Tetrahydrocannabinol/Cannabidiol Oromucosal Spray in Patients With Multiple Sclerosis: A Pilot Study on the Plasma Concentration-Effect Relationship

Contin, Manuela; Mancinelli, Luca; Perrone, Alessandro; Sabattini, Loredana; Mohamed, Susan; Scandellari, Cinzia; Foschi, Matteo; Vacchiano, Veria; Riva, R.

doi:10.1097/wnf.0000000000000294

Cited by 11 publications

(16 citation statements)

References 18 publications

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“…Meanwhile, PD models define the relationship between drug exposure and response. For CBD, certain plasma concentrations have been shown to be associated with improved attention control, psychological symptoms, and multiple sclerosis‐related spasticity . Future PK/PD studies should aim to establish dose‐exposure‐response relationships in order to determine optimal CBD doses.…”

Section: Discussionmentioning

confidence: 99%

Model‐Based Analysis of Cannabidiol Dose‐Exposure Relationship and Bioavailability

2020

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Introduction There is a large variation in cannabidiol (CBD) pharmacokinetics and little information on its bioavailability. This study aims to establish the CBD dose‐exposure relationship and to evaluate the effects of dosage forms, food, and doses on CBD absorption. Methods Single‐dose (range: 5–6000 mg) CBD plasma concentration‐time profiles administered as oral solution (OS), oral capsule (OC), or oromucosal spray/drop (OM) from healthy volunteers were extracted from 15 published clinical studies. A dose‐exposure proportionality assessment was performed, and a population‐based meta‐analysis of CBD pharmacokinetics and systemic bioavailability was conducted with a nonlinear mixed‐effects modeling. A three‐compartment model with a Weibull or zero‐order absorption model was used to describe CBD disposition and absorption kinetics. Dosage form, food, and dose were assessed for covariation. Results Oral solution CBD exposures increased less than proportionally with doses of 750 mg or greater, and bioavailability (6.5% at 3000 mg) decreased with increasing dose. The bioavailability of OC (5.6%) and fed‐state OM (6.2%) were similar, whereas it was lower in fasted‐state OM (0.9%). The Weibull absorption model best described OS, OC, and fed‐state OM profiles. The slowest absorption rate was observed in OS, resulting in a time of maximum concentration of 4.75 hours, followed by fed‐state OM (3.13 hrs) and OC (2.1 hrs). The absorption kinetics of fasted‐state OM was best described by a zero‐order absorption for the duration of 1.71 hours. Conclusion The effects of doses, dosage forms, and feeding status on CBD pharmacokinetics were quantified and should be taken into consideration for dose optimization.

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Section: Discussionmentioning

confidence: 99%

Model‐Based Analysis of Cannabidiol Dose‐Exposure Relationship and Bioavailability

2020

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“…Overall, post-morning dose of THC and CBD plasma concentrations significantly increased over baseline values. Blood drawings were taken 2.5 h post-dose, on the basis of our previous findings from oromucosal spray ( 29 ), and reported CBs t max from oils ranging 1.3–2.5 h ( 16 , 17 , 27 ). In line with published data at comparable doses ( 26 , 29 , 30 ) CB's plasma concentrations proved low, up to maximum THC and CBD values of 3.86 and 1.88 ng/ml, respectively from oils and 4.94 and 1.77 ng/ml from oromucosal spray.…”

Section: Discussionmentioning

confidence: 99%

“…Blood drawings were taken 2.5 h post-dose, on the basis of our previous findings from oromucosal spray ( 29 ), and reported CBs t max from oils ranging 1.3–2.5 h ( 16 , 17 , 27 ). In line with published data at comparable doses ( 26 , 29 , 30 ) CB's plasma concentrations proved low, up to maximum THC and CBD values of 3.86 and 1.88 ng/ml, respectively from oils and 4.94 and 1.77 ng/ml from oromucosal spray. Values lower than the suggested minimum effective CB's blood concentrations of 1 ng/ml ( 26 ) were measured in 43% of patients after Bediol® and 38% after Sativex® dosing for THC and in 86% of patients after Bediol® and 69% after Sativex® for CBD.…”

Section: Discussionmentioning

confidence: 99%

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey

Sinaa

Lopane²,

Sabattini³

et al. 2022

Front. Neurol.

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Background and AimLimited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients' steady-state cannabinoids (CBs) plasma concentrations matched with different preparations.MethodsThis was a prospective, single-center, observational study. Patients underwent venous blood withdrawal before the CBs' morning dose and then 2.5 h post-dosing. Spasticity or pain were patient self-assessed by the Numeric Rating Scale (NRS) before the morning CB's administration and 2.5 h post-dosing.ResultsThirty-three patients were enrolled. Main indications for CBs were spasticity and chronic pain. Sixteen patients were treated with oromucosal spray formulation Sativex® and 17 with oil-based solutions. Both CBs trough plasma concentrations were ≤ limit of detection (0.1 ng/ml) in 45% of patients. Intrasubject CB's plasma levels significantly increased over baseline values in patients treated with Bediol® oil (p < 0.05) and Sativex® (p < 0.01). Post-dosing CB's bioavailability did not significantly differ between oral oil and oromucosal spray. NRS scores decreased (p < 0.01), matching the increase (p < 0.01) in CB's plasma concentrations.ConclusionThis is the first study investigating CB's plasma concentrations of oral and oromucosal preparations in real-world neurological practice. Findings of similar bioavailability for both CBD and THC after galenic oil compared with oromucosal spray dosing may be clinically relevant and deserve additional research in larger cohorts.

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“…In a double-blind, randomized phase II trial, nabiximols has been used to treat spasticity in patients affected by motor neuron disease (MND). The spasticity, a key symptom of both MND and MS, improved in patients who received the cannabinoid treatment (185). Moreover, nabiximols decreased patients' reported pain levels.…”

Section: Neurodegenerative Disordersmentioning

confidence: 93%

Cannabidiol and the central nervous system: translating into clinics

Saviano¹,

Raucci²,

Tallarico³

et al. 2021

Pharm Adv

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Cannabis plants contain more than a hundred cannabinoids of which we have only limited knowledge about their effects and exact mechanisms of action. Cannabidiol (CBD) represents one of the most studied; it was discovered at the beginning of the last century while only recently has attracted greater attention. CBD mechanism of action is still unclear and debated; in the plant only the (-) enantiomer can be found and it seems that only the (+) enantiomer is able to bind to the cannabinoid receptors although evidence of a modulation of the endocannabinoid system exists. Furthermore, several other mechanisms have been proposed which may be differently relevant for different disease spanning from ion channels to immune responses and modulation of inflammation. It is a highly lipophilic drug with a peculiar pharmacokinetic which has led to the use and proposal of different formulations and routes of administration; of note, CBD has a complex interaction with cytochromes and is at high risk of drug-drug interaction with many drugs. Nowadays, CBD has been studied for potential efficacy in several pathologies and central nervous system (CNS) diseases are the most promising with clinical studies already in the started and some formulations with CBD already authorized for the treatment of spasticity in multiple sclerosis and seizures in some specific epileptic syndromes such as Lennox-Gastaut or Dravet. This review article is summarizing the relevant studies and perspectives of CBD use in the most relevant areas of CNS disorders also including a detailed description of its proposed mechanism(s) of action, pharmacokinetic characteristics and safety profile.

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Tetrahydrocannabinol/Cannabidiol Oromucosal Spray in Patients With Multiple Sclerosis: A Pilot Study on the Plasma Concentration-Effect Relationship

Cited by 11 publications

References 18 publications

Model‐Based Analysis of Cannabidiol Dose‐Exposure Relationship and Bioavailability

Model‐Based Analysis of Cannabidiol Dose‐Exposure Relationship and Bioavailability

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey

Cannabidiol and the central nervous system: translating into clinics

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