Medicinal Cannabis - an update

Medicinal Cannabis
– an update
Dr Mahesh Jayaram
Consultant Psychiatrist
Editor Cochrane Schizophrenia Group
Senior Lecturer, Department of Psychiatry and MNC
University of Melbourne

Disclosures
I have not accepted any financial benefits from any
pharmaceutical company.
I received a grant of $10,000 from Western Health
Hospital research fund to run a pilot study on
cannabidiol and have applied to the NHMRC for
further funding.
I am having ongoing discussions with BSPG, Austria
to import cannabidiol into Australia
www.drmaheshjayaram.com

Case scenario 1
Mary and Rod come to see you as worried
parents of 16 year old Samantha. There is a
history of schizophrenia in their family - 2 of
Samantha's older cousins and an aunt. They
have caught Samantha smoking joints with her
friends, twice after school.
They wonder what is the role of cannabis in
schizophrenia. Does it cause it? Could it help?

Endo-cannabinoid-Mediated Control of Synaptic Transmission
Kano et al 2009 Physiol Rev 89: 309–380, 2009
2-arachidonoylglycerol

Can you predict who develops
schizophrenia?
Genetic
liability
to
psychosis
Environmental
and genetic
factors
Cannabis
use
initiation
Psychosis
Age of 1st use
Pattern of
cannabis use
Genetic
susceptibility to
cannabis effect

Genetic
liability
to
psychosis
Environmental
and genetic
factors
Cannabis
use
initiation
Psychosis
Age of 1st use
Pattern of
cannabis use
Genetic
susceptibility to
cannabis effect
Can you predict who develops
schizophrenia?

Kendler:
- initiation and early
patterns of use are
more environmental
factors
- later use and
abuse/dependence,
has some genetic
mediation
Regular Cannabis
Users
8% to 15%
with schizophrenia
Cannabis use and subclinical
psychosis…
– is it causal or self medication?

Evidence for Cannabis + Psychosis
• Christchurch study (examined people aged 18,
21 and 25):
– Cannabis use was causal > self medication
• Meta-analysis of prospective epidemiological
studies:
– Cannabis use predicts onset of psychotic disorder
– Associated with sub-threshold expression of
psychosis
• either in the form of schizotypy
• or subclinical psychotic experiences

Swedish conscript study
• 50,087 conscripted men
• Followed up over 15 years
• Heavy users (>50 times) before age of
18

Swedish conscript study
Results after 27 years
(OR 3.1 CI 1.7 to 5.5):
General population:
1% 6.7%

Dunedin birth cohort
1037 individuals born and followed up.
Of those who used cannabis aged 15, the
following number were diagnosed with
schizophrenia:
1972 1973

Dunedin birth cohort
1037 individuals born between 1972 and 1973
were followed up - 10.3% of those who used
cannabis aged 15 were diagnosed with
schizophrenia 26 years later
Results
(After 26 years):
General population:
1% 10.3%

Theresa HM Moore, Stanley Zammit, Anne Lingford-Hughes, Thomas RE Barnes, Peter B Jones, Margaret Burke, Glyn Lewis
Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review
null, Volume 370, Issue 9584, 2007, 319–328
Psychosis following cannabis use
Line of no
difference
Pooled result

Crude (a) and adjusted (b) odds ratios for suicide and schizophrenia
in relation to frequency of cannabis use.
Ceri Price et al. BJP 2009;195:492-497 www.drmaheshjayaram.com

Arch Gen Psychiatry. 2011;68(2):138-147. doi:10.1001/archgenpsychiatry.2010.132
Genetic vulnerability?

Brain volume changes in cannabis
users

Yücel et al Arch of Gen Psy 2008
Brain volume
changes in
cannabis users

Is CBD protective?
Solowij et al 2016

Emerging strategies for exploiting cannabinoid receptor agonists as
medicines
British Journal of Pharmacology
Volume 156, Issue 3, pages 397-411, 17 FEB 2009 DOI: 10.1111/j.1476-5381.2008.00048.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2008.00048.x/full#f1

Case scenario 2
Some family members cornered you at a recent
family gathering, asking about your opinion of
the role of cannabis in mental health problems -
they had read a blog that had argued
that cannabis should be promoted as a
substance for treating anxiety/mood disorders.
Is there any truth in this assertion?

Cannabis and depression

Cannabis and depression
• 14 studies included were included in the quantitative
analysis (total number of subjects = 76058).
• The OR for cannabis users developing depression
compared with controls was 1.17 [95% confidence
interval (CI) 1.05-1.30].
• The OR for heavy cannabis users developing depression
was 1.62 (95% CI 1.21-2.16), compared with non-users
or light users.
Lev-Ran et al The association between cannabis use and depression: a
systematic review and meta-analysis of longitudinal studies. Psychol Med. 2014
Mar;44(4):797-810 www.drmaheshjayaram.com

Meta analysis of 31 Studies:
Association between anxiety disorders and cannabis use or
cannabis-use disorders in the general population
Kedzior and Laeber BMC Psychiatry. 2014; 14: 136.
Positive association

Case scenario 3
Harry comes to see you. He is a patient with chronic
persisting back pains for 10 years, following a
workplace injury. Work cover issues are behind him
now, and he has undergone two pain management
programs in the past 5 years. These have helped him
approach life more productively, but his daily pain gets
him down. He comes in today wondering about
cannabis. He's read it can be used for pain relief and
would like to try it, if you thought it would work.
Does cannabis have a role on chronic pain
management?

Hello Dr Jayaram,
I understand you will be speaking at GP ADD 2016 on medicinal cannabis.
I hope that you are fully aware of the suffering because of others not
doing what they should be!
I personally suffer from chronic arthritis and cannabis helps me a great deal. I
do not know the science behind this and I don't care. What I do care about is
healthcare practitioners sitting on their hands while others suffer.
Please be aware of it. When I can't get access to cannabis, pain comes back to
me and I get extremely angry during those times, like now. I suffer as I write
this because our health practitioners are not standing up enough.
Please do whatever you can. Thank you.
Regards,

Emerging strategies for exploiting cannabinoid
receptor agonists as medicines
British Journal of Pharmacology
Volume 156, Issue 3, pages 397-411, 17 FEB 2009 DOI: 10.1111/j.1476-5381.2008.00048.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2008.00048.x/full#f1

Cannabis related drugs
2000
1980
1981: 1985:
Nabiximols (Sativex®)
• Contains +/- equal
amounts Δ9-THC &
cannabidiol.
• Prescribed for pain
relief in neuropathic
pain in adults with MS
& as an adjunctive
analgesia for adult
patients with advanced
cancer.
2005:
1990
1992:

Case scenario 4
Sally, a long term patient, recently underwent biliary surgery
and has just been discharged. You note the discharge
summary mentioned intractable post-operative nausea for
over a week, before it eventually subsided, delaying her
expected discharge.
She was approached about taking part in a clinical trial, which
she had declined: "They said they were testing to see
if cannabis would help with my nausea/loss of appetite. I said
no because I don't 'do drugs', but now I wonder if I would
have been better off trying it. That week was awful.”
What do we know about the role of cannabis as an anti-
emetic?

Cannabis as an anti-emetic
An
overlooked
victim?
Should we
consider it?
What is
the
evidence?

Cannabis related drugs
2000
1980
1981:
Nabilone (Cesamet®)
• First of the CB1/CB2
receptor agonist,
• Synthetic Δ9-THC
analogue
• Licensed for
suppression of nausea
and vomiting
produced by
chemotherapy.
1985:
Dronabinol (Marinol®)
• Δ9-THC is also a
licensed medicine.
• Licensed as anti-
emetic & in 1992 as
an appetite
stimulant, for
example for AIDS
patients
experiencing
excessive loss of
body weight.
Nabiximols (Sativex®)
• Contains +/- equal
amounts Δ9-THC &
cannabidiol.
• Prescribed for pain
relief in neuropathic
pain in adults with MS
& as an adjunctive
analgesia for adult
patients with advanced
cancer.
2005:
1990
1992:

Efficacy, tolerability, and safety of cannabinoids for
chemo-induced N&V
Systematic review (incl 6 RCTs):
Tafelski et al, Efficacy, tolerability, and safety of cannabinoids for chemotherapy-induced nausea and
vomiting-a systematic review of systematic reviews. Schmerz. 2016 Feb;30(1):14-24.
CONCLUSIONS:
CBs not recommended as 1st or 2nd line therapy for CINV.
Some guidelines recommend pharmaceutical CBs as 3rd-line treatment in the
management of breakthrough nausea and vomiting.
Control arm:
Placebo or conventional
antiemetics
Treatment arm:
Dronabinol, levonantradol, and
nabilone or whole plant extract
(e.g., nabiximol)
RESULTS:
Moderate quality evidence that CBs LESS tolerated and LESS safe than placebo
or conventional antiemetics in CINV.
VS

Cannabinoids for nausea and vomiting in adults with cancer receiving
chemotherapy
Cochrane Database of Systematic Reviews
12 NOV 2015 DOI: 10.1002/14651858.CD009464.pub2
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009464.pub2/full#CD009464-fig-00103
Cannabinoid vs placebo
Outcome: Absence of nausea and vomiting
2.86 [1.76, 4.65]

Cannabinoids for nausea and vomiting in adults with cancer receiving
chemotherapy
Cochrane Database of Systematic Reviews
12 NOV 2015 DOI: 10.1002/14651858.CD009464.pub2
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009464.pub2/full#CD009464-fig-00201
Cannabinoid vs other antiemetics
Outcome: Absence of nausea
More adverse effects and withdrawal from study compared with prochlorperazine
1.46 [0.67, 3.15]

Case scenario 5
Isaac saw your GP colleague a month ago when he came in quite
distressed, anxious about his finances, having missed that day's
work saying "stress is so bad I had to stay home. Smoking a joint
was the only thing that calmed me down.” Further history revealed
a growing debt problem due to cannabis use and repeated
absenteeism. When asked whether Isaac thought he had a problem
with cannabis, he replied "'Choof''s not addictive... it's just too
expensive". Your colleague issued Isaac a medical certificate for a
day's absence from work, on the proviso that he return to further
discuss his drug use/work situation. He reluctantly agreed. He
returns today, booking in to see you instead.
How do you assess if a patient is addicted to cannabis? Is there a
role for cannabinoid pharmacotherapy in this context?

Cochrane review
• 14 RCTs
• 958 cannabis-dependent participants
• Average age – 33 years
• 10 Studies in USA, 3 in Australia, 1 in Israel
Drugs studied
• THC, SSRIs, combination antidepressants,
mood stabilisers (e.g. gabapentin), glutamate
modulator (NAC)

Case scenario 6
Jeremy, a patient in his 30s, has just been diagnosed with
multiple sclerosis. Whilst shocked at his diagnosis and the possible
poor prognosis, he's pleased he's currently able to maintain his
independence, driving to his work and girlfriend's house, looking
after himself at home. His neurologist however informed him that
his current mild tremor and pain may progress to a point where he
would be unfit to drive. There is a clinical trial being promoted in
the outpatient clinic, which looks at cannabis for MS related tremor
and pain. He is considering participating in this trial. He comes in to
ask your advice regarding the legalities of medicinal cannabis,
especially regarding his driving.
Does cannabis help these symptoms? What if he was drug-driving
tested, whilst driving? What would happen?

Thank you for your participation.
Please contact me at:
mahesh.jayaram@unimelb.edu.au

Medicinal Cannabis - an update

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