Latest marijuana and MS published research

[ActiveMSers]

Long-term Effectiveness of tetrahydrocannabinol: Cannabidiol Oromucosal Spray in Clinical Practice: results from a 18-months Multicenter Italian Study

Francesco Patti, et al

Objective:
We aimed to provide real life data on clinical outcomes of a large population of Italian patients with treatmentresistant multiple sclerosis (MS) spasticity receiving 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD)
oromucosal spray (Sativex®).

Background: THC:CBD oromucosal spray is used as mono or add-on therapy for moderate to severe MS spasticity resistant to other medications.

Design/Methods: This 18-months observational, prospective, multicentre study evaluated patients with resistant MS spasticity treated with THC:CBD according to approved labelling. Data were collected from the mandatory Italian medicines agency (AIFA) e-registry from January 2015 to June 2018. Spasticity assessment with the 0-10 numerical rating scale (NRS) was performed at baseline, after 1 month of treatment (T1) and every 6 months until 18 months (T4) from the treatment initiation.

Results: A total of 1845 patients were recruited from 32 Italian MS centres. At T1, 1502 (81.4%) of patients reached an NRS improvement of ≥20% and 814 (40.2%) a of ≥30%, with a mean NRS score reduction of 28.9% at T1 and of 36.8% at T4. Daily number of puffs was generally stable through the observation period (6.9±2.4 at T1 vs 6.3±3.1 at T4, p=0.8). At T4, 727 (39.4%) patients have discontinued treatment; 388 (53.4%) because of lack of effectiveness and 339 (46.6%) for adverse events: 127 (37.5%) reported vertigo, 118 (34.8%) sleepiness, 96 (28.3%) worsening of fatigue, and 54 (15.9%) cognitive symptoms. The multivariate analysis showed that higher NRS score at baseline (OR 2.21 95%CI 1.12-6.28, p<0.01) and higher difference of NRS between T1 and baseline (OR 2.03 95%CI 1.04-8.14, p<0.05) were associated to an increased probability to stay on therapy after 18 months.

Conclusions: Real-life data from a large Italian MS population confirmed the long-term effectiveness of THC:CBD for the treatment of resistant MS spasticity in everyday clinical practice. Treatment effects were sustained for 18-months with a relatively stable number of puffs/day.

[ActiveMSers]

More from 2019's AAN conference currently ongoing in Seattle.

Multiple Sclerosis and Use of Medical Cannabis: A Retrospective Review Evaluating Symptom Outcomes

Katelyn McCormack, et al

Objective:
The purpose of this study was to investigate the role of medical cannabis in improving symptomatology in patients diagnosed with multiple sclerosis (MS). We also sought to collect data on other pertinent outcomes related to the use of cannabis to enhance understanding of the potential benefits this complementary therapy offers.

Background:
Although medical cannabis is approved in 30 states and the District of Columbia for use in multiple sclerosis there remains a dearth of research clinically evaluating its effectiveness and patient experience.

Design/Methods:
A retrospective chart review of 77 patients diagnosed with multiple sclerosis participating in treatment with medical cannabis for symptom management was conducted (F=53, M=24, Mean Age=49±12). A variety of objective and subjective variables that pertain to alleviation of MS symptoms were collected from each of the first four appointments following initiation of medical cannabis. A cross-sectional review of self-rating scales completed by patients was also conducted to determine gross changes in mental health.

Results:
Subjective improvement endorsed by patients was extensive, with alleviation of symptomatology seen most in pain (71%), spasticity (43%), and sleep (42%). In addition, 34% of patients were able to decrease and discontinue other medications including opioids, stimulants, and benzodiazepines (McNemar's test for symmetry; p<0.001), indicative of symptom improvement. Medical cannabis was also well-tolerated within the multiple sclerosis patient population. The most common adverse reaction observed was somnolence (6%). No significant weight change was noted over 335 day average duration of therapy. A low rate of discontinuation (14%) was observed, most frequently due to cost (36%) and lack of efficacy (36%).

Conclusions:
Patients with multiple sclerosis who initiated medical cannabis treatment experienced improved symptomology with good tolerability and were able to decrease or altogether discontinue opioids, stimulants and benzodiazepines. Further controlled studies are needed to confirm and clarify these results.

[Suebee]

Ditto! Thanks for keeping us informed.

I point out that it is yet another example of anecdotal evidence that something helps patients with "invisible disease" to later garner scientific proof....

[Fit Paul]

Amazing. Thanks for your work compiling this information.

[ActiveMSers]

This just posted. Interesting. - D

Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis

Sabrina Giacoppoa, Federica Pollastrob, Gianpaolo Grassic, Placido Bramantia, Emanuela Mazzona

Received 26 September 2016, Revised 11 November 2016, Accepted 19 November 2016, Available online 25 November 2016

Abstract

This study was aimed to investigate whether treatment with purified cannabidiol (CBD) may counteract the development of experimental multiple sclerosis (MS), by targeting the PI3K/Akt/mTOR pathway. Although the PI3K/Akt/mTOR pathway was found to be activated by cannabinoids in several immune and non-immune cells, currently, there is no data about the effects of CBD in the PI3K/Akt/mTOR activity in MS.

Experimental Autoimmune Encephalomyelitis (EAE), the most common model of MS, was induced in C57BL/6 mice by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35–55. After EAE onset, which occurs approximately 14*days after disease induction, mice were daily intraperitoneally treated with CBD (10*mg/kg mouse) and observed for clinical signs of EAE. At 28*days from EAE-induction, mice were euthanized and spinal cord tissues were sampled to perform immunohistochemical evaluations and western blot analysis.

Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR. Also, an increased level of BNDF in CBD-treated mice seems to be involved in the activation of PI3K/Akt/mTOR pathway. In addition, our data demonstrated that therapeutic efficacy of CBD treatment is due to reduction of pro-inflammatory cytokines, like IFN-γ and IL-17 together with an up-regulation of PPARγ. Finally, CBD was found to promote neuronal survival by inhibiting JNK and p38 MAP kinases.

These results provide an interesting discovery about the regulation of the PI3K/Akt/mTOR pathway by cannabidiol administration, that could be a new potential therapeutic target for MS management.

[ActiveMSers]

And another....

Cannabis controling spasticity

Posted: 25 Oct 2016 11:00 PM PDT

Squintani G, Donato F, Turri M, Deotto L, Teatini F, Moretto G, Erro R. Cortical and spinal excitability in patients with multiple sclerosis and spasticity after oromucosal cannabinoid spray. J Neurol Sci. 2016;370:263-268. doi: 10.1016/j.jns.2016.09.054.

BACKGROUND:*Delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) has been recently approved for the management of treatment-resistant multiple sclerosis (MS) spasticity. Although the symptomatic relief of Sativex® on MS-spasticity has been consistently demonstrated, the pathogenetic implications remain unclear and the few electrophysiological studies performed to address this topic yielded controversial results. We therefore aimed to investigate the mechanisms underpinning the modulation of spastic hypertonia by Sativex®, at both central and spinal levels, through an extensive neurophysiological battery in patients with MS.

METHODS:*Nineteen MS patients with treatment-resistant spasticity were recruited. Before and after 4weeks of treatment with Sativex® patients were clinically assessed with the Modified Ashworth Scale (MAS) and underwent a large neurophysiological protocol targeting measures of excitability and inhibition at both cortical [e.g., intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)] and spinal level [e.g., H-reflex, H/M ratio and recovery curve of the H-reflex (HRC)]. A group of 19 healthy subjects served as controls.

RESULTS:*A significant reduction of the MAS score after 4 weeks of Sativex® treatment was detected. Before treatment, an increase in the late facilitatory phase of HRC was recorded in patients compared to the control group, that normalised post treatment. At central level, SICI and LICI were significantly higher in patients compared to healthy subjects. After therapy, a significant strengthening of inhibition (e.g. reduced LICI) and a non-significant facilitation (e.g. marginally increased ICF) occurred, suggesting a modulatory effect of Sativex® on different pathways, predominantly of inhibitory type. Sativex® treatment was well tolerated, with only 3 patients complaining about dizziness and bitter taste in their mouth.

DISCUSSION: Our results confirm the clinical benefit of Sativex® on spastic hypertonia and demonstrate that it might modulate both cortical and spinal circuits, arguably in terms of both excitation and inhibition. We suggest that the clinical benefit was likely related to a net increase of inhibition at cortical level that, in turn, might have influenced spinal excitability.

[ActiveMSers]

And one more, this done with mice. Could it reduce inflammation? - D

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Cannabidiol mechanisms in the treatment of adoptively transferred EAE

C. González García1, J.A. García-Merino1, L. Campos Ruíz1, I. Moreno Torres1, R. García Hernández1, M.J. Coronado Albí2, A. García Grande3, L. Rodríguez Esparragoza1, A.J. Sánchez-López1 1Neuroimmunology, 2Confocal Microscopy Unit, 3Flow Citometry Unit, University Hospital Puerta de Hierro Research Institute, Majadahonda, Spain

Background: Cannabidiol (CBD), non-psychoactive cannabinoid, has been reported to bind cannabinoid receptors (CB1-CB2) with weak affinity, although its mechanisms of action are not clear. Previous results showed an improvement in clinical symptoms in adoptively transferred EAE (at-EAE) treated with CBD. This model avoids interferences of inflamed sites with encephalitogenic cell circulation and allows a better delineation of the effector phase of the disease.

Objectives: To analyze CBD in adoptively transferred EAE and to elucidate its mechanisms of action in vitro.

Methods: After at-EAE induction, clinical signs were evaluated in at-EAE+vehicle and at-EAE+CBD 50mg/kg/d. In vitro, expression of CB1, CB2 and GPR55 receptors was determined by confocal microscopy. Viability was studied by MTT assay in spleen reactive cells treated with CBD and/or CB1 or CB2 antagonists or GPR55 ligand (SR1, SR2 or lysophosphatidylinositol (LPI) respectively). Reactive species of oxygen (ROS) were determined by flow cytometry after pre-incubation with CBD. MRI of the brain was carried out at 7T.

Results: CB1, CB2 and GPR55 receptors were present in the encephalitogenic spleen cells. CBD culture decreased viability of these cells and this was not restored by pre-incubation with SR1, SR2 or LPI; furthermore, CBD treatment significantly elevated the level of total cellular ROS. Reduction in clinical signs correlated with a significant decrease of apparent diffusion coefficient values in the brain subiculum after CBD treatment.

Conclusions: Clinical signs and MRI findings after CBD treatment correlated with a reduced recruitment of inflammatory cells into the CNS. The decrease in infiltrating cells could be due to the diminished viability of encephalitogenic spleen cells found in vitro with CBD treatment, an effect related to ROS increase. The viability reduction of encephalitogenic cells, independent of CB1-CB2 and GPR55 receptors, may be one of the mechanisms through which this compound exerts its therapeutic action.

[ActiveMSers]

A few studies were released at the just-completed ECTRIMS conference. - D

Effect of THC/CBD oromucosal spray on spasticity in MS: an open label clinical-neurophysiological study

A. Nuara, A. Giordano, L. Ferrè, V. Martinelli, F. Martinelli Boneschi, F. Esposito, G. Comi, L. Leocani Ospedale San Raffaele, Milan, Italy

Background: Spasticity, manifesting as muscle stiffness, spasms and pain, is a frequent symptom of multiple sclerosis (MS), with a strong impact on quality on life of patients. Cannabis derivatives and endocannabinoid system modulator (such as Sativex, a THC/CBD oromucosal spray) have been reported to relieve symptoms of spasticity in MS. Despite demonstrated symptomatic relief of MS spasticity, few studies have investigated neurophysiological baseline characteristics on predicting treatment response, as well as the neurophysiological changes induced by theraphy with cannabinoids in MS.

Objectives: To assess the clinical-neurophysiological correlates of Sativex effect on spasticity in MS and the predictive value of neurophysiological baseline features on treatment response.

Methods: 20 outpatients affected by multiple sclerosis (6M, 14F, age 31-64, EDSS 4.0-7.5) with spasticity-associated symptoms (baseline spasticity NRS>4) underwent the following clinical evaluations at baseline (T0) and after a 4-week (T4) Sativex titration period: EDSS, 10 meters walking test, Ambulation Index (AI), Modified Ashworth Scale (MAS), spasticity and pain numerical-rating-scale (NRS). Neurophysiological baseline features (resting motor threshold [RMT], Motor-evoked-potentials [MEP's] amplitude of First Digital Interosseus [FDI] at 120% of RMT, intracortical inhibition/facilitation [ICI/ICF] were collected at T0 in the whole group ad in 10 patients at T4.

Results: From T0 to T4, a significant improvement of spasticity was observed, considering both subjective (NRS 7+1.45 vs 5.15+1.38, p=0.0001) and physician-reported (MAS 3.3+1.94 2.93+1.70) spasticity. No significant changes in neurophysiological measures were observed. Grouping patients according to treatment responsiveness (NRS improvement >20%, 9 responder), no significant differences were found in neurophysiological baseline features.

Conclusion: Our findings confirm the clinical benefit of Sativex on MS spasticity. The lack of both corresponding changes in corticospinal excitability and baseline neurophysiological predictors of efficacy, suggest the involvement of other neurophysiological mechanisms underlying Sativex effect on spasticity.

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The use of medical-grade Cannabis (Bedrocan®) in patients non-responders to nabiximols (sativex®)

F. Saccà1, C. Pane1, A. Carotenuto1, M. Massarelli1, R. Lanzillo1, E.B. Florio2, V. Brescia Morra1 1Department of Neuroscience, Reproductive, and Odontostomatological Sciences, Federico II University, 2Farmacia Florio Dr. Ettore SNC, Napoli, Italy

Introduction: Spasticity is one of the most common symptoms in Multiple sclerosis (MS). It causes disability, and is chronically present. Historical treatment includes several drugs with very limited patient and physician satisfaction. Nabiximols (Sativex®) is a cannabis extract containing a 1:1 ratio of delta-9-tetrahydrocannabinol to Cannabidiol. Several studies showed its superiority over placebo in reducing the Numeric Rating Scale (NRS). Unfortunately, half of treated patients do not respond to Nabiximols and for them therapeutic options are absent.

Methods: We retrospectively enrolled patients that had been treated with Nabiximols (Sativex®) for 28 days and were judged non-responders (reduction < 20% from baseline NRS), and were subsequently treated with medical-grade cannabis (Bedrocan®) for at least 28 days. Bedrocan was fractionized at authorized ISO 9001:2008 pharmacies into 50 mg sachets. Patients were instructed to take Bedrocan at a dose of 50-100 mg /day.

Results: We found 13 patients (Table 1) corresponding to our inclusion criteria. Non-response to Nabiximols was caused by insufficient NRS reduction for all patients. Bedrocan was administered orally to eleven patients, and through smoking for two. Mean NRS for Nabiximols Baseline was 7.6±1.5 and 7.4±1.6 after 28 days (-0.2; CI -0.65, +0.15; p=0.493). Mean NRS for Bedrocan baseline was 7.6±1.8 and 5.3±2.4 after 28 days (-2.3; CI -3.58, -1.12; p< 0.001). Patients continued Bedrocan administration for 205±182 days (range 46-700). Two patients suspended therapy, one for the onset of dizziness, and the other for the drug's cost. Mean NRS at follow-up was 5.6±2.3, resulting in a significant reduction as compared to baseline (-2.0; CI -.2.9, -1.2; p< 0.001). During Bedrocan therapy, only 3 AEs were reported in three patients, as compared to 15 AEs in 11 patients during Nabiximols treatment (Odds Ratio 5.0; CI 1.45, 17.27; p< 0.02).

Discussion: This is the first study that investigates rescue strategies for Nabiximols non-responders. Bedrocan was very well tolerated with 85% responders at 28 days and 70% at the end of the individual follow-up. This is a high response rate if compared to previous trials. Future randomized, placebo-controlled studies are necessary to conclude, at a higher class of evidence, that medicinal-grade cannabis is a good option for Nabiximols non-responders.

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Nabixol (Sativex) in spasticity responders multiple sclerosis patients is effective on subjective but not on objective measures of walking ability

C. Solaro1, E. Trabucco2, M. Cella1, A. Mattioda3, S. Masera3, P. Cavalla3 1ASL3 Genovese, genova, 2Università di genova, of Experimental Medicine, Section of Diagnostic Radiology, 3Centro SM, Dep. of Neuroscience, AOU Città della Salute e della scienza, torino, Italy

Background: Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) [Sativex(®)] is an oromucosal spray formulation is approved in a number of countries, included Italy, as add-on therapy for moderate-to-severe multiple sclerosis (MS) treatment-resistant spasticity symptoms.

Objective: The aim of the study is to provide real- life observational data of effect of Sativex on walking objective measures and patients' perceptions of the impact of MS on walking ability

Materials and methods: This was an observational, prospective study conducted in 2 italian MS centres. Patients with moderate to severe spasticity, with a score at the numerical rating scale (NRS) greater than 4 were included in the study. A battery of tests including Symbol Digit (SDT), Nine Hole Peg Test (9HPT), Fatigue Severity Scale (FSS), 12-item Multiple Sclerosis Walking Scale (MSWS-12), Two Minutes Walking Test (2MWT) and Timed 25-foot Walk (T25FW) was performed at baseline (T0) and 30 days later (T1). Responders had been defined by the literature as subjects with an improvement at the NRS score for spasticity greater than 20%

Results: Out of 75 subjects enrolled 33 were female and 42 male. Mean age was 53.7 years (range 28.26 - 81.43) , mean disease duration 13 years (range 0.7 - 39), 25 (29.3%) subjects had relapsing remitting, 34 (45.3%) secondary progressive and 19 (25.4%) had primary progressive disease course. Mean EDSS score was 6.2 (range 4 - 8.5).
A significant improvement (>20%) at NRS was observed in 49 patients (responders), 26 patients were classified as “no responders”.
Considering patients able to walk (EDSS < = 6.5, n°32) mean NRS for spasticity at T0 was 7.9 (range 1-10) in 20/32 patients mean score decreased greater than >40%. MSWS-12 score decreased more than 6 points in 19/32 patients and an improvement (>20%) in FSS was reported in 5/32 subjects.
An improvement (>20%) in walking speed (T25FW) was observed in 2/32 patient and in endurance (2MWT) in only 1/32 patients. No patients improved in 9HPT and SDT

Conclusions: Real-life data confirm Sativex(®) as an effective on spasticity (65.3% responders) and well tolerated treatment option for MS patients. A positive effect was highlighted on measuring patients' perceptions of walking scale such as fatigue and MS12 while an effect on objective measures on walking performance was not found.