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30th August 2023
Recreational drug (RD) use was detected via the urine samples of approximately one in 10 patients (11%) admitted to an intensive cardiac care unit, according to the findings of a multi-centre French study.
Published online in the journal Heart, the study also found the presence of such drugs was independently associated with a higher risk of in-hospital major adverse events (MAEs).
The use of RDs is already known to be associated with a higher risk of cardiac arrhythmias. However, there is some uncertainty over the prevalence of RD use among patients admitted to hospital with heart problems, or to what extent this affects the likely course of their condition.
The researchers aimed to assess the prevalence of RD use and its association with in-hospital MAEs in patients admitted to intensive cardiac care units. Among those admitted, systematic screening for RDs was performed by prospective urinary testing.
The primary outcome was the prevalence of RD detection. In-hospital MAEs were defined as death, resuscitated cardiac arrest or haemodynamic shock.
In 499 consecutive patients with a mean age of 63 years (70% male), 161 (11%) had a positive test for a RD, including cannabis (9.1%), opioids (2.1%), cocaine (1.7%), amphetamines (0.7%) and MDMA (0.6%). Despite these findings, only 57% of those testing positive declared recreational drug use.
Patients who used RDs exhibited a higher MAE rate than non-users (13% vs 3%, respectively, p < 0.001).
After adjustment for comorbidities, RD use was independently associated with a higher rate of in-hospital MAEs (odds ratio, OR = 8.84, 95% CI 4.68 – 16.7, p < 0.001). In fact, cannabis, cocaine and MDMA, when assessed separately, were independently associated with in-hospital MAEs.
Multiple drug detection was frequent (28% of positive patients) and also associated with an even higher incidence of MAEs (OR = 12.7, 95% CI 4.80 – 35.6, p < 0.001).
29th June 2023
AEF0117 is a novel agent signalling specific inhibitor of the cannabinoid receptor 1, which, in a double-blind, placebo-controlled randomised trial, reduced the positive subjective effects of cannabis in patients with cannabis use disorder (CUD).
Although most people using cannabis do not have problems related to its use, between 10% and 30% of users report symptoms consistent with CUD. Most of the effects of cannabis linked to the psychoactive component tetrahydrocannabinol (THC) are mediated via interaction with the type 1 cannabinoid receptor, which has become a promising drug target.
Currently, there are no effective treatments for CUD, but AEF0117 appears to selectively inhibit a subset of intracellular effects resulting from THC binding without modifying behaviour. Moreover, AEFO117 potently inhibits the effects of THC without producing any psychoactive effects.
Writing in the journal Nature Medicine, researchers initially found that AEF0117 decreased cannabinoid self-administration and THC-related behavioural impairment, but without producing significant adverse effects. Based on these initial phase 1 findings, they tried using the drug in patients with CUD.
In a randomised, double-blind, placebo-controlled, crossover phase 2a trial, researchers randomised volunteers with CUD to two ascending-dose cohorts (0.06 mg and 1 mg), which were given every day.
The primary outcome was the effect of AEFO117 on cannabis’ positive subjective effects, which were measured using a visual analogue scale. The results showed that the drug significantly reduced the positive subjective effects of cannabis by 19% with the 0.06 mg dose but 38% for the 1 mg dose, compared to placebo (p < 0.04).
In addition, a 1 mg dose of AEFO117 also reduced cannabis self-administration (p < 0.05). It appeared to be well tolerated and did not precipitate cannabis withdrawal.
19th June 2023
With increasing evidence that cannabis use is associated with adverse cardiovascular effects, questions are undoubtedly being asked about the safety of the drug for medical uses. Rod Tucker investigates.
Cannabis was one of the first plants cultivated by man, and its first use can be traced to ancient China where evidence suggests it was used for medical purposes from around 2,700 BC and for textiles and other uses as early as 4,000 BC.
Although the plant contains hundreds of compounds, the two most well studied are tetrahydrocannabinol (THC) and cannabidiol (CBD). In the late 1980s and early 1990s, the site of action for cannabis was identified with the discovery of two major cannabinoid receptors, CB1 and CB2, and their endogenous ligands, which form part of the endocannabinoid system.
While THC is the main psychoactive compound in cannabis that produces the euphoric ‘high’ sensation, over the last decade it has become increasingly clear that it is CBD that has a number of therapeutic benefits. Recognition of this fact has given rise to the terms ‘medical cannabis’ or ‘medical marijuana’.
In a 2021 meta-analysis published in the BMJ, researchers concluded that there was moderate- to high-certainty evidence that medical cannabis or cannabinoids results in a small to very small improvement in pain relief, physical functioning and sleep quality in patients with both chronic, non-cancer pain and cancer-related pain.
Although medical cannabis use is associated with some adverse effects such as cognitive impairment, vomiting, drowsiness and impaired attention, there has been little attention paid to any potential adverse cardiovascular (CV) sequelae. One likely explanation is that there remains some uncertainty over the magnitude of these effects and therefore whether such risks should be highlighted.
In fact, in a statement on the use of cannabis and its CV effects, the American Heart Association (AHA) states that ‘overall, evidence is still inconclusive for cannabis use and adverse cardiovascular outcomes’ and it called for carefully designed prospective studies to examine this issue in more detail.
Since the publication of the AHA statement, more evidence has come to light, which suggests that the use of cannabis has several adverse effect on the CV system.
For several states in the US and many other countries such as Canada, use of recreational cannabis has been legalised although this has had some unintended consequences, such as an increase cannabis and alcohol poly use, in addition to adverse cardiovascular effects.
In a recent abstract in the Journal of the Society for Cardiovascular Angiography and Interventions, researchers found that cannabis users were at a more than three times greater risk of developing peripheral artery disease than non-users (Odds ratio, OR = 3.68, p<0.001). Fortunately, however, there was no increased risk for any subsequent intervention or mortality from their peripheral ischaemia.
Despite this, a further abstract revealed that cannabis users were at a statistically significant higher risk of having a myocardial infarction (OR = 3.33, p < 0.001) and an increased likelihood of requiring a percutaneous coronary intervention during hospitalisation (OR = 1.76, p <0.001). Furthermore, users were also at a markedly increased risk of all-cause mortality during hospitalisation (OR = 14.77, p < 0.001).
Cannabis use also increases the risk of arrhythmias and in particular, atrial fibrillation (AF) as well as myocardial injury in those without pre-existing cardiovascular disease. While these studies are concerning, a 2020 systematic review on the cardiac effects of cannabis use concluded that while there is an increased risk of cardiac dysrhythmia, which can be life-threatening, this is rare.
A more recent meta-analysis of observational studies published in 2023 in the journal Toxicology Reports, indicated that cannabis use does increase the risk of an acute myocardial infarction, stroke and any adverse cardiovascular event. Nevertheless, while the pooled odds ratio estimates for each event were non-significant there was also a high degree of heterogeneity among studies.
With a clear body of evidence implicating the development of adverse CV outcomes among cannabis users, a limitation of the data is that it is derived from self-reported, recreational use. Furthermore, the focus of research has been on the adverse cardiovascular effects of THC, whereas medical cannabis is predominately based on CBD.
So, is there evidence that CBD-based medical cannabis is harmful to the heart? While there is currently a paucity of data on the CV effects of medicinal cannabis, the available information is somewhat reassuring.
One review highlighted the anti-inflammatory and anti-oxidant effects of CBD and suggested that it appears to have positive effect on the CV system. Further evidence to support the beneficial impact of CBD on the CV system comes from studies in patients with hypertension.
For instance, a study of medicinal cannabis use in older hypertensives published in the European Journal of Internal Medicine, found that after only three-months use of mainly cannabis oil, there was a signification drop in blood pressure. Interestingly, the researchers were unable to detect any adverse changes to participant’s ECGs and no new sustained arrhythmias developed, even though the median daily intake of THC and CBD was roughly the same (21 mg). Similar blood pressure reducing effects were seen in a recent randomised, placebo-controlled, cross-over trial in hypertensive patients using an oral CBD product.
Additionally, repeated CBD dosing has been shown to reduce arterial stiffness and improve endothelial function, revealing a potentially valuable role for those with vascular diseases. Whilst studies to date are largely positive and do not suggest harmful effects on the heart, a recent analysis by Danish researchers sounded a note of caution. Using a national registry, the team examined the potential adverse cardiac effects of CBD when used for the management of chronic pain. Their findings revealed a 64% increased risk of arrhythmias among CBD users compared to non-users.
While it has become recognised that the recreational use of cannabis is associated with deleterious effects on the cardiovascular system, this seems to be less likely with medical cannabis. Nonetheless, research to more clearly delineate the cardiovascular risks associated with medicinal cannabis use is urgently required. In the meantime, clinicians need to remain wary, because the jury is still out on whether or not medical cannabis and the cardiovascular system represents a dangerous combination.
2nd November 2022
The misuse of the illicit substances methamphetamine, cocaine, opiates and cannabis has been found to increase the risk of incident atrial fibrillation (AF) according to the findings of a longitudinal analysis by Californian researchers.
Atrial fibrillation is the most frequent cardiac arrhythmia, and it has been estimated that 6 -12 million people worldwide suffer from the condition. Moreover, the presence of the arrhythmia is also independently associated with a higher risk of all-cause mortality. While it has become well established that a higher intake of alcohol as well as smoking, increases the risk of AF, the relationship with the misuse of illicit drugs is less clear. Whereas prior work has suggested that methamphetamine abuse leads to ECG changes that pose a higher risk for ventricular arrhythmias and most notably torsades de pointes, less is known about the effect on AF. However, there is some data linking an increased risk of AF from use of both cannabis and cocaine though these findings are derived from case studies. But in contrast, one study actually identified how cannabis use was associated with a lower odds of AF.
In the present study, the US researchers sought to determine whether misuse of the illicit substances, methamphetamine, cocaine, opiates and cannabis were a predictor of incident AF. The team used several California healthcare databases, e.g., emergency department and inpatient to capture repeat visits for a given patient. They extracted demographic and co-morbidity data and excluded those with known AF and looked at cases where substance use was considered present at the first healthcare encounter. The researchers then compared the baseline and clinical characteristics of patients for each of the different drugs and examined the association with AF, adjusting for covariates known to be associated with AF.
Illicit substance misuse and incident atrial fibrillation
In a total of 23,561,884 individuals, 98,271 used methamphetamine, 48,701 cocaine, 10,032 opiates and 132,834 cannabis. From this total, 4.2% developed incident AF during the period of study from 2005 to 2015. The mean age of participants ranged from 32.3 years (cannabis) to 41.1 (cocaine) and the proportion of females from 28.3% to 55%.
After adjustment for covariates, methamphetamine use was associated with an 86% higher risk of developing incident AF (Hazard ratio, HR = 1.86, 95% CI 1.81 – 1.92). Similar and significantly elevated risks were seen for cocaine (HR = 1.61), opiates (HR = 1.74) and cannabis (HR = 1.35). Interesting, polysubstance use was also associated with a higher risk of AF compared to single drug misuse (HR = 1.63, 95% CI 1.61 – 1.66).
The authors concluded that for each of the misused substances analysed, there was a higher risk of developing incident AF after controlling for conventional AF risk factors.
Citation
Lin AL et al. Cannabis, cocaine, methamphetamine, and opiates increase the risk of incident atrial fibrillation. Eur Heart J 2022
25th June 2021
Cannabis is one of the world’s most widely used psychoactive substance with a 2015 report finding that there were around 183 million people, i.e., 3.8% of the world’s population, who reported using the drug in the past year. Moreover, in a study 4-year follow-up study of adolescent use of alcohol and cannabis, it was observed that only cannabis had an important and lasting, negative impact on cognitive functioning. Legislation aimed at de-criminalising or legalising the use of cannabis in the US appears to lead to greater levels of cannabis use disorder among adolescents. With some animal studies suggesting that exposure to cannabis during adolescence appears to affect neurodevelopment as seen by long-term impairment of specific components of learning and memory. However, there is a lack of longitudinal neuroimaging data studying the links between adolescent cannabis use and any potential impact on neurodevelopment. Given these concerns, a team of researchers from the Department of Psychiatry, University of Vermont Larner, Burlington, Canada, turned to the data held on individuals as part of the IMAGEN study. This European project makes use of both brain imaging and genetics, to examine how biological, psychological and environmental factors during adolescence might affect brain development. Within this cohort, the researchers identified cannabis naïve individuals at baseline and who had neuroimaging data both at baseline and at a 5-year follow-up. The researchers sought to determine the degree to which initiation of cannabis was associated with age-related cortical thickness change (from ages 14 to 19). With previous research indicating that cannabis use was associated with impulse control, the team focused on cannabis-related cortical thinning and 3 domains of impulsiveness using a self-reported questionnaire. In addition, baseline and follow-up questionnaires measured cannabis use in the past 30 days using a scale ranging from 0 (never) to 7 (> 40 times).
Findings
The study included 1598 MR images from 799 participants with a mean age at baseline of 14.4 years (56.3% male). Levels of self-reported cannabis use at follow-up ranged from 0 to more than 40 uses, with 161 participating reporting 10 to more than 40 uses. The MR imaging after 5 years showed evidence of a dose-dependent association between lifetime cannabis use and cortical thickness. In particular, there was a negative association cannabis use and cortical thickness in the left and right prefrontal cortices. They also observed no significant link between baseline cortical thickness and lifetime cannabis use. In other words, the neuroanatomical differences observed at follow-up, did not precede cannabis use. Cannabis-related cortical thinning was also present in the right dorsomedial prefrontal cortex, which the authors felt was related to the self-reported attentional impulsiveness at the 5-year follow-up. Finally, using PET scans, the authors found increased levels of endocannabinoid receptors in cortical areas found to have thinned at follow-up.
Discussing these results, the author suggested that the totality of their evidence pointed to how cannabis use during middle to late adolescence may be associated with altered cortical, particularly in prefrontal regions. They concluded that given the increasing de-criminalisation of the drug, further longitudinal studies of adolescent cannabis users were needed to confirm these findings.
Citation
Albaugh MD et al. Association of Cannabis Use During Adolescence with Neurodevelopment. JAMA Psychiatry 2021
4th December 2020
Whether or not, cannabidiol, the derivative widely used as medicinal cannabis, also impairs driving performance is largely unknown.
Cannabis is available in three different varieties (or technically, chemovars) which are cannabidiol (CBD) dominant, tetrahydrocannabinol (THC) dominant and a CBD-THC equivalent mixture. Individuals inhale the THC dominant form because of its intoxicating effects. Whether the CBD dominant form, used medicinally, has sedating properties is currently equivocal.
As a result, researchers from the Lambert Initiative for Cannabinoid Research, University of Sidney, Australia, conducted a randomised trial to examine the extent and duration to which each of the different cannabis chemovars impaired driving performance. They recruited 26 individuals with a history of occasional cannabis use and employed a cross-over design study that involved four on-road driving periods, one week apart.
For the study, the participants inhaled one of vapourised cannabis containing 13.75mg CBD, THC, CBD-THC equal mixture or placebo. The driving tests twice; 40 to 100 minutes and 240 to 300 minutes post-vaporisation. The primary outcome was the mean standard deviation of lateral position (SDLP), which measures the extent of lane weaving, swerving and overcorrecting.
Findings
The mean age of the 26 individuals was 23.2 years (including 16 women), all of whom completed the 8 driving tests. At 40 to 100 minutes and following inhalation of cannabis, the mean SDLP after CBD was 84.07cm, 86.94cm after THC, 84.07cm after the CBD-THC mixture and 84.41cm after placebo and these values remained similar between 240 and 300 minutes.
Pairwise comparisons revealed that both SDLP values for THC and the THC-CBD were higher than placebo at 40 to 100 minutes, but not between 240 and 300 minutes. In other words, both THC and the combination but not, CBD, impaired driving performance in the short-term, but that this effect was abolished in the longer term.
Although a limitation in the study, recognised by the authors, was that the dosages used might not reflect common usage, their data implied that CBD did not affect driving ability.
Citation
Arkell TR et al. Effect of cannabidiol and delta-nine tetrahydrocannabiniol on driving performance. A randomised clinical trial. JAMA Net Open 2020 doi:10.1001/jama.2020.21218.
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