Medicinal Cannabis - an update

Medicinal Cannabis – an update

Dr Mahesh JayaramConsultant Psychiatrist

Editor Cochrane Schizophrenia GroupSenior 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

http://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 liabilityto

psychosis

Environmental and genetic

factors

Cannabis use

initiation

Psychosis

Age of 1st use

Pattern of cannabis use

Genetic susceptibility to cannabis effect



Genetic liabilityto

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?www.drmaheshjayaram.com


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 useLine 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 www.drmaheshjayaram.com


Is CBD protective?

Solowij et al 2016 www.drmaheshjayaram.com


Emerging strategies for exploiting cannabinoid receptor agonists as medicines

British Journal of PharmacologyVolume 156, Issue 3, pages 397-411, 17 FEB 2009 DOI: 10.1111/j.1476-5381.2008.00048.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2008.00048.x/full#f1 www.drmaheshjayaram.com

http://onlinelibrary.wiley.com/doi/10.1111/bph.2009.156.issue-3/issuetoc

http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2008.00048.x/full%23f1


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 associationwww.drmaheshjayaram.com


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,www.drmaheshjayaram.com


Emerging strategies for exploiting cannabinoid receptor agonists as medicines

British Journal of PharmacologyVolume 156, Issue 3, pages 397-411, 17 FEB 2009 DOI: 10.1111/j.1476-5381.2008.00048.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2008.00048.x/full#f1 www.drmaheshjayaram.com

http://onlinelibrary.wiley.com/doi/10.1111/bph.2009.156.issue-3/issuetoc

http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2008.00048.x/full%23f1


Cannabis related drugs

20001980

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

20001980

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 Reviews12 NOV 2015 DOI: 10.1002/14651858.CD009464.pub2http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009464.pub2/full#CD009464-fig-00103

Cannabinoid vs placeboOutcome: Absence of nausea and vomiting

2.86 [1.76, 4.65]


http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009464.pub2/full%23CD009464-fig-00103


Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy

Cochrane Database of Systematic Reviews12 NOV 2015 DOI: 10.1002/14651858.CD009464.pub2http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009464.pub2/full#CD009464-fig-00201

Cannabinoid vs other antiemeticsOutcome: Absence of nausea

More adverse effects and withdrawal from study compared with prochlorperazine

1.46 [0.67, 3.15]


http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009464.pub2/full%23CD009464-fig-00201


Case scenario 5Isaac 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 6Jeremy, 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.

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Medicinal Cannabis - an update