración & dosificación , Emociones/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Memoria/efectos de los fármacos , Persona de Mediana Edad , Desempeño Psicomotor/efectos de los fármacos , Adulto JovenRESUMEN
The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Delta 9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D(2)/D(3) receptor tracer [(11)C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [(11)C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Dronabinol/farmacología , Administración por Inhalación , Adulto , Moduladores de Receptores de Cannabinoides/fisiología , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Dronabinol/análogos & derivados , Dronabinol/sangre , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética , Masculino , Placebos , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , Racloprida/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismoRESUMEN
What is currently needed for optimal use of medicinal cannabinoids is a feasible, nonsmoked, rapid-onset delivery system. Cannabis "vaporization" is a technique aimed at suppressing irritating respiratory toxins by heating cannabis to a temperature where active cannabinoid vapors form, but below the point of combustion where smoke and associated toxins are produced. The goal of this study was to evaluate the performance of the Volcano vaporizer in terms of reproducible delivery of the bioactive cannabinoid tetrahydrocannabinol (THC) by using pure cannabinoid preparations, so that it could be used in a clinical trial. By changing parameters such as temperature setting, type of evaporation sample and balloon volume, the vaporization of THC was systematically improved to its maximum, while preventing the formation of breakdown products of THC, such as cannabinol or delta-8-THC. Inter- and intra-device variability was tested as well as relationship between loaded- and delivered dose. It was found that an average of about 54% of loaded THC was delivered into the balloon of the vaporizer, in a reproducible manner. When the vaporizer was used for clinical administration of inhaled THC, it was found that on average 35% of inhaled THC was directly exhaled again. Our results show that with the Volcano a safe and effective cannabinoid delivery system seems to be available to patients. The final pulmonal uptake of THC is comparable to the smoking of cannabis, while avoiding the respiratory disadvantages of smoking.