Research Updates

The evaluation of the therapeutic potential of cannabis medicine is the subject of research both within Australia and internationally. Significant developments will be updated in this section.

This website publishes only peer-reviewed articles that have been published in scientific or medical journals.  Peer-reviewed articles have been evaluated by subject matter experts and an editorial board for scientific accuracy, consistency, clarity and how the research adds to our knowledge and understanding.
 
Recent articles and reports can be found below.

Clinical trial outcomes reported in peer-reviewed journals and presented at conferences can be found at the bottom of this page.

National evidence review 

The Commonwealth Department of Health through the Therapeutic Goods Administration (TGA), and with the support of the NSW, Victorian and Queensland state governments, commissioned a team to review the available scientific evidence for the use of cannabis medicines in five areas. Under the coordination of the National Drug and Alcohol Research Centre (NDARC) this included research experts from the University of NSW, the University of Sydney and the University of Queensland. Information about the clinical trials and studies identified in the review can be found here.

Recent articles and reports from the peer-reviewed literature

A prospective observational study of problematic oral cannabinoid use

A prospective observational study of problematic oral cannabinoid use 
Ware, M.A., Martel, M.O., Jovey, R. and Singer, J. (2017) Psychopharmacology doi: 10.1007/s00213-017-4811-6

The study examined the incidence of problematic prescription cannabinoid use (PPCBU) in 265 patients over 12 months initiating cannabinoid therapy, and factors associated with PPCBU. PPBCU is commonly used to describe any problematic drug-related behaviors that arise over the course of therapy; and may also reflect more serious problems e.g. prescription drug misuse, addiction, diversion. Patients were prescribed oral cannabinoids (89.7% used nabilone; 9.2% used Sativex; 1.1% used Sativex in addition to nabilone) and completed baseline questionnaires assessing demographic, clinical, and substance use variables. Patients were assessed for PPCBU at 3, 6, and 12 months. 105 patients completed the study.

RESULTS: 

  • At any follow-up time point, 25.6% of patients demonstrated PPCBU. Psychiatric history was significantly associated with PPBCU, with depression, anxiety and insomnia cited. Tobacco and daily herbal cannabis use were also significantly associated with PPCBU. Past-year substance abuse was the strongest predictor of PPCBU. 
  • Discontinuation of the trial was mostly due to lack of efficacy and/or financial reasons. Early termination was most frequently due to adverse events. 
  • Findings suggest that PPCBU should be routinely assessed and monitored over the course of treatment.

Cannabinoid Disposition After Human Intraperitoneal Use: An Insight Into Intraperitoneal Pharmacokinetic Properties in Metastatic Cancer

Cannabinoid Disposition After Human Intraperitoneal Use: An Insight Into Intraperitoneal Pharmacokinetic Properties in Metastatic Cancer 
Lucas, C.J., Galettus, P., Song, S., Solowij, N., Reuter, S.E., Schneider, J. and Martin, J.H. (2018) Clinical Therapeutics doi: 10.1016/j.clinthera.2017.12.008

The authors discuss the cases of two patients with stage IV ovarian cancer that presented to NSW hospitals with adverse effects following intraperitoneal injection of cannabis. Case 1 presented to hospital 2 days after receiving 12 g of unknown cannabis solubilised in coconut oil into the abdomen, with fevers, abdominal distension and severe pain, vomiting, anorexia, dehydration and confusion. Clinicians predicted blood THC concentration at time of presentation was ~60ng/mL (>5 ng/mL being associated with substantial cognitive and psychomotor impairment) and THC concentration predicted to remain above 5ng/mL about 49 days after administration. Case 2 presented with abdominal distension and pain, decreased mobility, a 1-day history of increased drowsiness, and other symptoms. The authors highlight the unknown pharmacokinetic properties of cannabis administered intraperitoneally. However the assessment of the two cases provides insight into absorption and distribution of cannabis administered intraperitoneally, particularly in an advanced cancer setting. 


"Positive" urine testing for Cannabis is associated with increased risk of traffic crashes

Positive urine testing for Cannabis is associated with increased risk of traffic crashes

Del Balzo, G., Gottardo, R., Mengozzi, S., Dorizzi, R.M., Bortolotti, F., Appolonova, S. and Tagliaro, F. (2018) Journal of Pharmaceutical and Biomedical Analysis doi: 10.1016/j.jpba.2017.12.059 

The study assessed the association between cannabis and traffic accidents. The authors compared the frequency of a positive urine for a secondary metabolite of delta-9-tetrahydrocannabinol (THC-COOH) in drivers involved in traffic accidents and admitted to hospital for injuries (n = 1406) with a control population undergoing mandatory urine drug testing (n = 1953). A positive reading was a concentration of THC-COOH of >15 ng/mL. Samples positive for other controlled drugs in urine or blood alcohol in concentrations >0.5 mg/mL were excluded.
  
The authors found an association between cannabis use identified through urine samples positive for THC-COOH and traffic accidents with injuries to the driver. Study limitations include higher cut-off limits for other psychoactive drugs which could impair drivers; and not controlling for other factors which could contribute to a higher incidence of traffic accidents. These include medical conditions, use of other medications, fatigue and distractions The paper does not comment on when the cannabis was last used, route of administration or strength of THC.

Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model

Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model
Wray, L., Stott, C., Jones, N. and Wright, S. (2017) Cannabis and Cannabinoid Research doi: 10.1089/can.2017.0032

In vitro studies (studies undertaken outside living organisms such as animals and humans) have shown that cannabidiol (CBD) can be converted to delta-9-tetrahydrocannabinol (THC) with prolonged exposure to simulated gastric fluid. However, this may not be representative of the effect in vivo (in studies undertaken in living organisms). Synthetic CBD (100 mg/mL) was administered twice daily to 3 minipigs (miniature pigs) in 15 mg/kg doses for 5 consecutive days. Blood samples were taken before and 1, 2, 4, and 6 hours after morning doses on days one and five.

RESULTS
: 

  • THC and the metabolite 11-OH-THC were not detected in any of the gastrointestinal tract samples, confirming that standard clinical doses of CBD in a sesame oil formulation do not convert to THC in the minipig.
  • The authors comment caution should be taken when extrapolating in vitro results to the in vivo situation and suggest clinical trials measuring 11-COOH-THC and THC may be required to confirm that the conversion of CBD to THC does not occur in vivo.

Second-Hand Exposure of Staff Administering Vaporised Cannabinoid Products to Patients in a Hospital Setting

Second-Hand Exposure of Staff Administering Vaporised Cannabinoid Products to Patients in a Hospital Setting
 
The study was undertaken to determine whether patients, nurses, and clinical or research staff are at risk of exposure to delta-9-tetrahydrocannabinol (THC) through second-hand vapours when administering vaporised products to patients. Two staff provided blood samples after administering 6mg THC to three patients using a vaporiser (the authors’ commenting this is a relatively low dose of THC). Four blood samples were collected from the two staff over 2.5 hours. The first sample was taken before drug administration and the remaining three tests were taken 5 min after each of the three patients completed inhalation of THC, with participants spaced approximately 1 hour apart. The limit of quantitation was 0.5 ng/mL for THC and the metabolites OH-THC and COOH-THC. The limit of detection was 0.2 ng/mL for THC, 0.15 ng/mL for OH-THC and 0.25 ng/mL for COOH-THC.

RESULTS: 

  • no cannabinoids were detected in plasma from either staff member at any of the time points. Urinary and salivary tests for THC were also negative. 
  • Further studies are warranted with larger sample size, more time points, alternate vaporisers, and with vaporisation of cannabis plant matter

The Achilles Heel of Medical Cannabis Research—Inadequate Blinding of Placebo-Controlled Trials

The Achilles Heel of Medical Cannabis Research—Inadequate Blinding of Placebo-Controlled Trials
Casarett, D. (2017) JAMA Internal Medicine doi:10.1001/jamainternmed.2017.5308

The author examines inadequate blinding, a common flaw of placebo-controlled trials of cannabis and cannabis medicines. Inadequate blinding occurs when the trial participants are able to distinguish between the active cannabis medicine and the placebo. This is a particular problem for trials of cannabis medicines because patients are able to detect the psychoactive effects of THC which are hard to mimic in a placebo. Where patients know that they are receiving an active treatment and not a placebo, the trial results tend to overestimate actual benefits as patient experiences are often driven by their expectations. 
The author gives an example of a recent placebo-controlled crossover trial of cannabis for pain where 14 out of 15 participants who were first assigned to active cannabis guessed their treatment correctly. Of the participants who received placebo cannabis first, only 5 of 13 guessed correctly, but 12 of 13 guessed correctly when they crossed over to active cannabis.
 
The author proposes four ways trials could to improve blinding:

  • Include a psychoactive placebo control which mimics the effect of THC;
  • Recruit participants to the trial who are naïve to cannabis use and therefore potentially less likely to accurately determine if they are receiving the placebo;
  • Assess the adequacy of blinding by assessing subjective sensations of physiologic and psychological effects;
  • Evaluate cannabis medicines enriched for CBD, which does not have the psychoactive effects of THC.

Labelling Accuracy of Cannabidiol Extracts Sold Online

Labelling Accuracy of Cannabidiol Extracts Sold Online
Bonn-Miller, M.O., Loflin, M.J.E., Thomas, B.F., Marcu, J.P., Hyke, T. and Vandrey, R., (2017) JAMA doi: 10.1001/jama.2017.11909

The authors examined the label accuracy of CBD products sold online, including identification of cannabinoids found present in products but unlabelled. 84 products from 31 companies were purchased and analysed. Product labels were sent for analysis of cannabinoid content (cannabidiol, cannabidiolic acid, cannabigerol, cannabinol, Δ-9-tetrahydrocannabinol, Δ-9-tetrahydrocannabibolic acid). 

RESULTS:

  • Analysed CBD concentration: 0.10 mg/mL - 655.27 mg/mL (median, 9.45 mg/mL)
  • Labelled concentration: 1.33 mg/mL - 800.00 mg/mL (median 15.00 mg/mL)
  • 42.85% of products had higher CBD levels than expressed on the label; 26.19% had lower CBD levels than expressed on the label and 30.95% of products were accurately labelled. 
  • Accuracy of labelling depended on product type, with vaporisation liquid most frequently mislabelled; while oils were most frequently labelled accurately.  
  • Concentration of unlabelled cannabinoids was generally low but THC was detected (up to 6.43 mg/mL) in 18 of the 84 samples tested 
  • The authors conclude that findings highlight the need for manufacturing and testing standards and oversight of medicinal cannabis products.

Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: A survey of the status in the chapters of the European Pain Federation

Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: A survey of the status in the chapters of the European Pain Federation
Krcevski-Skvarc, N., Wells, C. and Häuser, W. (2017) European Journal of Pain. doi: 10.1002/ejp.1147

The European Pain Federation (EFIC) conducted a survey where 31 of 37 national representatives contributed information about approval of cannabis-based medicines, insurance cover and position papers of a national medical association. Despite increase in access programmes across Europe, medical organisations are cautious because of insufficient evidence of medical cannabis’s benefits and risks. The paper states that there is a significant gap between the public perception of the effectiveness and the safety of medicinal cannabis and the position of some medical associations. EFIC countries are encouraged to collaborate with the European Medicines Agency to publish a comment document on cannabis-based medicine in medical care.

RESULTS:

  • Nabiximols (Sativex®) is approved and available for treatment-resistant spasticity in multiple sclerosis in 21 EFIC countries and reimbursed by health insurance companies or state social security systems in 10 countries. 
  • Dronabinol is approved in Austria, Denmark and Ireland for chemotherapy-induced nausea and vomiting (CINV) in oncology and palliative care and for cancer pain in Denmark. It is also approved for appetite stimulation in HIV in Ireland. Costs are not covered by health insurance companies. In Germany, dronabinol can be prescribed for any type of chronic pain and for any condition in palliative care although it is not approved for these conditions by the German Medicines Agency but may be reimbursed by health insurance companies. 
  • Nabilone is approved for CINV in four countries (Austria, Germany, Ireland and Serbia) and costs are reimbursed by health insurance companies. 
  • Cannabis extracts are used in an exceptional use programme in eight countries. Five EFIC countries and Israel have an expanded access programme. A national government-controlled system for production and supply of cannabis is available in Israel, Italy and the Netherlands and is scheduled for 2019 in Germany.
  • Three EFIC countries had a position paper by a national medical association on the use of medical cannabis: The Journal of the Finnish Medical Association; The German Pain Society and Israeli Pain Association.

Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings

Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings
Lötsch, J., Weyer-Menkhoff, I. and Tegeder, I. (2017) European Journal of Pain. doi: 10.1002/ejp.1148

The authors discuss evidence from preclinical studies of the effects of cannabinoids in blocking the detection of painful stimuli by sensor neurons compared with a review of 23 clinical trials involving 1,998 patients with persistent pain who reported mixed effects of cannabinoid medications on various clinical pain settings. The authors conclude that while preclinical evidence supports the antinociceptive effects of cannabinoids, clinical evidence provides limited support for a broad clinical use of cannabinoid-based medications in pain therapy. 

The authors found:

  • Controlled studies showed a lack of robust analgesic effects.
  • Half of the patients (n = 973) had participated in studies that provided no analgesic effect.
  • All studies reported large variability between individuals.
  • Cannabis was nearly always associated with analgesia in open-label or retrospective studies, possibly indicating an effect on increased well-being, sleep or mood rather than on sensory pain.

Cannabinoids concentration variability in cannabis olive oil galenic preparations

Cannabinoids concentration variability in cannabis olive oil galenic preparations
Carcieri, C., Tomasello, C., Simiele, M., De Nicolò, A., Avataneo, V., Canzoneri, L., Cusato, J., Di Perri, G. and D'Avolio, A. (2017) Journal of Pharmacy and Pharmacology. doi: 10.1111/jphp.12845

The authors aimed to quantify cannabinoids found in different oil preparations sourced from different laboratories using the same extraction procedure to evaluate the overall variability in different cannabis types. The main cannabinoid levels for THC and CBD from 201 cannabis oil samples from 10 pharmacies were analysed. The authors found wide variability in cannabinoid concentrations, both between and within laboratories, using the same cannabis strains and oil.

Adverse Reactions Associated With Cannabis Consumption as Evident From Search Engine Queries

Adverse Reactions Associated With Cannabis Consumption as Evident From Search Engine Queries
Yom-Tov. E. and Lev-Ran. S. (2017) JMIR Public Health Surveill. doi: 10.2196/publichealth.8391

The authors tested whether internet search engine queries could be used to detect adverse reactions to illicit cannabis use to help identify long-term effects of use. Web search query logs for adverse reactions in the United States were analysed over a 6 month period (Nov 2016 – April 2017) and assessed against the prevalence of known users in a geographic region using the National Survey on Drug Use in the Household survey. Queries for adverse drug reactions by people who also searched for cannabis included known adverse effects of illicit cannabis use: anxiety, depression-related symptoms, cough, chronic bronchitis, paranoia and hallucinations. Authors conclude the method can be useful for the study of adverse reactions of illicit drugs, particularly given limits of other methods and when false reporting is common. 

Clinical trial outcomes reported in peer-reviewed journals and conference presentations

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial
Thiele, E.A., Marsh, E.D., French, J.A., Mazurkiewicz-Beldzinska, M., Benbadis, S.R., Joshi, C., Lyons, P.D., Taylor, A., Roberts, C. and Sommerville, K. (2018) doi: 10.1016/S0140-6736(18)30136-3

Results of a Phase 3 randomised, double-blind, placebo-controlled trial to investigate the efficacy of cannabidiol (CBD) as add-on therapy for drop seizures (sudden falls due to seizures) in patients with treatment-resistant Lennox-Gastaut syndrome. After a 2 week dose escalation period, 171 patients across 24 clinical sites began a 12 week dosing period of 20mg/kg/day; administered as two equally divided doses morning and evening. Patients who completed treatment were eligible to enrol in an open-label extension trial.
 
RESULTS: 72 patients in the CBD group and 84 patients in the placebo group completed the study. 

  • Participants in the CBD group had a mean decrease in drop seizures compared to baseline of 43.9% compared to 21.8% in the placebo group
  • Significantly more patients in the CBD group than the placebo group achieved reductions of 25% or more or 75% or more in monthly frequency of drop seizures
  • Three patients in the CBD group who completed treatment were drop seizure free throughout the 12-week maintenance period; no patients in placebo group were drop seizure free
  • 12 (14%) patients in the CBD group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient died in the CBD group, but was considered unrelated to treatment; and 58 (78%) of 74 patients in the CBD group and 57 (97%) of 59 patients in the placebo group reported adverse events that were mild or moderate in severity
  • A higher occurrence of somnolence was observed in patients on antiepileptic drug regimens that included clobazam than those that did not include clobazam, or were in the placebo group

Synthetic Transdermal Cannabidiol for the Treatment of Focal Epilepsy in Adults

Synthetic Transdermal Cannabidiol for the Treatment of Focal Epilepsy in Adults
O’Brian, T., Berkovic, S.F., French, J., Messenheimer, J., Gutterman, D. Sebree, T. 2017 American Epilepsy Society Annual Meeting, Washington, DC. December 1-5, 2017.

188 adults aged 18 to 70 years with good health at screening and minimum of two year history of epilepsy with partial onset (focal) seizures were randomised to a 195mg/day or 390 mg/day of synthetic CBD gel for transdermal delivery or a placebo for 12 weeks. Patients could then elect to participate in an open label extension and receive 390mg/day for 18 months.

Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology

Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology
Atsmon, J., Heffetz, D., Deutsch, L., Deutsch, F. and Sacks, H. (2017) Clinical Pharmacology in Drug Development. doi: 10.1002/cpdd.408

15 healthy male adults randomised to PTL101, an oral capsule containing highly purified cannabidiol (CBD) embedded in gelatin matrix beads, and Sativex oralmucosal spray, to compare pharmacokinetic profiles and relative bioavailability of CBD.


Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea (OSA)

Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea (OSA)
Carley, D.W., Prasad, B., Reid, K.J., Malkani, R., Attarian, H., Abbott, S.M., Vern, B., Xie, H., Yuan, C. and Zee, P.C. (2017) Sleep. doi: 10.1093/sleep/zsx184

73 patients with moderate-to-severe OSA received placebo for 5-10 days, then were randomised to Dronabinol at 2.5mg/day or 10 mg/day, or placebo, for 6 weeks.

Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients

Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients
Schimrigk, S., Marziniak, M., Neubauer, C., Kugler, E.M., Werner, G. and Abramov-Sommariva, D. (2017) European Neurology. doi: 10.1159/000481089

240 patients with multiple sclerosis and associated neuropathic pain were randomised to Dronabinol or placebo for 16 weeks. After 16 weeks, patients received Dronabinol for a 32 week open-label period.