Cannabidiol prescription in clinical practice: an audit on the first 400 patients in New Zealand

Abstract

Background:
Cannabidiol (CBD) is the non-euphoriant component of cannabis. In 2017, the New Zealand Misuse of Drugs Regulations (1977) were amended, allowing doctors to prescribe CBD. Therapeutic benefit and tolerability of CBD remains unclear.

Aim:
To review the changes in self-reported quality of life measurements, drug tolerability, and dose-dependent relationships in patients prescribed CBD oil for various conditions at a single institution.

Design & setting:
An audit including all patients (n = 400) presenting to Cannabis Care, New Zealand, between 7 December 2017 and 7 December 2018 seeking CBD prescriptions METHOD: Indications for CBD use were recorded at baseline. Outcomes included EuroQol quality of life measures at baseline and after 3 weeks of use, patient-reported satisfaction, incidence of side effects, and patient-titrated dosage levels of CBD.

Results:
Four hundred patients were assessed for CBD and 397 received a prescription. Follow-up was completed on 253 patients (63.3%). Patients reported a mean increase of 13.6 points (P<0.001) on the EQ-VAS scale describing overall quality of health. Patients with non-cancer pain and mental-health symptoms achieved improvements to patient-reported pain and depression and anxiety symptoms (P<0.05). There were no major adverse effects. Positive side effects included improved sleep and appetite. No associations were found between CBD dose and patient-reported benefit.

Conclusion:
There may be analgesic and anxiolytic benefits of CBD in patients with non-cancer chronic pain and mental health conditions such as anxiety. CBD is well tolerated, making it safe to trial for non-cancer chronic pain, mental health, neurological, and cancer symptoms.

Full text

Gulbransen G etal. BJGP Open 2020; DOI: 10.3399/bjgpopen20X101010 1 of 8
RESEARCH
*For correspondence: doctor@
cannabiscare. nz
Competing interest: The authors
declare that no competing
interests exist.
Received: 12 August 2019
Accepted: 24 September 2019
Published: 05 February 2020
This article is Open Access: CC
BY license (https:// creativecom-
mons. org/ licenses/ by/4.0/)
Author Keywords: community
care, therapy in mental health,
prescribing, cannabidiol,
cannabis, anti- anxiety agents,
mental health, depression,
chronic pain, analgesics, patient
reported outcome measures
Copyright © 2020, The Authors;
DOI:10.3399/
bjgpopen20X101010
Cannabidiol prescription in clinical
practice: an audit on the first 400
patients in NewZealand
Graham Gulbransen, MBChB, FAChAM, FRNZCGP1*, William Xu2, Bruce Arroll,
MBChB, PhD, FRNZCGP3
1Private Practitioner, Cannabis Care NZ, West Care Specialist Centre, Auckland,
New Zealand; 2Medical Student, Department of General Practice and Primary Health
Care, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New
Zealand; 3Professor and Head of Department, Department of General Practice and
Primary Health Care, Faculty of Medical and Health Sciences, University of Auckland,
Auckland, New Zealand
Abstract
Background: Cannabidiol (CBD) is the non- euphoriant component of cannabis. In 2017, the New
Zealand Misuse of Drugs Regulations (1977) were amended, allowing doctors to prescribe CBD.
Therapeutic benefit and tolerability of CBD remains unclear.
Aim: To review the changes in self- reported quality of life measurements, drug tolerability, and dose-
dependent relationships in patients prescribed CBD oil for various conditions at a single institution.
Design & setting: An audit including all patients (n = 400) presenting to Cannabis Care, New Zealand,
between 7 December 2017 and 7 December 2018 seeking CBD prescriptions
Method: Indications for CBD use were recorded at baseline. Outcomes included EuroQol quality of
life measures at baseline and after 3 weeks of use, patient- reported satisfaction, incidence of side
effects, and patient- titrated dosage levels of CBD.
Results: Four hundred patients were assessed for CBD and 397 received a prescription. Follow- up was
completed on 253 patients (63.3%). Patients reported a mean increase of 13.6 points (P<0.001) on
the EQ- VAS scale describing overall quality of health. Patients with non- cancer pain and mental- health
symptoms achieved improvements to patient- reported pain and depression and anxiety symptoms
(P<0.05). There were no major adverse effects. Positive side effects included improved sleep and
appetite. No associations were found between CBD dose and patient- reported benefit.
Conclusion: There may be analgesic and anxiolytic benefits of CBD in patients with non- cancer chronic
pain and mental health conditions such as anxiety. CBD is well tolerated, making it safe to trial for non-
cancer chronic pain, mental health, neurological, and cancer symptoms.
How this fits in
CBD prescription in primary care was legalised in New Zealand in 2017. Previous preclinical trials
have shown CBD to have anxiolytic and anti- inflammatory properties but there remains a paucity
of studies investigating its therapeutic potential. In this quantitative observational study of the first
400 patients prescribed CBD in New Zealand, CBD was well tolerated amongst patients with a wide
range of conditions and symptoms. Quality- of- life benefit was experienced to a greater degree in
patients living with non- cancer chronic pain and anxiety- related mental- health conditions, and to a
lesser degree in patients with cancer or neurological symptoms.

Gulbransen G etal. BJGP Open 2020; DOI: 10.3399/bjgpopen20X101010
2 of 8
Research
Introduction
With the amendment of the New Zealand Misuse of Drugs Regulations 1977 in 2017, CBD has
become a legal prescription medicine. The amendment recognises the right of New Zealand doctors
to prescribe CBD products that contain no more of 2% of 9-Δ-tetrahydrocannabinol (9-Δ-THC) in the
product.1
CBD and 9-Δ-THC are cannabinoids, active compounds found within the Cannabis genus of
plants.2 While 9-Δ-THC is the main psychoactive component responsible for euphoria and the ‘high’
associated with marijuana, CBD is the non- euphoriant component.2,3
CBD is currently FDA- approved for the treatment of Dravet and Lennox- Gastaut syndrome, two
childhood seizure disorders.4 Randomised controlled trials (RCTs) have shown that, when CBD is added
to existing anti- epileptic medication in patients with these syndromes, seizure frequency decreases.5,6
However, CBD shows potential therapeutic use beyond this. Pre- clinical studies demonstrate that
CBD has potential anti- inflammatory effects via inhibition of immune cell migration, which may be
useful in chronic inflammatory conditions.7
Moreover, preclinical studies have demonstrated anxiolytic effects of CBD.3,8–10 Crippa et al found
that in patients with generalised anxiety disorder given 400 mg of oral CBD, there was decreased
cerebral blood flow to anxiety processing areas of the brain and a decrease in patient- reported
anxiety when compared to placebo.8 CBD in one double- blinded placebo- controlled RCT decreased
symptoms of social anxiety disorder patients and fear of public speaking.10 CBD may also reduce
psychotic symptoms of schizophrenia.11
CBD appears to be safe for patients, with a recent phase I dosage trial showing purified CBD oil
is well tolerated up to doses of 6000 mg.12 However, due to a paucity of clinical studies, prescribing
guidelines are lacking.
The aim of this study was to conduct a clinical audit on the patient population referred to Cannabis
Care (a primary care clinic in Auckland, New Zealand) for CBD oil. The authors explored the indications
for prescribing CBD oil, patient quality of life, patient satisfaction, and self- titrated dosage levels.
Method
The STROBE statement for reporting observational studies was followed.13
Patients
Patients included in this audit were those who were prescribed CBD from 7 December 2017 to 7
December 2018. Patients included in this audit either were referred by their primary care provider
or self- referred to the service. Patients were prescribed CBD oil (Tilray CBD100, Tilray, Nanaimo, BC,
Canada) containing 100 mg CBD/mL in 25 mL bottles administered orally via a dropper. Bottles costed
approximately USD300 each, which was self- funded as CBD is not on the New Zealand government-
subsidised pharmaceutical schedule (PHARMAC).
Outcomes
Patient sex, age, and details of medical condition were recorded at first consultation. Each participant
was grouped into one of four broad clinical groups based on their presenting medical symptoms: non-
cancer chronic pain symptoms, neurological symptoms, mental health- related symptoms, or cancer
symptoms. When a patient presented with symptoms fitting multiple categories, the clinician assigned
the patient to the category fitting their primary presenting complaint.
Patients completed an EQ- 5D- 5L questionnaire at baseline before taking CBD, and again after at
least 3 weeks of using the medicine as part of routine clinical assessment. The EQ- 5D- 5L is a two- part
tool consisting of the EQ- 5D- 5L descriptive system and the EQ Visual Analogue scale (EQ- VAS).14
The descriptive system measures five domains (mobility, self- care, usual activities, pain or discomfort,
anxiety or depression) each with five levels of severity: no problems, slight problems, moderate
problems, severe problems, and extreme problems. The EQ- VAS is a 20 cm vertical printed scale from
0 to 100 whereby the upper endpoint of the scale corresponds the ‘best health you can imagine’ and
the lower corresponds to the ‘worst health you can imagine’. The patient rated their current overall
health on this visual scale to yield a corresponding numerical score.

3 of 8
Research
Gulbransen G etal. BJGP Open 2020; DOI: 10.3399/bjgpopen20X101010
Patients also rated their satisfaction with their CBD use at follow- up. They rated their experience
as ‘no benefit, good, very good, or excellent’ and reported any side effects. In addition, variations
in patient dosage and the duration and frequency of CBD oil intake were recorded where possible.
Statistical methods
The EQ- 5D- 5L data was measured on ordinal scales and hence considered as non- parametric data.
The EQ- VAS scores were recorded on a continuous scale and treated as a parametric variable. Non-
parametric data was presented as median (interquartile range [IQR]) and analysed for differences
using the Wilcoxon rank sum test. Change in patient EQ- VAS scores was presented as mean (standard
deviation [SD]) and analysed using one- way analysis of variance (ANOVA) to assess any differences
between indication categories. Binary logistic regression was used to analyse potential dose-
dependent responses, dose of CBD, and patient- reported benefit.
Categorical data such as the indications for CBD, patient satisfaction with CBD use, and side effects
of use were presented as frequencies. A P value of ≤0.05 was taken as statistically significant. SPSS
software (version 23.0) was used for statistical analysis.
Results
A total of 400 patients presented to Cannabis Care from 7 December 2017 to 7 December 2018.
Three patients did not receive a prescription based on a clinician decision that they would not benefit.
Patients receiving CBD prescription consisted of 214 females (53.9%) and 183 males (46.1%), for a
total of 397 individuals. The mean age of patients was 51.48 years (SD 19.1). Of those prescribed CBD,
61 patients (15.4%) fit more than one category of indication and were assigned to a group based on
their primary condition.
Patient indication for CBD prescription is shown in Table1. The non- cancer pain symptoms group
included patients with fibromyalgia, osteoarthritis, rheumatoid arthritis, neuropathic pain, chronic non-
specific pain, pain due to ulcerative colitis, and migraines. Cancer- related symptoms included pain,
nausea, poor appetite, emotional distress, and adverse effects of radiotherapy and/or chemotherapy
treatment. Mental health symptoms included anxiety disorders, depressive disorders, post- traumatic
stress disorder, and insomnia. Neurological symptoms included Parkinson’s disease, multiple sclerosis,
epilepsy, autism spectrum disorder with challenging behaviour, amyotrophic lateral sclerosis, multiple
system atrophy, various neuropathies, and tremors.
Of the 397 patients initially prescribed the CBD oil, 253 (63.7%) were followed up either through
a second appointment with the clinician or by phone. In total, 250 patients (63.0%) reported their
satisfaction with CBD use, with three patients (0.8%) refusing to comment. Within these 250 patients,
a subset of 110 patients (27.7%) completed before and after EQ- 5D- 5L questionnaires; 144 patients
(36.3%) did not complete follow- up assessment, with 82 patients (20.7%) lost to follow- up and 62
patients (15.6%) choosing not to take the CBD. Reasons for patients not taking the CBD included
death, financial barriers preventing purchase of the oil, severe illness, participation in a clinical trial, or
consumption of alternative illicit cannabis products.
Median follow up duration for patients who completed their CBD prescription was 36 days (IQR
28–65).
Table 1 Baseline characteristics
Characteristic Frequency, nProportion, %
Mean age, years (±SD) 51.48 (±19.1) –
Sex Male 183 46.1
Female 214 53.9
Indication for CBD prescription Non- cancer pain symptoms 181 45.6
Mental health symptoms 64 16.1
Neurological symptoms 60 15.1
Cancer symptoms 92 23.2

Gulbransen G etal. BJGP Open 2020; DOI: 10.3399/bjgpopen20X101010
4 of 8
Research
Outcomes of CBD treatment
Results from Wilcoxon rank sum tests for EQ- 5D- 5L domains found that patients experiencing non-
cancer pain symptoms had a significant improvement of self- reported mobility scores (P = 0.02), ability
to complete their usual activities (P = 0.007), self- reported pain (P<0.001), and self- reported anxiety
or depression (P = 0.017). Patients with mental- health related symptoms experienced improvements
to their ability to carry out their usual activities (P = 0.002), pain (P = 0.039), and anxiety or depression
(P = 0.02). Patients with neurological symptoms experienced no statistically significant differences
in any of the five domains. Patients with cancer symptoms experienced improvements in pain (P =
0.047). Complete results of EQ- 5D- 5L questionnaires are shown in Table2.
Treatment with the CBD in all population groups showed an increase in the EQ- VAS score. There
was an overall mean increase of EQ- VAS score of 13.6 points (P<0.001, 95% CI = 9.72 to 16.76).
Overall, EQ- VAS scores represented an improvement in self- reported health. Results of one- way
ANOVA tests showed that there were no significant differences between indication groups for the
improvement of EQ- VAS scores.
Patient- reported satisfaction of CBD treatment found that 175 patients (70.0% of the 250 patients
for whom there was available data, or 44.1% of the 397 patients prescribed the CBD), reported some
level of satisfaction with CBD use (good, very good, or excellent). Seventy- five patients (30.0% of
250 patients, or 19.0% of 397 patients) reported no benefit from CBD use. There was no statistically
significant relationship found between patient age or sex and patient- reported satisfaction.
Table 2 Baseline and follow- up EQ- 5D- 5L
Indication for CBD
prescription
Domain of
EQ- 5D- 5L
Baseline EQ- 5D-
5L scores, median
(IQR)
Follow- up EQ- 5D- 5L
scores, median (IQR) P value
Non- cancer pain
symptoms
(n = 53)
Mobility 2.0 (1.0 to 3.0) 2.0 (1.0 to 3.0) 0.022
Self- care 1.0 (1.0 to 2.0) 1.0 (1.0 to 2.0) 0.046
Usual activities 3.0 (2.0 to 4.0) 2.0 (1.0 to 3.0) 0.007
Pain/discomfort 3.5 (3.0 to 4.0) 3.0 (2.0 to 3.0) <0.001
Anxiety/depression 2.0 (1.0 to 3.0) 2.0 (1.0 to 2.0) 0.017
Mental health
symptoms
(n = 21)
Mobility 1.0 (1.0 to 1.0) 1.0 (1.0 to 1.0) 0.577
Self- care 1.0 (1.0 to 1.75) 1.0 (1.0 to 1.0) 0.096
Usual activities 3.0 (2.0 to 3.0) 1.0 (1.0 to 2.0) 0.002
Pain/discomfort 2.0 (1.0 to 3.0) 1.0 (1.0 to 2.0) 0.039
Anxiety/depression 4.0 (3.0 to 4.0) 2.0 (1.5 to 3.0) 0.002
Neurological symptoms
(n = 11)
Mobility 1.0 (1.0 to 3.0) 1.5 (1.0 to 2.0) 0.317
Self- care 1.0 (1.0 to 3.0) 1.5 (1.0 to 2.0) 0.317
Usual activities 3.0 (1.75 to 4.0) 2.5 (1.75 to 3.25) 0.194
Pain/discomfort 3.0 (1.5 to 3.5) 3.0 (1.5 to 3.0) 0.18
Anxiety/depression 3.0 (2.0 to 3.0) 1.5 (1.0 to 3.0) 0.194
Cancer symptoms
(n = 24)Mobility 1.0 (1.0 to 2.0) 1.0 (1.0 to 2.0) 0.56
Self- care 1.0 (1.0 to 2.0) 1.0 (1.0 to 1.0) 1
Usual activities 2.0 (1.0 to 2.75) 2.0 (1.0 to 3.0) 1
Pain/discomfort 3.0 (2.0 to 3.0) 2.0 (1.0 to 2.5) 0.047
Anxiety/depression 2.0 (1.0 to 3.0) 1.0 (1.0 to 2.0) 0.11
Score of 1 = no problems, 2 = slight problems, 3= moderate problems, 4 = severe problems, 5 = extreme
problems. P values are calculated from Wilcoxon rank sum tests. ‘Before’ scores taken at rst consultation. ‘After’
scores taken after at least 3 weeks of cannabidiol intake.
CBD = cannabidiol. IQR = interquartile range.

5 of 8
Research
Gulbransen G etal. BJGP Open 2020; DOI: 10.3399/bjgpopen20X101010
Side effects
Adverse effects such as sedation and vivid dreams were experienced by 25 out of 253 patients
(9.9%). A worsening of a pre- existing condition was reported by 2 of 253 (0.8%) patients upon follow-
up. Thirty- eight of followed- up patients (15.0%) reported positive side effects of CBD use, such as
improved sleep or improved appetite. Side effects experienced by follow- up patients are summarised
in Table3.
Dosage
Amongst those who completed the course of CBD, the dose per day ranged from 40mg/day to
300mg/day. However, dosage information was incomplete, existing for only 110 patients out of the
253 followed- up patients (43.5%). The clinician recommended dosing to at least 100 mg/day. Overall
dosage between patients varied widely and was reported inconsistently by patients. Binary logistic
regression analysis was conducted for the existing values and there was no significant association
between dosage and patient- reported benefit from CBD (P = 0.145).
Discussion
Summary
CBD treatment improved self- reported quality of life measures for patients in the non- cancer pain and
mental health- related symptom groups. There was no statistically significant improvement in those
with cancer or neurological symptoms. Of those prescribed CBD, 44.1% (or 70.0% of the follow-
up group) reported good to excellent benefit for relatively intractable conditions; 19.0% of those
prescribed CBD (or 30.0% of the follow- up group) reported no benefit. CBD is well tolerated in most
patients and may be of benefit to patients with various intractable chronic conditions.
Strengths and limitations
The strength of this study is that it assesses effects of CBD on a large range of chronic medical
conditions in a clinical context. Only three patients were excluded (due to extreme severity of their
conditions).
Table 3 Side effect profile of the followed- up patients (n = 253)
Side effect Frequency, n (%)
Positive effects
Improved sleep 31 (12.3)
Improved appetite 7 (2.8)
Adverse effects
Sedation 5 (2.0)
Vivid dreams 5 (2.0)
Emotional disturbances eg, irritable,
depressed, anxious
5 (2.0)
Disorientation 3 (1.2)
Sleeplessness 1 (0.4)
Nausea 1 (0.4)
Constipation 1 (0.4)
Diarrhoea 1 (0.4)
Headaches 1 (0.4)
Oral mucosa irritation 1 (0.4)
Hallucinations 1 (0.4)

Gulbransen G etal. BJGP Open 2020; DOI: 10.3399/bjgpopen20X101010
6 of 8
Research
There are several limitations to this present audit. There was a large loss to follow- up due to patients
not attending follow- up and cost barriers. Hence, the results reported may not be fully representative
of the entire patient population. Moreover, patients had to pay USD300 for 2500 mg of the CBD oil,
USD150 for an initial consultation, and USD75 for follow- up. Most patients had refractory chronic pain
and conditions resistant to conventional treatment uncommon in the wider population, increasing
risk of selection bias. These patients are unlikely to be representative of a wider, more generalised
cohort of patients. It is difficult to elucidate the effect of selection bias on these findings. The high cost
barriers may augment the placebo effect of treatment,15 resulting in an overestimation of treatment
effects. However, due to many patients having resistant symptoms, CBD may conversely prove more
efficacious in patients with less severe symptoms.
The follow- up period was variable, resulting in interviews with some patients who had stopped
taking CBD for a period of months. This may have confounded the patient’s recollection of the
effects of CBD, likely causing an underestimation of the effect. Some follow- up was completed by the
clinician instead of a non- clinical author. This increased the risk of expectation bias by the clinician,
likely overestimating the effect. Considering these limitations, results should be interpreted with the
appropriate caution.
Comparison with existing literature
Numerous preclinical trials9,10 and neuro- imaging studies8 have demonstrated the anxiolytic effects of
CBD. A recently published case- series in psychiatric patients found a benefit of CBD for anxiety and
sleep,16 which is in agreement with the above findings.
On a pharmacological level, preclinical trials suggest CBD’s analgesic action is due to its effect on
certain receptors: TRPV1 and a3 GlyRs, involved in nociceptive transmission. However, human studies
are still inconclusive.17–19 The apparent benefit of CBD on pain reported by patients in this audit
remains difficult to interpret. Current guidelines for the prescription of medicinal cannabis, including
both 9-Δ-THC and CBD, recommend it as a third- line treatment for ‘neuropathic pain, palliative and
end- of- life pain, chemotherapy- induced nausea and vomiting, and spasticity due to multiple sclerosis
or spinal cord injury’.20 However, RCTs investigating the use of CBD alone for the treatment of pain
are lacking.
The ineffectiveness of the CBD oil for 75 of the 250 patients with available data (30.0%) may be
due to lack of patient compliance and inadequate dosing. The expense of the pure CBD 100 mg/
mL may have influenced patient attitudes towards this matter. Previous studies investigating CBD’s
anxiolytic effect have shown a U- shaped dose curve with highest efficacy at 300 mg as a single- dose.21
This audit did not find a statistically significant dose- response, likely due to missing data and the
aforementioned factors regarding financial cost.
CBD’s ineffectiveness in improving self- reported health in patients in the cancer and neurological
groups may be due to the high heterogeneity of the clinical presentations within these groups.
Additionally, patients within these groups had more severe disease progression compared to the
mental health and non- cancer pain symptom groups, which may have limited efficacy.
Overall, CBD treatment was well tolerated with mild adverse effects, most commonly related to
sedation. This is consistent with the findings of a phase I clinical trial showing the main side effects
of CBD were related to the gastrointestinal and central nervous system.12 Patient- reported sleep
benefits are likely related to these sedative effects. While cannabis (containing both 9-Δ-THC and
CBD) has been indicated for use as an appetite stimulant in HIV- affected patients with cachexia,22,23 it
remains unclear if CBD alone has significant appetite stimulating effects beyond placebo. Long- term
side effects were not analysed in this current audit and future study is still needed to clarify chronic
effects of CBD administration.24
Implications for research and practice
Some urgency on this topic exists due to the increasing worldwide legalisation of cannabis and its
related products. A focus should be placed on confirming the anxiolytic effects of CBD in clinical
conditions. Future studies should investigate the effectiveness of full spectrum CBD oil with the
retention of terpenes, the essential oils found in cannabis plants. Terpenes may enhance the effects of
pure CBD because of a synergistic effect known as the entourage effect.

7 of 8
Research
Gulbransen G etal. BJGP Open 2020; DOI: 10.3399/bjgpopen20X101010
Overall, this audit demonstrated the potential benefit of CBD in treating anxiety and pain. The
present study shows that it improves quality of life for a diverse range of patients. CBD in this
population has been shown to be safe and well tolerated. However, despite potential biases of
patients influenced by the high treatment cost, pure CBD is not effective for all. Benefit was more
pronounced in patients who had conditions with less severe disease progression (such as mental
health or non- cancer chronic pain conditions). Due to lack of a control group, high drop- out rate, and
an extreme patient population, these study results should be interpreted with caution. Future studies
should investigate effects of long- term CBD use, which could not be analysed in this present audit.
Funding
This research was not funded.
Ethical approval
The NZ National Health and Disability Ethics Committee does not require ethics approval for audit
data.
Provenance
Freely submitted; externally peer reviewed.
Acknowledgements
The authors would like to acknowledge and thank Associate Professor Stephen Buetow for assis-
tance in proofing the manuscript and Bert van der Werf for statistical guidance.
References
1. Mateparae J. Misuse of Drugs Amendment Regulations 2014. Wellington: New Zealand Parliament; 2014.
http://www. legislation. govt. nz/ regulation/ public/ 2014/ 0199/ latest/ DLM6156029. html? search= qs_ regulation%
40deemedreg_ Misuse+ of+ drugs+ act_ resel_ 25_ h& p=1
2. Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Braz J Psychiatry
2008; 30(3): 271–280. DOI: https:// doi. org/ 10. 1590/ S1516- 44462008000300015
3. Rong C, Lee Y, Carmona NE, etal. Cannabidiol in medical marijuana: research vistas and potential opportunities.
Pharmacol Res 2017; 121: 213–218. DOI: https:// doi. org/ 10. 1016/ j. phrs. 2017. 05. 005
4. US Food and Drug Administration. Press announcements — FDA approves first drug comprised of an active
ingredient derived from marijuana to treat rare, severe forms of epilepsy. 2018; https://www. fda. gov/ news- events/
press- announcements/ fda- approves- first- drug- comprised- active- ingredient- derived- marijuana- treat- rare- severe-
forms (accessed 14 Jan 2020).
5. Devinsky O, Cross JH, Laux L, etal. Trial of cannabidiol for drug- resistant seizures in the Dravet syndrome. N Engl
J Med 2017; 376(21): 2011–2020. DOI: https:// doi. org/ 10. 1056/ NEJMoa1611618
6. Devinsky O, Patel AD, Cross JH, etal. Effect of cannabidiol on drop seizures in the Lennox- Gastaut syndrome. N
Engl J Med 2018; 378(20): 1888–1897. DOI: https:// doi. org/ 10. 1056/ NEJMoa1714631
7. Lunn CA, Fine JS, Rojas- Triana A, etal. A novel cannabinoid peripheral cannabinoid receptor- selective inverse
agonist blocks leukocyte recruitment in vivo. J Pharmacol Exp Ther 2006; 316(2): 780–788. DOI: https:// doi. org/ 10.
1124/ jpet. 105. 093500
8. Crippa JAS, Derenusson GN, Ferrari TB, etal. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized
social anxiety disorder: a preliminary report. J Psychopharmacol 2011; 25(1): 121–130. DOI: https:// doi. org/ 10.
1177/ 0269881110379283
9. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on human experimental
anxiety. J Psychopharmacol 1993; 7(1 Suppl): 82–88. DOI: https:// doi. org/ 10. 1177/ 026988119300700112
10. Bergamaschi MM, Queiroz RHC, Chagas MHN, etal. Cannabidiol reduces the anxiety induced by simulated public
speaking in treatment- naïve social phobia patients. Neuropsychopharmacology 2011; 36(6): 1219–1226. DOI:
https:// doi. org/ 10. 1038/ npp. 2011.6
11. Leweke FM, Piomelli D, Pahlisch F, etal. Cannabidiol enhances anandamide signaling and alleviates psychotic
symptoms of schizophrenia. Transl Psychiatry 2012; 2.e94. DOI: https:// doi. org/ 10. 1038/ tp. 2012. 15
12. Taylor L, Gidal B, Blakey G, etal. A phase I, randomized, double- blind, placebo- controlled, single ascending dose,
multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in
healthy subjects. CNS Drugs 2018; 32(11): 1053–1067. DOI: https:// doi. org/ 10. 1007/ s40263- 018- 0578-5
13. von Elm E, Altman DG, Egger M, etal. The strengthening the reporting of observational studies in epidemiology
(STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008; 61(4): 344–349. DOI:
https:// doi. org/ 10. 1016/ j. jclinepi. 2007. 11. 008
14. Brooks R, De Charro F. EuroQol: the current state of play. Health Policy 1996; 37(1): 53–72. DOI: https:// doi. org/
10. 1016/ 0168- 8510( 96) 00822-6

Gulbransen G etal. BJGP Open 2020; DOI: 10.3399/bjgpopen20X101010
8 of 8
Research
15. Espay AJ, Norris MM, Eliassen JC, etal. Placebo effect of medication cost in Parkinson disease: a randomized
double- blind study. Neurology 2015; 84(8): 794–802. DOI: https:// doi. org/ 10. 1212/ WNL. 0000000000001282
16. Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in anxiety and sleep: a large case series. Perm J 2019; 23:
18–41. DOI: https:// doi. org/ 10. 7812/ TPP/ 18- 041
17. De Gregorio D, McLaughlin RJ, Posa L, etal. Cannabidiol modulates serotonergic transmission and reverses both
allodynia and anxiety- like behavior in a model of neuropathic pain. Pain 2019; 160(1): 136–150. DOI: https:// doi.
org/ 10. 1097/ j. pain. 0000000000001386
18. Maione S, Piscitelli F, Gatta L, etal. Non- psychoactive cannabinoids modulate the descending pathway of
antinociception in anaesthetized rats through several mechanisms of action. Br J Pharmacol 2011; 162(3): 584–596.
DOI: https:// doi. org/ 10. 1111/ j. 1476- 5381. 2010. 01063.x
19. Xiong W, Cui T, Cheng K, etal. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine
receptors. J Exp Med 2012; 209(6): 1121–1134. DOI: https:// doi. org/ 10. 1084/ jem. 20120242
20. Allan GM, Ramji J, Perry D, etal. Simplified guideline for prescribing medical cannabinoids in primary care. Can
Fam Physician 2018; 64(2): 111–120.
21. Zuardi AW, Rodrigues NP, Silva AL, etal. Inverted U- shaped dose- response curve of the anxiolytic effect of
cannabidiol during public speaking in real life. Front Pharmacol 2017; 8: 259. DOI: https:// doi. org/ 10. 3389/ fphar.
2017. 00259
22. Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with
HIV/AIDS. Cochrane Database Syst Rev 2013; (4): CD005175. DOI: https:// doi. org/ 10. 1002/ 14651858. CD005175.
pub3
23. Riggs PK, Vaida F, Rossi SS, etal. A pilot study of the effects of cannabis on appetite hormones in HIV- infected
adult men. Brain Res 2012; 1431: 46–52. DOI: https:// doi. org/ 10. 1016/ j. brainres. 2011. 11. 001
24. Ifand K, Grotenhermen F. An update on safety and side effects of cannabidiol: a review of clinical data and
relevant animal studies. Cannabis Cannabinoid Res 2017; 2(1): 139–154. DOI: https:// doi. org/ 10. 1089/ can. 2016.
0034