Can we make cannabis safer?

doi:10.1016/S2215-0366(17)30075-5

The Lancet Psychiatry

Volume 4, Issue 8, August 2017, Pages 643-648

https://doi.org/10.1016/S2215-0366(17)30075-5 Get rights and content

Summary

Cannabis use and related problems are on the rise globally alongside an increase in the potency of cannabis sold on both black and legal markets. Additionally, there has been a shift towards abandoning prohibition for a less punitive and more permissive legal stance on cannabis, such as decriminalisation and legalisation. It is therefore crucial that we explore new and innovative ways to reduce harm. Research has found cannabis with high concentrations of its main active ingredient, δ-9-tetrahydrocannabinol (THC), to be more harmful (in terms of causing the main risks associated with cannabis use, such as addiction, psychosis, and cognitive impairment) than cannabis with lower concentrations of THC. By contrast, cannabidiol, which is a non-intoxicating and potentially therapeutic component of cannabis, has been found to reduce the negative effects of cannabis use. Here, we briefly review findings from studies investigating various types of cannabis and discuss how future research can help to better understand and reduce the risks of cannabis use.

Introduction

The cannabis landscape is rapidly changing. Following the Single Convention on Narcotic Drugs in 1961, possession, distribution, and use of cannabis were criminalised and cannabis-related arrests increased substantially in Europe and North America, particularly among young and ethnic-minority populations.¹ In the decades following the convention, there has been an overall trend towards greater cannabis use in most parts of the world.² This trend might be due to prohibitive measures (eg, banning substances or law enforcement) having little or no effect on the harms related to the use or abuse of cannabis, as suggested by a systematic review.³ In the UK, demand for the treatment of cannabis-related problems increased by 56% in adults and 51% in those younger than 18 years between 2005–06 and 2013–14.⁴ Increased treatment seeking for problems related to cannabis use has also been evident in the USA,⁵ and cannabis has become the primary illicit drug responsible for first-time entry to drug treatment in Europe, although one-quarter of first-time entries in Europe are thought to be referrals from the criminal justice system.⁶

Certain US states, including California, Oregon, Alaska, Maine, Massachusetts, Washington, Nevada, and Colorado, and Uruguay have decided to allow cannabis to be sold for recreational purposes.⁷ Canada is set to legalise recreational use of cannabis in 2017, and several European countries have lessened or abolished criminal sanctions on cannabis possession and use.⁸ Although it is likely that such moves will decrease crime-related financial costs to the state, the effects that they will have on cannabis consumption and the prevalence of cannabis-associated harms are unclear.

In any event, moves toward legalisation of medicinal or recreational cannabis are unlikely to decrease the number of people who use cannabis. However, these moves could facilitate measures to reduce population levels of harm—for example, by regulating cannabis potency and promoting safer (eg, non-tobacco) routes of administration.⁹ Therefore, those concerned about cannabis-related harms should consider other means by which the use of cannabis might be made safer.

Section snippets

Increasing potency of cannabis

Cannabis sativa L. contains at least 144 different compounds known as cannabinoids, which are specific to the cannabis plant, and more than 1100 other compounds, such as terpenoids and flavonoids.¹⁰ The most abundant of the cannabinoids are δ-9-tetrahydrocannabinol (THC) and cannabidiol (often known as CBD), which the plant produces in different ratios from the same precursor cannabigerol.¹¹ Hence, increased THC content in cannabis will be at the cost of cannabidiol content. Furthermore,

Significance of cannabidiol

The main adverse effects associated with cannabis use are dependence, cognitive and educational impairment, and psychosis.²¹ Crucially, evidence suggests that the incidence of adverse effects related to cannabis use is associated with the concentrations of THC and cannabidiol. Encouragingly, increasing the concentration of cannabidiol does not appear to alter the pleasurable effects of THC, such as the subjective feeling of “stoned”. A recent study showed that cannabidiol given orally up to 800

Dependence

Approximately one in 11 people who try cannabis will become dependent in their lifetime,²⁶ although this risk is almost doubled if use starts in adolescence²⁷ and is between 25% and 50% for people who use cannabis daily.²⁸ However, not all varieties of cannabis have the same liability towards dependence. An online survey²⁹ of more than 2514 cannabis users found that use of high-potency cannabis was associated with a greater severity of cannabis dependence, alongside self-reported memory

Psychosis

High-potency cannabis is also associated with a higher risk of psychosis, and an earlier onset of psychosis, than low-potency forms.34, 35 In a case-control study³⁶ of patients with first-episode psychosis, daily use of cannabis containing high concentrations of THC and low concentrations of cannabidiol was associated with a 5-fold increase in the risk of psychosis, although no such increase was found among users of low-potency resin.

In a Dutch population study of 1877 participants,³⁷ people

Cognition and intelligence

Whether the use of cannabis has lasting negative effects on memory functioning, intelligence, and other aspects of cognition in the normal population has been extensively debated.²¹ A study⁴⁹ of three large samples found that cannabis use before the age of 17 years was related to decreased rates of high school completion and degree attainment. Similarly, a 1-year follow-up study⁵⁰ of 1155 adolescents found that weekly cannabis use was related to a poorer performance (albeit less than tobacco)

Insights from cannabinoid experiments

Although epidemiological studies are fundamental to understand the population effect of a behaviour or exposure, they come with some clear limitations. For example, when exploring the different outcomes for cannabis users and non-users, it is often unclear whether the observed effects (eg, impaired cognition) are due to cannabis use itself or confounding variables. Experimental studies, such as randomised trials, allow inference of causality, although with the caveat of only allowing

Making cannabis safer

It is vital, especially now that cannabis is becoming increasingly liberalised, that researchers, clinicians, and policy makers explore alternative and innovative ways by which we can reduce and mitigate cannabis-related harms.

First, more focus on the co-use of tobacco and cannabis and the additive harm it poses is needed, especially since cannabis is frequently used together with tobacco, particularly in Europe.⁷⁴ Use of other routes of administration, such as smoke-free vapourisers, has the

Search strategy and selection criteria

This narrative, critical Personal View was not done using the standard search criteria and methods for a systematic review. The articles in this Personal View were obtained by searches of PubMed and Google Scholar, Google Scholar alerts for key terms (“cannabis”, “marijuana”, “cannabidiol”) up to Oct 7, 2016, reference lists in existing reviews and papers, and conference presentations.

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Cited by (109)

Effects of cannabinoids on resting state functional brain connectivity: A systematic review
2023, Neuroscience and Biobehavioral Reviews
Cannabis products are widely used for medical and non-medical reasons worldwide and vary in content of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Resting state functional connectivity offers a powerful tool to investigate the effects of cannabinoids on the human brain. We systematically reviewed functional neuroimaging evidence of connectivity during acute cannabinoid administration. A pre-registered (PROSPERO ID: CRD42020184264) systematic review of 13 studies comprising 318 participants (mean age of 25 years) was conducted and reported using the PRISMA checklist. During THC and THCv exposure vs placebo reduced connectivity with the NAcc was widely reported. Limited evidence shows that such effects are offset by co-administration of CBD. NAcc-frontal region connectivity was associated with intoxication levels. Cannabis intoxication vs placebo was associated with lower striatal-ACC connectivity. CBD and CBDv vs placebo were associated with both higher and lower connectivity between striatal-prefrontal/other regions. Overall, cannabis and cannabinoids change functional connectivity in the human brain during resting state as a function of the type of cannabinoid examined.
Δ9-Tetrahydrocannabinol does not upregulate an aversive dopamine receptor mechanism in adolescent brain unlike in adults
2023, Current Research in Neurobiology
Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC) and altered dopaminergic function. As dopamine D1-D2 receptor heteromer activation causes anxiety and anhedonia, this signaling complex was postulated to contribute to THC-induced affective symptoms. To investigate this, we administered THC repeatedly to adolescent monkeys and adolescent or adult rats. Drug-naïve adolescent rat had lower striatal densities of D1-D2 heteromer compared to adult rat. Repeated administration of THC to adolescent rat or adolescent monkey did not alter D1-D2 heteromer expression in nucleus accumbens or dorsal striatum but upregulated it in adult rat. Behaviourally, THC-treated adult, but not adolescent rat manifested anxiety and anhedonia-like behaviour, with elevated composite negative emotionality scores that correlated with striatal D1-D2 density. THC modified downstream markers of D1-D2 activation in adult, but not adolescent striatum. THC administered with cannabidiol did not alter D1-D2 expression. In adult rat, co-administration of CB1 receptor (CB1R) inverse agonist with THC attenuated D1-D2 upregulation, implicating cannabinoids in the regulation of striatal D1-D2 heteromer expression. THC exposure revealed an adaptable age-specific, anxiogenic, anti-reward mechanism operant in adult striatum but deficient in adolescent rat and monkey striatum that may confer increased sensitivity to THC reward in adolescence while limiting its negative effects, thus promoting continued use and increasing vulnerability to long-term adverse cannabis effects.
High-Potency Cannabis Use in Adolescence
2023, Journal of Pediatrics
Citation Excerpt :
The clinician can also consider discussing the CBD:THC of cannabis products as another means of harm reduction. Studies have demonstrated CBD may reduce THC's harmful effects on anxiety, cognition, and psychotic symptoms.7-9,65 In a crossover study, use of THC-dominant and THC/CBD-equivalent cannabis both impaired driving, but use of CBD-dominant cannabis did not.66
Trends and characteristics of cannabis-associated emergency department visits in the United States, 2006–2018
2022, Drug and Alcohol Dependence
Cannabis policies are rapidly changing in the United States, yet little is known about how this has affected cannabis-associated emergency department (ED) visits.
We studied trends in cannabis-associated ED visits and identified differences by visit characteristics. Cannabis-associated ED visits from 2006 to 2018 were identified from the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project’s (HCUP) Nationwide Emergency Department Sample (NEDS). JoinPoint analysis was used to identify trends from 2006 to 2014, prior to medical coding changes in 2015, and Z-tests were used to compare annual rate changes from 2016 to 2018. Changes in rates from 2017 to 2018 were examined by visit characteristics.
From 2006–2014, the rate of cannabis-associated ED visits increased, on average, 12.1% annually (p < 0.05), from 12.3 to 34.7 visits per 100,000 population. The rate increased 17.3% from 2016 to 2017 (p < 0.05) and 11.1% from 2017 to 2018 (p < 0.05). From 2017–2018, rates of visits increased for both males (8.7%; p < 0.05) and females (15.9%; p < 0.05). Patients 0–14 years and 25 years and older had significant rate increases from 2017 to 2018 as did the Midwest region (36.8%; p < 0.05), the Northeast (9.2%; p < 0.05), and the South (4.5%; p < 0.05).
Cannabis-associated ED visits are on the rise and subgroups are at increased risk. Some potential explanations for increases in cannabis-associated ED visits include increased availability of cannabis products, increased use, and diversity of products available in marketplaces. Strategies are needed to prevent youth initiation, limit potentially harmful use among adults, and ensure safe storage where cannabis use is legal.
Cannabinoids for the treatment of cannabis use disorder: New avenues for reaching and helping youth?
2022, Neuroscience and Biobehavioral Reviews
Cannabis use peaks during adolescence and emerging adulthood, and cannabis use disorder (CUD) is associated with a wide range of adverse outcomes. This is particularly pertinent in youth, because the developing brain may be more vulnerable to adverse effects of frequent cannabis use. Combining evidence-based psychosocial interventions with safe and effective pharmacotherapy is a potential avenue to improve youth outcomes, but we lack approved CUD pharmacotherapies. Here, we review new potential avenues for helping youth with CUD, with a particular focus on cannabinoid-based treatments. Evidence from placebo-controlled RCTs suggests synthetic delta-9-tetrahydrocannabinol (THC) decreases withdrawal symptoms, but not cannabis use, in adults with daily cannabis use/CUD, while findings regarding formulations containing THC combined with cannabidiol (CBD) are mixed. Preliminary evidence from two placebo-controlled RCTs in adults with CUD suggests that both Fatty Acid Amide Hydrolase inhibitors and CBD can reduce cannabis use. However, larger trials are needed to strengthen the evidence. Findings from adults point to cannabinoid-based treatments as a potential strategy that should be examined in youth with CUD.
Lower-Risk Cannabis Use Guidelines (LRCUG) for reducing health harms from non-medical cannabis use: A comprehensive evidence and recommendations update
2022, International Journal of Drug Policy
Citation Excerpt :
CBD is a common non-intoxicating cannabinoid constituent of cannabis. It has demonstrated neuroprotective, anti-inflammatory, and anxiolytic effects in laboratory studies and attenuates some of the neurocognitive and behavioral effects of THC, with few and mostly mild adverse effects of itself (Bonaccorso, Ricciardi, Zangani, Chiappini, & Schifano, 2019; Dos Santos et al., 2020; Englund, Freeman, Murray, & McGuire, 2017; Solowij et al., 2019). In clinical trials for CUD, CBD-based pharmacotherapies have somewhat reduced cannabis use frequency, craving and withdrawal symptoms (Batalla, Janssen, Gangadin, & Bossong, 2019; Freeman et al., 2020; Sholler, Schoene, & Spindle, 2020).
Cannabis use is common, especially among young people, and is associated with risks for various health harms. Some jurisdictions have recently moved to legalization/regulation pursuing public health goals. Evidence-based ‘Lower Risk Cannabis Use Guidelines’ (LRCUG) and recommendations were previously developed to reduce modifiable risk factors of cannabis-related adverse health outcomes; related evidence has evolved substantially since. We aimed to review new scientific evidence and to develop comprehensively up-to-date LRCUG, including their recommendations, on this evidence basis.
Targeted searches for literature (since 2016) on main risk factors for cannabis-related adverse health outcomes modifiable by the user-individual were conducted. Topical areas were informed by previous LRCUG content and expanded upon current evidence. Searches preferentially focused on systematic reviews, supplemented by key individual studies. The review results were evidence-graded, topically organized and narratively summarized; recommendations were developed through an iterative scientific expert consensus development process.
A substantial body of modifiable risk factors for cannabis use-related health harms were identified with varying evidence quality. Twelve substantive recommendation clusters and three precautionary statements were developed. In general, current evidence suggests that individuals can substantially reduce their risk for adverse health outcomes if they delay the onset of cannabis use until after adolescence, avoid the use of high-potency (THC) cannabis products and high-frequency/-intensity of use, and refrain from smoking-routes for administration. While young people are particularly vulnerable to cannabis-related harms, other sub-groups (e.g., pregnant women, drivers, older adults, those with co-morbidities) are advised to exercise particular caution with use-related risks. Legal/regulated cannabis products should be used where possible.
Cannabis use can result in adverse health outcomes, mostly among sub-groups with higher-risk use. Reducing the risk factors identified can help to reduce health harms from use. The LRCUG offer one targeted intervention component within a comprehensive public health approach for cannabis use. They require effective audience-tailoring and dissemination, regular updating as new evidence become available, and should be evaluated for their impact.

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Personal ViewCan we make cannabis safer?

Summary

Introduction

Section snippets

Increasing potency of cannabis

Significance of cannabidiol

Dependence

Psychosis

Cognition and intelligence

Insights from cannabinoid experiments

Making cannabis safer

Search strategy and selection criteria

Lancet Psychiatry

Nat Prod Rep

Biol Psychiatry

Eur Neuropsychopharmacol

Drug Alcohol Depend

Int J Drug Policy

Drug Alcohol Depend

Lancet Psychiatry

Schizophr Res

Drug Alcohol Depend

Lancet Psychiatry

Lancet Psychiatry

Eur Neuropsychopharmacol

Lancet Psychiatry

Drug Alcohol Depend

Biol Psychiatry Cogn Neurosci Neuroimaging

Eur J Pharmacol

Pharmacol Biochem Behav

Drug Alcohol Depend

Drug Alcohol Depend

Lancet Psychiatry

Drug Alcohol Depend

Addict Behav

Drug Alcohol Depend

Int J Drug Policy

Cannabis policy: moving beyond stalemate

World Drug Report 2015

World Drug Report 2014

European Drug Report 2015

Legalizing a market for cannabis for pleasure: Colorado, Washington, Uruguay and beyond

Addiction

A quiet revolution: drug decriminalisation policies in practice across the globe

Legal regulated markets have the potential to reduce population levels of harm associated with cannabis use

Addiction

Evolution and classification of Cannabis sativa (marijuana, hemp) in relation to human utilization

Bot Rev

A review of the cultivation and processing of cannabis (Cannabis sativa L.) for production of prescription medicines in the UK

Drug Test Anal

Increasing delta-9-tetrahydrocannabinol (Δ-9-THC) content in herbal cannabis over time: systematic review and meta-analysis

Curr Drug Abuse Rev

Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology

J Forensic Sci

Home Office cannabis potency study

Potency trends of Δ(9)-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005–2015

Addiction

An overview of cannabis potency in Europe

Understanding dabs: contamination concerns of cannabis concentrates and cannabinoid transfer during the act of dabbing

J Toxicol Sci

Synthetic cannabinoid-related illnesses and deaths

N Engl J Med

Keep off the grass? Cannabis, cognition and addiction

Nat Rev Neurosci

Personal View
Can we make cannabis safer?