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Cannabis exposure as an interactive cardiovascular risk factor and accelerant of organismal ageing: a longitudinal study


With increasing availability of cannabis derivatives

in many parts of North America, and

intensifying research on the physiology and

pharmacology of the endocannabinoid

system, cannabinoids are becoming increasingly

prominent on the public and research

agenda. The Global Burden of Disease

project identified that cannabis abuse had a

global prevalence of 13 625 000 and was associated

with 396 000 years of life lived with disability

(YLD), a figure which has increased

by 22% from 1990 to 2013.1 Moreover, as

substance abuse and mental illness were

Strengths and limitations of this study

▪ Study strengths include its design features

including combined cross-sectional and longitudinal

structure, the detailed annotation of the

database including consideration of multiple clinical,

pathological and cardiovascular variables

incorporating information on time from exposure

to consider exclude cannabinoid effects.

▪ Advanced conceptual understanding and statistical

modelling employed.

▪ Significant cannabis exposure in contrast to

many previously published studies.

▪ Study limitations included that only 11

cannabis-only patients could be identified of the

125 cannabis-exposed patients.

▪ Significant coefficient of variation was found

with the biomarker of cardiovascular–organismal

age employed; use of an alternative parameter

such as epigenetic age based on DNA methylation

would allow more refined and detailed

studies in smaller patient groups.

Reece AS, et al. BMJ Open 2016;6:e011891. doi:10.1136/bmjopen-2016-011891 1

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some of the five major causes of increasing YLD globally1

and with the role of cannabis now established as a

gateway drug to various drug dependency syndromes2–5

with several serious psychological disorders,2–5 it is likely

that its impact on the global YLD may be larger than is

usually measured.

While cannabinoid toxicology is well established in

the respiratory and neurological–psychiatric literature, it

is less well known that a variety of fascinating studies also

exist which portray its effects on the cardiovascular

system. The effects of cannabinoids on the cardiovascular

system are currently believed to be mediated by

several signalling systems and intracellular transduction

pathways. These include the cannabinoid receptor type

1 (CB1R), cannabinoid receptor type 2 (CBR2), vanilloid,

prostanoid, lysophospholipid and unidentified

endocannabinoid pathways, among others,6 which interact

in complex ways with immune active cells and cytokines,

7–9 all of which are subject to increasingly complex

levels of epigenetic regulation.10 Case reports exist of

serious adverse effects including supraventricular and

ventricular arrhythmias, coronary thrombosis, sudden

cardiac death, asystole, angina, epicardial coronary

spasm and microvascular mediated no-flow phenomena

frequently in very young patients or patients without

other cardiovascular risk factors which have been

recently collated.11 12 A threefold to fivefold elevation of

all causes and cardiac death has been shown within

1 hour of cannabis use in cross-sectional13 and longitudinal

studies.14 A large longitudinal study of 1913 individuals

showed a dose–response relationship between

cannabis exposure and cardiovascular mortality.14 Both

acute strokes and reversible cerebral vasoconstriction

syndrome have been reported in a number of case

reports particularly from France, with the mean age of

the patients much younger than usual at 32–33 years of

age.12 Moreover the very complexity of endocannabinoid

vascular physiology implies that it is both nuanced

and interactive as CB1- mediated effects are often proand

CB2- effects anti -vasculitic and -arteriopathic.15 16

Cannabis is now believed to contain 104 cannabinoid

compounds.12 As cannabis use becomes more widespread

a more complete appreciation of its clinical presentations

becomes an increasing imperative.

Implicit within its diverse multi-system toxicological

profile, which also includes an association with cancers

of several sites,4 17–19 is the distinct possibility that it may

be altering the underlying rate of ageing of the whole

organism. Immune modulation–oxidative stress20 and

epigenetic change21 are believed to be major drivers of

the ageing process, and cannabinoids are now known to

be involved in both.22 Cannabinoids have also been

linked with stem cell physiology23 24 as well as increased

mitochondrial uncoupling and oxyradical flux.25 26

Moreover, it is established in cardiovascular medicine

that since the majority of deaths in western nations are

due to cardiovascular causes, one’s cardiovascular age is

a powerful surrogate for organismal or biological

age.27 28 Many stem cell niches have a vascular component.

29 30 It follows therefore that if one could measure

cardiovascular age, a surrogate for organismal age could

be established and one could test the hypothetical link

between cannabis use and the ageing process.

Indeed, just such an opportunity was afforded recently

in our clinic with the secondary analysis of a longitudinal

cardiovascular database. Encoded cannabis use

details in text format were available. The AtCor

SphygmoCor system measures arterial stiffness and links

it algorithmically to vascular–biological age. As we see

both general and drug-addicted patients and as cannabis

use is common among the latter group, it was decided

to undertake the present analysis.


Patient selection

Patients were not selected. Patients presenting to the

clinic were studied in consecutive order in accordance

with the dictates of workflow on the day of presentation.

Patients were restudied, again opportunistically, on presentation

to the clinic at approximately the 2-year and

5-year marks. Opioid-dependent patients were prescribed

buprenorphine both at presentation and

throughout their care.

Our clinic sees 250–350 patients weekly. We have

worked in addiction medicine since 1998. We have seen

more than 2699 of the ∼5500 known registered opioiddependent

patients in Queensland.

Radial arterial pulse wave tonometry (RAPWT)

Radial arterial pulse wave tonometry (RAPWT) was performed

with the Atcor SphygmoCor (Sydney, Australia)

system V.7.0 as previously described.31 Patients were positioned

supine on a bed and the radial arterial pulse

wave was sampled using a probe containing a Millar

micromanometer sensor. Input biophysical data were

analysed by the SphygmoCor software. Accepted studies

were required to have an Operator Index >70% and to

be technically satisfactory. All studies were performed in

quintuplicate. The central waveform was standardised

against the brachial blood pressure obtained sphygmanometrically

using an Omron HEM-907 automated

blood pressure device (Tokyo, Japan). Many indices

were collected from this system including central and

peripheral pressure augmentation, timing indices and

pressure indices. The vascular and reference ages (VA,

  1. RA) were calculated internally by the software from an

algorithm matching the degree of arterial stiffening with

height, age and sex. Patients were allowed to eat, drink

and smoke prior to study.

Demographic and laboratory data

At the time RAPWT was performed, patients were asked

about drug use and the duration for which these drugs

had been used. Patients usually quantified cannabis use

as cones/day, which equates to ∼0.1 g/day. They were

2 Reece AS, et al. BMJ Open 2016;6:e011891. doi:10.1136/bmjopen-2016-011891

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Downloaded from http://bmjopen.bmj.com/ on November 8, 2016 – Published by group.bmj.com

also asked when they had last used drugs, including

tobacco, as this can affect the RAPWT result. This information

was entered as notes into a RAPWT database.

The RAPWT data were linked with our clinical pathology

database. Clinical pathology testing of our patients was

performed by Queensland Medical Laboratories, which

are accredited to both the Australian Standard AS-15189

and the International Laboratory Standard ISO- 9001.

Data are listed as mean±SEM. Blood was drawn at initial

presentation and as clinically indicated thereafter and

also on an approximately annual basis to update their

clinical profiles. Laboratory data from the time of their

RAPWT was combined with the clinical and RAPWT

data for analysis.


Data were held in Microsoft Excel spreadsheets

(Redmond, Washington, USA). All data shown are listed

as mean (±SEM). Categorical data were compared using

EpiInfo from Centres for Disease Control,

Atlanta, Georgia, USA. Bivariate analysis was conducted

using Statistica V.7.1 (Statsoft Tulsa, Oklahoma, USA).

All t-tests were two-tailed. Linear regression was performed

in ‘R’ V.3.2.3 from the Cloud Central R Archive

Network (CRAN) mirror using the base, reshape,

ggplot2, and nlme packages. In order to comply with

normality assumptions, continuous variables were log

transformed as indicated by the Shapiro test.

Time-dependent analyses were conducted using

repeated measures non-linear mixed effects restricted

maximum likelihood estimator (REML) models with

unity and the patient’s unique identifier as random

effects. Models were fitted as suggested by loess plots

and quantitated using analysis of variance (ANOVA)

models. Repeated measures models were compared by

maximum likelihood (ML) methods. Model reduction

was conducted classically, with the progressive elimination

of the least significant term. Missing data were

casewise deleted. To calculate effect sizes, mean dependent

variable parameters (age, BMI and time) were used

together with the coefficient estimates obtained from

the final regression models. Standard abbreviations relating

to statistical models such as degrees of freedom

(DF), Akaike Information Criterion (AIC), Bayesian

Information Criterion (BIC) and Log-likelihood ratio

(Log.Lik) are used. p<0.05 was considered significant.


All patients gave informed consent to the performance

of the RAPWT and the inclusion of their anonymised

data in the present analysis. The study was approved by

the Human Research Ethics Committee of South City

Medical Centre, which is registered with the National

Health and Medical Research Council of Australia. The

study was compliant with the Declaration of Helsinki.


Data from 13 657 RAPWT studies were collected from

1553 patients. Three hundred and ninety cases were

excluded because of exposure to conditions (hypertension,

drug withdrawal) or medications (amphetamine,

alcohol, heroin), which were known to interfere with

central cardiovascular status. Cocaine use was not

reported by our patients. Cocaine use in Australia is very

uncommon outside of Sydney and outside of certain

sociodemographically restricted subgroups. Methadone

has also been shown by our group to perturb cardiovascular

status32 and was therefore also excluded. This left

1163 patients including 817 (70.25%) males. The breakdown

by study group is shown in figure 1, and by age,