Dr Eli Silber, Kings College Hospital

1. Cannabis, the good, the bad
and the ugly
Dr Eli Silber
Kings College Hospital

3. Outline
 What is cannabis
 Where does it act/ how and
why may it work?
 Legal position
 Is it disease modifying?
 What symptoms may it
alleviate
 Real life use
 Personal suggestions

4. Cannabis contains over 500
chemical compounds
 Cannabidiol (CBD) Not
psychoactive
 Δ9 tetrahydrocannabinol
(Δ9-THC). Psychoactive “high”

5. G Protein coupled receptors
 Receptors on cell
membrane
 Can affect hundreds of
secondary messengers in
the cell.
 Therefore a variety of
effects.
 The body produces our
own endocannibinoids

6. Cannabis receptors are
spread throughout the body
 CB-1: Mainly CNS
(also lungs, liver,
kidney)
 CB-2 CNS and
Peripheral, including
immune and
haematopoietic cells

7. Spread of cannabis

8. Changes in the USA

9. Changes in the USA
a paradigm shift

10. International legal position
Blue Legal, Yellow decriminalised, pink unenforced, red illegal

11. UK position (2019)
 Class B (Misuse of drugs act 1971)
 If <0.2% THC legal for distribution as artisanal products
 No consistent quality control
 2016 MHRA all classified as medicines and require a
product license.
 July 2018 cannabis based products can be prescribed by
senior clinicians (later limited)
 Still prosecutions for medicinal use

12. The Evening Standard

13. Uses: if it sounds too good to
be true…

14. Is cannabis disease
modifying in MS?
 CB-2 receptors on a variety of immune cells esp. B
Lymphocytes > macrophages and monocytes
 Also CB-2 receptors on immunocompetent cell in
the CNS and neurons
 ? Neuroprotective
 Trialled in animal models of MS (EAE), Stroke

15. Direct suppression of CNS autoimmune inflammation via the
cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells.
K Maresz, Nature medicine, 2007

16. Neuroprotection in Experimental Autoimmune Encephalomyelitis and
Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids;
Pryce et al 2014.

17. CUPID Study
 Progressive MS
 Dronabinol: contains the
principal psychoactive
constituent Δ⁹-
tetrahydrocannabinol,
found in cannabis.
Dronabinol does not
include any other THC
isomers or any cannabidiol.
 Was this the best substance
to choose?

18. CUPID Study

19. CUPID Study

20. Thus far insufficient
evidence as a DMT
 Repeat trials with different compounds?
 Use in combination?
 Do we have more potent DMTs to try?

21. Management of MS
symptoms
May have beneficial
effects
 Spasticity
 Pain
 Diplopia/ Oscillopsia
 Bladder
 Mood
 Sleep
Unlikely to have effects
 Gait
 Coordination
 Optic nerve damage
 Speech/ Swallow
 Bowels
 Sex
 Cognition
 Fatigue

22. Measurement of symptomatic
benefit can be difficult
 How do you measure
subjective responses such as
pain, spasticity, sleep, mood
 We sometimes measure what
we can and then ascribe
importance to it
 How good is the correlation
between objective measures
such as number of times
urinating compared to effects
on QOL

23. Calculating costs for
symptomatic therapies
 Cheap therapies have to
jump through fewer hoops
than more expensive
therapies.
 Do our value judgments
affect how we calculate
benefits?
 Longevity thus potentially
long treatment courses
 It is more challenging
calculating efficacy in
therapies when there are a
small group of patients who
have a significant response
Quality adjusted life years
All patients have a 10% improvement
1.0 x 0.1= 10% improvement
VS
20% of patients have a 50% improvement
0.2 x 0.5 = 10% improvement
Equal from health economic but not clinical perspective

24. Research to date

25. Apples and pears?

26. Spasticity

29. Enriched study design
all on therapy initially, responders
randomised to Sativex or placebo

30. Enriched study design
all on therapy initially, responders
randomised to Sativex or placebo

31. Sativex meta analysis

32. Sativex: Italian study
F Patti et al. J Neurol Neurosurg Psychiatry 2016;87:944-951
Results A total of 1615 patients were recruited from 30
MS centres across Italy. After one treatment month
(trial period), we found 70.5% of patients reaching a
≥20% improvement (initial response, IR) and 28.2%
who had already reached a ≥30% improvement
(clinically relevant response, CRR), with a mean NRS
score reduction of 22.6% (from 7.5 to 5.8). After a
multivariate analysis, we found an increased
probability to reach IR at the first month among
patients with primary and secondary progressive MS,
(n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among
patients with >8 NRS score at baseline (OR 1.8 95% CI
1.3–2.4 p<0.001). During the 6 months observation
period, 631(39.5%) patients discontinued treatment.
The main reasons for discontinuation were lack of
effectiveness (n=375, 26.2%) and/or adverse events
(n=268, 18.7%).

33. Sativex: Italian study
F Patti et al. J Neurol Neurosurg Psychiatry 2016;87:944-951

34. About 60% of patients treated for spasticity
remain on therapy (efficacy and side-effects)
Sativex in resistant multiple sclerosis spasticity: Discontinuation study in a large population
of Italian patients (SA.FE. study)
; Solaro

35. Meta analysis of patient
rating scale for spasticity

39. Neurogenic bladder

40. Neurogenic bladder: Management

41. Cannabis may be helpful in
treating bladder dysfunction
 The reduction in daily number of urinary incontinence episodes from baseline
to end of treatment (8 weeks) showed little difference between Sativex and
placebo. Four out of seven secondary endpoints were significantly in favour of
Sativex: number of episodes of nocturia, Overall Bladder Condition, Number
of voids and daytime voids /day and patients global impression of change.
The improvement in I-QOL was in favour of Sativex but did not reach
statistical significance. Kavia 2010.
 The effect of cannabis on urge incontinence in patients with multiple sclerosis:
a multicentre, randomised placebo-controlled trial (CAMS-LUTS). The CAMS
study randomised 630 patients to receive oral administration of cannabis
extract, Delta(9)-tetrahydrocannabinol (THC) or matched placebo. For this
substudy subjects completed incontinence diaries. RESULTS:All three groups
showed a significant reduction, p<0.01, in adjusted episode rate (i.e. correcting
for baseline imbalance) from baseline to the end of treatment: cannabis extract,
38%; THC, 33%; and placebo, 18%. Both active treatments showed significant
effects over placebo. Freeman

42. Cannabis Is it a medicine or a social
drug?
Social drug
 Freedom of choice
 Harm reduction
 Risks v.s. other social drugs
e.g. alcohol
 Legislate for safety/
consistency
 Tax
Medicine
 Compare to other drugs of
similar efficacy
 Evidence of efficacy rather
than just no/ limited harm

43. Adverse effects
 Neuropsychiatric “high”
 Drowsy
 Dizzy/ ataxic
 Cognitive
 Psychosis risks
 Smoking risks
 Balance against other drugs e.g.
baclofen, gabapentinoids

44. Adverse effects
The most common adverse
effects were drowsiness (30%),
feeling quiet/subdued (23%)
and dizziness (13%). Banwell
Cupid study: Dronabinol

45. What proportion of PwMS try an
use cannabis for medicinal
purposes?
 About 47% have considered using, 26% have tried, 16%
currently use. (Cotfield 2017)
 49% had used cannabis at least once. Cannabis was used within the
past year (current user) by 21%, and only 21% of those received
prescribed cannabis-based medicine. Recreational use was reported
by 17%. The primary reasons for use were to alleviate pain (61%),
spasticity (52%) and sleep disturbances (46%). Gustavsen 2019
 54.3%s approved of the drug while 75 (33.2%) were neutral. Legalization
was endorsed by 98 (43.7%) participants, while 98 (43.7%) were in favour
of legalization for medical use only. Current use was endorsed by 44
(19.5%) people with 125 (56.1%) reporting lifetime use. If cannabis were
legal, 113 (50.2%) participants would use it. The most common symptoms
for which cannabis was being used were: sleep (86%), pain (75%), anxiety
(73%) and spasticity (68%). Banwell 2016

47. Cannabis use amongst people with
MS in the South East
 109 (43%) had ever used cannabis
 59 (23%) started use after diagnosis (90% for MS symptoms)
 30% reported use to attempt to relieve symptoms
 46 (18%) used in last month, 12% to relieve MS symptoms
 Most common symptoms pain and spasticity
 Most 1-5 doses/ week, 5> 20

48. Patterns of use
Risks for use
 Married/ cohabiting
 Smokers
 Increased lower limb
disability
 Symptoms that used
for: pain, spasticity,
bladder, sleep

49. (Most of) our patients are
not silly

50. Why is there resistance?
 Illicit drug (but what about
opioids)
 “Black drug” in the USA
 Grey area between recreational
and medicinal use
 Lack of pharmaceutical
company support
 Medicinal forms are expensive

51. What about
opioids?

52. In summary
 Cannabinoids have been around for millennia and are
variable in constituents and potency
 They work in a variety of ways in both the central and
peripheral nervous system
 There is insufficient evidence thus far to suggest that
they have a substantial disease modifying effect.
 Like other symptomatic medications there may be
variable responses
 There is often an overlap with MS symptoms including
spasticity, pain, sleep and mood

53. In summary
 Many of our patients try and then continue to use
cannabinoids to manage symptoms
 They are not a panacea but have a valuable role in the
management of symptoms resistant to other therapies, in
particular pain and spasticity.
 They are generally well tolerated and have a similar risk
profile compared to other symptomatic therapies for
spasticity and neuropathic pain
 There is a need for more good quality trials in all
symptomatic therapies, including cannabinoids.
 Cannabinoids should be incorporated into care pathways
for symptom relief in MS.