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

I suppose you could ask your doctor to get Sativex from the UK off label for your spasticity.

Sativex, a cannabis based spray, was approved in England in 2019 for use in moderate to severe spasticity(only MS) when other treatments haven’t worked.

Currently, Sativex is not approved for any indication in the US, so you are totally screwed unless you are in a legal marijuana state and want to experiment on your own. But you can't, that would only be allowed if prescribed by your doctor. And your doctor will never prescribe marijuana.

 

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

Susan Mohamed¹, Giovanna Lopane¹, Loredana Sabattini¹, Cinzia Scandellari¹, Diletta Zardi², Vincenzo Donadio¹, Giovanni Rizzo¹, Alessandro Perrone¹, Alessandra Lugaresi^1,2† and Manuela Contin^1,2*†

• ¹IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
• ²Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

Background and Aim: Limited 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.

Methods: This 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.

Results: Thirty-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.

Conclusion: This 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.

Introduction

The cannabis plant contains several substances, such as more than one hundred cannabinoids (CBs) (1). There is great interest in the use of cannabis for the management of many diseases and symptoms (2) and the attention has been focused in particular on the two CBs, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) (3).

Two types of CB receptors have been identified, CB1 and CB2, which are parts of the human endocannabinoid system, involved in various functions, such as muscle spasticity, analgesic activity, anticonvulsant properties, vasodilatory and hypotensive action, and appetite (3).

THC is a partial agonist of CB1 and CB2 receptors. The main pharmacological effects of THC are psychoactivity, analgesia, muscle relaxation, anti-vomiting, and stimulation of appetite (3). Muscle relaxant effects are also recognized for hyper-reflexic bladder (4, 5).

Cannabidiol does not have a direct effect on the CB1 or CB2 receptors responsible for cannabis psychoactivity but it has been shown to have a negative allosteric activity on CB1 (6). From experimental models of epilepsies, different CBD mechanisms have emerged, such as antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and interactions with voltage-gated sodium and potassium channels (7). Other mechanisms associated with anti-inflammatory pathways include direct agonistic activity on serotonin 1A and adenosine A2A receptors (8). The main pharmacological effects of CBD are antiseizure, muscle relaxant, anxiolytic, and anti-inflammatory (1).

In the literature, several works have examined the efficacy and safety of CB's preparations in the treatment of a series of symptoms associated with neurological diseases, such as multiple sclerosis (MS), epilepsies, Huntington's disease, Parkinson's disease, cervical dystonia, and Tourette's syndrome. These applications were reviewed by an ad hoc guideline development subcommittee of the American Academy of Neurology (9). Chronic pain is another field of use of therapeutic cannabis, although few rigorous studies have evaluated its effectiveness (10).

Available data on CB's safety from clinical trials and real-world experience show that the most common adverse effects (AEs) associated with THC are dizziness, drowsiness, dry mouth, nausea/vomiting, impairment in cognitive function (perception disorders, euphoria, and confusion) and psychomotor skills, balance, and coordination problems (11). Studies on recreational cannabis have suggested a link between early, frequent use of high potency THC, and earlier onset of psychosis in subjects with a personal or family history of schizophrenia or psychotic disorders (12). CBD's common AEs include diarrhea, somnolence, pyrexia, decreased appetite, vomiting, and upper respiratory tract infection (11).

In Italy, two cannabis medicinal products are authorized: one based on THC and CBD, in the approximate 1:1 dose ratio (2.7 mg THC and 2.5 mg for CBD), in a spray for oral mucosa (Sativex^®, GW Pharmaceuticals, UK), indicated to relieve symptoms in adult patients who suffer from moderate to severe spasticity due to MS. The other, marketed from the end of June 2021, is based on purified plant-based CBD, in an oil oral formulation (Epidiolex, GW Pharmaceuticals, UK), indicated as an adjunct treatment of seizures associated with two rare, severe forms of epilepsy with childhood onset, the Lennox-Gastaut and Dravet syndromes. Furthermore, there are several available cannabis galenical preparations (i.e., oil extracts, decoctions) characterized by different percentages of THC and CBD (Supplementary Table 1), which can be prescribed by physicians to users registered on the Italian Ministry of Health database (13). Eligible indications of medical cannabis include the management of the chronic pain associated with MS and spinal cord injury, the control of nausea and vomiting due to chemotherapy, radiotherapy, or HIV therapy, the handling of appetite loss in oncologic and HIV-positive patients. Medical cannabis is also indicated for its appetite stimulant effect in cachexia and anorexia, its hypotensive effect in glaucoma, and as antispasmodic in Tourette's syndrome (14).

Despite the substantial number of published studies, data on the pharmacokinetics of THC and CBD are limited (15, 16). In particular, the pharmacokinetics of CBs from oral galenical preparations has not been extensively studied in clinical settings (17). CB's posological protocols for physicians are missing (14), thus, currently the management of dosing is largely empirical, based on a balance between the desired therapeutic effects and the prevention of the adverse ones. Knowledge of CB's pharmacokinetics from different available formulations could help the prescribers in optimizing therapeutic regimens.

The purpose of this study was to investigate the use of cannabis-based products at the Institute of Neurological Sciences of Bologna (ISNB), such as indications, type of patients treated, formulations, dosages, evidence of efficacy, and AEs, and to monitor steady-state CB's plasma concentrations matched with different cannabis-based products.

More at link.

Does Spasticity Reduction by Botulinum Toxin Type A Improve Upper Limb Functionality in Adult Post-Stroke Patients? A Systematic Review of Relevant Studies

So no improvement seen in functional activity. Is your doctor still using botox after 8 years of knowing this? I saw zero improvement  in my left arm functionality after my shots, 2 courses of them. Of course I wasn't treated with Sativex since that was after my stroke and I'm not in the UK. 

Sativex, a cannabis based spray, was approved in England in 2019 for use in moderate to severe spasticity(only MS) when other treatments haven’t worked.

Currently, Sativex is not approved for any indication in the US, so you are totally screwed unless you are in a legal marijuana state and want to experiment on your own. But you can't, that would only be allowed if prescribed by your doctor. And your doctor will never prescribe marijuana.

 

Does Spasticity Reduction by Botulinum Toxin Type A Improve Upper Limb Functionality in Adult Post-Stroke Patients? A Systematic Review of Relevant Studies

Domenico Intiso

Andrea Santamato

2013, Journal of Neurology & Neurophysiology

 Domenico Intiso
1
*, Valentina Simone
2
, Filomena Di Rienzo
1
, Andrea Santamato
3
, Mario Russo
1
, Maurizio Tolfa
1
, and Mario Basciani
1
1
Neuro-Rehabilitation Unit, Scientic Institute, Hospital ‘Casa Sollievo della Sofferenza’, Italy
2
Foundation rehabilitation “Gli Angeli di P.Pio”, San Giovanni Rotondo, Italy
3
Department of Physical Medicine and Rehabilitation, “OORR Hospital”, University of Foggia, Italy
*Corresponding author:
 Domenico Intiso MD, Neuro-Rehabilitation Unit, Hospital
Scientic Institute “Casa Sollievo della Sofferenza”, Viale dei Cappuccini, 71013 San Giovanni Rotondo (FG), Italy, Tel: 039 882 410 942; Fax: 039 882 410 942; E-mail: d.intiso@operapadrepio.it
,
 d.intiso@alice.it
Received
 
July 02, 2013;
Accepted
 October
 09, 2013;
Published
 October
 15
,
2013
Citation:
 Intiso D, Simone
V, Rienzo FD
, Santamato A, Russo
M, et al.
 
(2013)
Does
Spasticity Reduction by Botulinum Toxin Type A Improve Upper Limb Functionality in Adult Post-Stroke Patients? A Systematic Review of Relevant Studies.
 J Neurol
Neurophysiol 4: 167. doi:10.4172/2155-9562.1000167
Copyright:
 © 2013
Intiso D
. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keyword
:
Botulinum toxin; Spasticity; Stroke; Upper limb; Functionality
Introduction
Spasticity is a common disabling disorder that occurs from 17 to 43% in patients with stroke affecting both the upper and the lower limb [1-4]. If le󰀀 untreated, it can hamper functional outcome by promoting persistent abnormal posture that in turn produces muscular-tendon contractures and bone deformity. Several functional limitations arise from spasticity including impaired movement, hygiene, self-care, poor self-esteem, body image, pain and pressure ulcers that increase carer burden. Furthermore, patients with severe spasticity can develop poor social participation and quality of life (QOL) [5]. Because of these concerns and related high social costs [6], many therapeutic strategies have been proposed for the treatment of this disorder including surgical, medical and rehabilitative procedures. Among these, botulinum toxin type A (BTX-A) is became the first line to treat focal/multifocal spasticity, in the clinical practice. ere is now, a well-established body of evidence demonstrating the effectiveness of BTX-A for post-stroke spasticity reduction both in the upper and the lower limb [7-18]. Nevertheless, its impact on motor performance and functional outcome remains controversial [19,20]. In particular, the effect of reduced spasticity on upper limb ability recovery a󰀀er stroke is unclear. e central thread in treating spasticity is the assumption that it contributes to the limitation of activities, and that its reduction will bring about an improvement in function. e aim of present review was to ascertain if the reduction of spasticity by use of BTX-A was linked to a functional gain in upper limb or in activity of daily living in post-stroke patients. erefore, relevant studies addressing upper limb (UL) spasticity reduction and functional improvement a󰀀er BTX-A treatment in adult post-stroke patients were reviewed.
Method
Search of relevant studies was conducted on MEDLINE (from 1995 to July 2012), the Cochrane Central Register of Controlled Trials and EMBASE (1995 to July 2012). Search terms varied slightly across databases but included: “cerebrovascular accident” or “stroke” and the terms “botulinum toxin”, “spasticity” as either MeSH terms, key words, or subject headings. Only randomized studies (RT) treating patients with UL post-stroke spasticity by BTX-A injection were included. Studies of treatment for both lower and/or UL spasticity were included if the results for patients with UL spasticity were reported separately. Prospective open label, case series, cohort studies and case reports were excluded. Furthermore, because confounding results, RTs were also excluded whether: i) post-stroke spasticity was treated by different serotype neurotoxin; ii) botulinum toxin was given early a󰀀er the stroke, before clinical evidence of severe spasticity was established; iii) mixed sample of subjects with spasticity secondary to stroke or other neurological disorders was enrolled; iv) spasticity followed a non-

Abstract

Objective: 

 

Botulinum toxin type A (BTX-A) use reduces upper limb (UL) spasticity in stroke patients, but the effects on functional recovery remain uncertain. The aim of present review was to ascertain if the reduction of spasticity by use of BTX-A was linked to a functional gain of UL or in activity of daily living in post-stroke patients.
 

Data source: 

 

Search of relevant studies was conducted on MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (1995 to July 2012).
 

Study selection: 

 

Only randomized studies (RT) treating patients with UL post-stroke spasticity by BTX-A injection were included. Prospective open label, case series, cohort studies and case reports were excluded.
 

Data synthesis: 

 

Thirty-four RTs were individuated, but only 16 were considered in the analysis. Trials varied widely in methodological design and measures used in assessing UL ability. Benet in UL functional recovery was reported in 13 studies, but only in six the result was signicant.
 

Conclusion: 

 

Some oriented-focused movements of UL unequivocally improve after reduced spasticity by BTX-A treatment, but evidence that arm functionality in adult post-stroke patients signicantly benet from this intervention is still doubt. No improvement in global functionality of activity daily living was observed.
 

 

Sativex, a cannabis based spray, was approved in England in 2019 for use in moderate to severe spasticity(only MS) when other treatments haven’t worked.

Currently, Sativex is not approved for any indication in the US, so you are totally screwed unless you are in a legal marijuana state and want to experiment on your own. But you can't, that would only be allowed if prescribed by your doctor.

 Sativex, a cannabis based spray, was approved in England in 2019 for use in moderate to severe spasticity(only MS) when other treatments haven’t worked.

Despite this, many people with MS are still being denied access to Sativex, because their local health bodies, called Clinical Commissioning Groups (CCGs), are not prescribing it. This has resulted in an unacceptable postcode lottery, with Sativex only funded in 49 out of 106 CCGs.

This must change - everyone with MS deserves access to effective treatments. Find out now if Sativex is available in your area and join our call for change. You can take action to ask your local CCG to start prescribing Sativex now. 

Join our #ApprovedButDenied campaign

Sativex doesn’t work for everyone, but when it does, the impact can be life changing. Our new report (PDF 2.7MB) explains this in more detail.

Across the UK

Wales 

Sativex has been approved for use on the NHS in Wales since 2014. We’re currently working with Health Boards to make sure services for people with MS are available as the NHS builds back from the impact of the pandemic. If you’d like to share with us your experience of trying to access Sativex, please email campaigns@mssociety.org.uk

Northern Ireland 

Sativex was approved for use in April 2021. So far, our monitoring suggests people with MS who meet the criteria are being offered the treatment after discussion with their consultant. If you're having any issues accessing Sativex, please let us know by emailing campaigns@mssociety.org.uk 

Scotland

While some people are already being prescribed Sativex, it's not currently recommended for use on the NHS in Scotland. We want GW, the manufacturer of Sativex, to make a submission to the Scottish Medicines Consortium. Your support will be vital in helping us to achieve our aim of Sativex being available in Scotland, if you'd like to share your story of what Sativex would mean to you, please email us at campaigns@mssociety.org.uk

 

Sativex Helps ALS, PLS Spasticity in Mid-Stage Trial

But does it work in stroke? Or will survivors have to test this out on their own? Because we have NO STROKE LEADERSHIP that actually will try to solve all the problems in stroke. Will your doctor have enough innovation to try this off-label for your spasticity? Or will incompetence reign again waiting for SOMEONE ELSE TO SOLVE THE PROBLEM?

 

 

Sativex Helps ALS, PLS Spasticity in Mid-Stage Trial

Pain scores improved, too

• by Judy George, Contributing Writer, MedPage Today December 14, 2018

An oromucosal spray containing cannabis extracts helped reduce spasticity in motor neuron disease patients, including those with amyotrophic lateral sclerosis (ALS), in the phase II CANALS trial in Italy.
Motor neuron disease patients taking first-line anti-spasticity drugs followed by nabiximols (Sativex), a cannabis derivative of equal parts delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), showed significant improvements in scores on the Modified Ashworth Scale at 6 weeks, reported Giancarlo Comi, MD, of the San Raffaele Scientific Institute in Milan, and colleagues in The Lancet Neurology.
"There is no cure for motor neuron disease so improved symptom control and quality of life are important for patients," co-author Nilo Riva, MD, also of the San Raffaele Scientific Institute, said in a statement.
"Our proof-of-concept trial showed a beneficial effect of THC-CBD spray in people on treatment-resistant spasticity and pain," Riva added. "Despite these encouraging findings, we must first confirm that THC-CBD spray is effective and safe in larger, longer term phase III trials."
The CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease) study is the first randomized controlled trial of the safety and efficacy of a pharmacological treatment for motor neuron disease spasticity, as well as the first trial of nabiximols for it, the researchers noted.
Previously, nabiximols has been shown to help relieve spasticity in multiple sclerosis patients. Preclinical studies of transgenic mice also supported the hypothesis that cannabinoids could exert an anti-spastic effect in ALS.
In this double-blind trial, researchers studied 59 adults with ALS or primary lateral sclerosis (PLS) from four tertiary motor neuron disease centers in Italy in 2013 and 2014. Patients had possible, laboratory-supported probable, probable, or definite amyotrophic lateral sclerosis as defined by revised El Escorial criteria or primary lateral sclerosis according to Pringle's criteria, and experienced spasticity symptoms for at least 3 months before the trial. They also were on a stable dose of any anti-spasticity medication for 30 days before enrolling and throughout the study.
The investigators randomized patients to nabiximols mouth spray (n=29) or placebo (n=30) for 6 weeks. Each 100 µL actuation of nabiximols contained 2.7 mg THC and 2.5 mg CBD. Participants self-titrated during the first 14 treatment days to a maximum of 12 actuations per 24 hours, then maintained that dose for 4 weeks. After dose titration, the mean number of daily actuations was 8.03 in the nabiximols group and 11.2 in the placebo group (P<0.0001).
Physicians rated the spasticity of each participant's joints on the Modified Ashworth Scale at baseline and at 6 weeks. Patients also kept a daily symptom diary, recording spasticity levels, pain, spasm frequency, and sleep disruption.
At 6 weeks, Modified Ashworth Scale scores improved by a mean of 0.11 in the nabiximols group, but deteriorated by a mean of 0.16 in the placebo group (adjusted effect estimate –0.32, 95% CI –0.57 to –0.069; P=0.013.)
The number of patients treated with nabiximols who reported improvements (55%; 16/29 participants) was higher than placebo (13%; 4/30). Self-reported pain scores also improved (-0.97 vs -0.06) in the nabiximols group.
Nabiximols was well tolerated and adverse events were mild to moderate and typical of cannabinoids; nausea, dizziness, asthenia, and confusion were common. Twenty-one patients (72%) in the nabiximols group reported at least one potentially treatment-related adverse event, but there were no serious adverse events and no one permanently discontinued treatment.
While the results of this study are promising, the trial had several limitations, observed Marianne de Visser, MD, PhD, of the Amsterdam University Medical Centre in the Netherlands, in an accompanying editorial.
"First, there was a bias towards patients with exclusive or predominant involvement of upper motor neurons (n=16) in the nabiximols group, in whom spasticity is the prevailing symptom," de Visser wrote. "These patients could have benefited more than the 13 patients with classic amyotrophic lateral sclerosis, which involves both upper and lower motor neurons".
Riva and colleagues did not distinguish between upper and lower limb spasticity, or whether or not patients had bulbar spasticity, she noted; these patients may be differently affected by spasticity.
And while the Modified Ashworth Scale has been used in previous positive studies of the efficacy of other anti-spastic treatments, de Visser wrote, "as Riva and colleagues acknowledge, it lacked sensitivity in studies of the efficacy of cannabinoids in patients with multiple-sclerosis-related spasticity, and new spasticity numeric ratings or visual analogue scales are being adopted."
The trial had other limitations, the researchers noted. The study had a double-blind design, but the side effects of THC-CBD might have unmasked that. Other adverse effects may appear with long-term exposure. The sample size was too small and study duration too short to observe any potential neuroprotective effect of cannabinoids in slowing disease progression, as preclinical ALS studies have suggested, they added.

This study was funded by Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA) and Fondazione Vialli e Mauro (CANALS Project). GW Pharma provided the study drug and placebo.
Researchers reported relationships with Abbvie, Biogen, Excemed, Merck Serono, Novartis, Teva, Genzyme, Almirall, Kedrion, CSL Behring, Baxter, Chugai, Roche, Sanofi-Aventis, and Receptos.
The editorialist declared no competing interests.

last updated 12.14.2018

• Primary Source

  The Lancet Neurology

  Source Reference: Riva N, et al "Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial" The Lancet Neurology 2018; DOI:https://doi.org/10.1016/S1474-4422(18)30406-X.

• Secondary Source

  The Lancet Neurology

  Source Reference: de Visser M "Evidence for treatment of spasticity in motor neuron disease" The Lancet Neurology 2018; DOI:https://doi.org/10.1016/S1474-4422(18)30493-9.