Exploring causal mechanisms of psychosis risk.

Robust epidemiological evidence of risk and protective factors for psychosis is essential to inform preventive interventions. Previous evidence syntheses have classified these risk and protective factors according to their strength of association with psychosis. In this critical review we appraise the distinct and overlapping mechanisms of 25 key environmental risk factors for psychosis, and link these to mechanistic pathways that may contribute to neurochemical alterations hypothesised to underlie psychotic symptoms. We then discuss the implications of our findings for future research, specifically considering interactions between factors, exploring universal and subgroup-specific factors, improving understanding of temporality and risk dynamics, standardising operationalisation and measurement of risk and protective factors, and developing preventive interventions targeting risk and protective factors.

Cannabidiol does not attenuate acute delta-9-tetrahydrocannabinol-induced attentional bias in healthy volunteers: A randomised, double-blind, cross-over study.

AIMS: To test how attentional bias and explicit liking are influenced by delta-9-tetrahydrocannabinol (THC) and whether these effects are moderated by cannabidiol (CBD). DESIGN: Double-blind, randomised, within-subjects cross-over study. SETTING: NIHR Wellcome Trust Clinical Research Facility at King's College Hospital, London, United Kingdom. PARTICIPANTS/CASES: Forty-six infrequent cannabis users (cannabis use <1 per week). INTERVENTION(S): Across four sessions, participants inhaled vaporised cannabis containing 10 mg of THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1) or 30 mg (3:1) of CBD, administered in a randomised order and counter-balanced across participants (a total of 24 order groups). MEASUREMENTS: Participants completed two tasks: (1) Attentional Bias (AB), comparing reaction times toward visual probes presented behind 28 target stimuli (cannabis/food) compared with probes behind corresponding non-target (neutral) stimuli. Participants responding more quickly to probes behind target than non-target stimuli would indicate greater attentional bias to cannabis/food; (2) Picture Rating (PR), where all AB stimuli were rated on a 7-point pleasantness scale, measuring explicit liking. FINDINGS: During the AB task, participants were more biased toward cannabis stimuli in the 0:1 condition compared with baseline (mean difference = 12.2, 95% confidence intervals [CIs] = 1.20-23.3, d = 0.41, P = 0.03). No other significant AB or PR differences were found between cannabis and food stimuli between baseline and 0:1 condition (P > 0.05). No significant CBD effect was found on AB or PR task performance at any dose (P > 0.05). There was additionally no cumulative effect of THC exposure on AB or PR outcomes (P > 0.05). CONCLUSIONS: A double-blind, randomised, cross-over study among infrequent cannabis users found that inhaled delta-9-tetrahydrocannabinol increased attentional bias toward cannabis in the absence of explicit liking, a marker of liability toward cannabis use disorder. At the concentrations normally found in legal and illegal cannabis, cannabidiol had no influence on this effect.

Co-use of cannabis and alcohol before and after Canada legalized nonmedical cannabis: A repeat cross-sectional study.

BACKGROUND: This study examined changes in population-level co-use of cannabis and alcohol before and 12 months after nonmedical cannabis legalization in Canada, relative to the United States that had previously legalized and not legalized (US legal and illegal states, respectively). METHODS: Data are from waves 1 and 2 of the International Cannabis Policy Study, collected in 2018 (before) and 2019 (12 months after legalization in Canada). Respondents aged 16-65 years from Canada (n = 25,313) and US legal (n = 25,189) and US illegal (n = 19,626) states completed an online survey. Changes in co-use between 2018 and 2019 in US legal and illegal states compared to those in Canada were assessed using multinomial logistic regression. RESULTS: Descriptive analyses show increases in cannabis use and monthly or more frequent (MMF) co-use between 2018 and 2019 in all jurisdictions. Compared to no MMF use of cannabis or alcohol, there was no evidence suggesting differences in changes in MMF co-use in US legal or illegal states relative to Canada. However, respondents in US legal states had 33% higher odds of MMF alcohol-only use (OR = 1.33, 99% CI: 1.12, 1.57) compared to no MMF use relative to Canada. CONCLUSIONS: Increases in co-use were observed between 2018 and 2019 in all jurisdictions regardless of the legal status of cannabis. These shifts were largely due to increases in cannabis use across the population, including those that use alcohol, and may indicate changing societal norms toward cannabis generally. As the cannabis legalization transition in Canada matures, evaluation over the longer term will improve understanding of the influence of cannabis liberalization on co-use.

The acute effects of cannabis with and without cannabidiol in adults and adolescents: A randomised, double-blind, placebo-controlled, crossover experiment.

BACKGROUND AND AIMS: Long-term harms of cannabis may be exacerbated in adolescence, but little is known about the acute effects of cannabis in adolescents. We aimed to (i) compare the acute effects of cannabis in adolescent and adult cannabis users and (ii) determine if cannabidiol (CBD) acutely modulates the effects of delta-9-tetrahydocannabinol (THC). DESIGN: Randomised, double-blind, placebo-controlled, crossover experiment. The experiment was registered on ClinicalTrials.gov (NCT04851392). SETTING: Laboratory in London, United Kingdom. PARTICIPANTS: Twenty-four adolescents (12 women, 16- to 17-year-olds) and 24 adults (12 women, 26- to 29-year-olds) who used cannabis 0.5-3 days/week and were matched on cannabis use frequency (mean = 1.5 days/week). INTERVENTION: We administered three weight-adjusted vaporised cannabis flower preparations: 'THC' (8 mg THC for 75 kg person); 'THC + CBD' (8 mg THC and 24 mg CBD for 75 kg person); and 'PLA' (matched placebo). MEASUREMENTS: Primary outcomes were (i) subjective 'feel drug effect'; (ii) verbal episodic memory (delayed prose recall); and (iii) psychotomimetic effect (Psychotomimetic States Inventory). FINDINGS: Compared with 'PLA', 'THC' and 'THC + CBD' significantly (P < 0.001) increased 'feel drug effect' (mean difference [MD] = 6.3, 95% CI = 5.3-7.2; MD = 6.8, 95% CI = 6.0-7.7), impaired verbal episodic memory (MD = -2.7, 95% CI = -4.1 to -1.4; MD = -2.9, 95% CI = -4.1 to -1.7) and increased psychotomimetic effects (MD = 7.8, 95% CI = 2.8-12.7; MD = 10.8, 95% CI = 6.2-15.4). There was no evidence that adolescents differed from adults in their responses to cannabis (interaction P ≥ 0.4). Bayesian analyses supported equivalent effects of cannabis in adolescents and adults (Bayes factor [BF01 ] >3). There was no evidence that CBD significantly modulated the acute effects of THC. CONCLUSIONS: Adolescent cannabis users are neither more resilient nor more vulnerable than adult cannabis users to the acute psychotomimetic, verbal memory-impairing or subjective effects of cannabis. Furthermore, in adolescents and adults, vaporised cannabidiol does not mitigate the acute harms caused by delta-9-tetrahydocannabinol.

Effects of cannabinoids on resting state functional brain connectivity: A systematic review.

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.

Does cannabidiol make cannabis safer? A randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios.

As countries adopt more permissive cannabis policies, it is increasingly important to identify strategies that can reduce the harmful effects of cannabis use. This study aimed to determine if increasing the CBD content of cannabis can reduce its harmful effects. Forty-six healthy, infrequent cannabis users participated in a double-blind, within-subject, randomised trial of cannabis preparations varying in CBD content. There was an initial baseline visit followed by four drug administration visits, in which participants inhaled vaporised cannabis containing 10 mg THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1), or 30 mg (3:1) CBD, in a randomised, counter-balanced order. The primary outcome was change in delayed verbal recall on the Hopkins Verbal Learning Task. Secondary outcomes included change in severity of psychotic symptoms (e.g., Positive and Negative Syndrome Scale [PANSS] positive subscale), plus further cognitive, subjective, pleasurable, pharmacological and physiological effects. Serial plasma concentrations of THC and CBD were measured. THC (0:1) was associated with impaired delayed verbal recall (t(45) = 3.399, d = 0.50, p = 0.001) and induced positive psychotic symptoms on the PANSS (t(45) = -4.709, d = 0.69, p = 2.41 × 10-5). These effects were not significantly modulated by any dose of CBD. Furthermore, there was no evidence of CBD modulating the effects of THC on other cognitive, psychotic, subjective, pleasurable, and physiological measures. There was a dose-response relationship between CBD dose and plasma CBD concentration, with no effect on plasma THC concentrations. At CBD:THC ratios most common in medicinal and recreational cannabis products, we found no evidence that CBD protects against the acute adverse effects of cannabis. This should be considered in health policy and safety decisions about medicinal and recreational cannabis.

Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Plasma Endocannabinoid Levels in Healthy Volunteers: A Randomized Double-Blind Four-Arm Crossover Study.

Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers. Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers (n=46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry. Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042 ng/mL [95%CI: 0.023-0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; +35.8%, 0.012 ng/mL [95%CI: 0.008-0.016]), oleoylethanolamide (+16.1%, 0.184 ng/mL [95%CI: 0.076-0.293]), and N-arachidonoyl-L-serine (+25.1%, 0.011 ng/mL [95%CI: 0.004-0.017]) (p<0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223-0.286] to 0.194 ng/mL [95%CI: 0.163-0.226], and from 0.039 ng/mL [95%CI: 0.032-0.045] to 0.027 ng/mL [95%CI: 0.020-0.034] (p<0.05), respectively. Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT05170217).

Can cannabis kill? Characteristics of deaths following cannabis use in England (1998-2020).

BACKGROUND: Cannabis is the most widely used illegal drug but is rarely considered a causal factor in death. AIMS: This study aimed to understand trends in deaths in England where cannabinoids were detected at post-mortem, and to evaluate the clinical utility of post-mortem cannabinoid concentrations in coronial investigations. METHODS: Deaths with cannabinoid detections reported to the National Programme on Substance Abuse Deaths (NPSAD) were extracted and analysed. RESULTS: From 1998 to 2011, on average 7% of all cases reported to NPSAD had a cannabinoid detected (n = 110 deaths per year), rising to 18% in 2020 (n = 350). Death following cannabis use alone was rare (4% of cases, n = 136/3455). Traumatic injury was the prevalent underlying cause in these cases (62%, n = 84/136), with cannabis toxicity cited in a single case. Polydrug use was evident in most cases (96%, n = 3319/3455), with acute drug toxicity the prevalent underlying cause (74%, n = 2458/3319). Cardiac complications were the most cited physiological underlying cause of death (4%, n = 144/3455). The median average Δ9-tetrahydrocannabinol post-mortem blood concentrations were several magnitudes lower than previously reported median blood concentrations in living users (cannabis alone: 4.3 µg/L; cannabis in combination with other drugs: 3.5 µg/L). CONCLUSIONS: Risk of death due to cannabis toxicity is negligible. However, cannabis can prove fatal in circumstances with risk of traumatic physical injury, or in individuals with cardiac pathophysiologies. These indirect harms need careful consideration and further study to better elucidate the role cannabis plays in drug-related mortality. Furthermore, the relevance of cannabinoid quantifications in determining cause of death in coronial investigations is limited.

Could COVID expand the future of addiction research? Long-term implications in the pandemic era.

BACKGROUND/AIMS: The COVID-19 pandemic has significantly impacted face-to-face research. This has propelled ideas and plans for more remote styles of research and provided new perspectives on conducting research. This paper aimed to identify challenges specific to conducting remote forms of experimental addiction research, although some of these challenges apply to all types of addiction research. ARGUMENT: The impact of the COVID-19 pandemic has led to important lessons for future addiction research. Although remote research has been conducted for decades, little experimental research has been performed remotely. To do so require a new perspective on what research questions we can ask and could also enable preferential capture of those who may be more reluctant to engage in research based in clinical settings. There may, however, be crucial factors that will compromise this process. We illustrate our argument with three real-world, ongoing case studies centred on gambling behaviour, opioid overdose, and cannabinoid psychopharmacology. We highlight the obstacles to overcome to enable more remote methods of study. CONCLUSIONS: The future of experimental research and, more generally, addiction research, will be shaped by the pandemic and may result in advantages, such as reaching different populations and conducting addiction research in more naturalistic settings.

Synthetic Cannabinoid-Related Deaths in England, 2012-2019.

Aim: To identify drug-related death trends associated with synthetic cannabinoid receptor agonists (SCRAs) reported to the National Programme on Substance Abuse Deaths (NPSAD) from England. Design: Case reports from NPSAD (England) where a SCRA was detected in post-mortem tissue(s) and/or implicated in the death were extracted, analyzed, and compared against non-SCRA-related deaths that occurred over the same time period (2012-2019). Findings: One hundred sixty-five death SCRA-related reports were extracted, with 18 different SCRAs detected. Following the first death in 2012, a subsequent sharp increase in reporting is evident. Acute SCRA use was the underlying cause of death in the majority of cases (75.8%) with cardiorespiratory complications the most frequently cited underlying physiological cause (13.4%). SCRA users were predominantly found dead (68.6%), with a large proportion of those witnessed becoming unresponsive described as suddenly collapsing (81.6%). Psychoactive polydrug use was detected in 90.3% of cases, with alcohol the most commonly co-detected (50.3%), followed by opioids (42.2%), benzodiazepines/Z-drugs (32.1%), stimulants (32.1%, [28.5% cocaine]), and cannabis (24.8%). Compared to all non-SCRA-related NPSAD deaths occurring over the same time period, SCRA-related decedents were more predominantly male (90.3% vs. 72.0%; p<0.01), and lived in more deprived areas (p<0.01). While a comparatively significant proportion of decedents were homeless (19.4% vs. 4.1%), living in a hostel (13.3% vs. 2.3%) or in prison (4.9% vs. 0.2%) at time of death (all p<0.01), the greatest majority of SCRA-related decedents were living in private residential accommodations (57.6%). Conclusions: This is the largest dataset regarding SCRA-related mortalities reported to date. Reporting of SCRA-related deaths in England have increased considerably, with polydrug use a specific concern. Lack of effective deterrents to SCRA use under current UK legislation, compounded by limited knowledge regarding the physiological impacts of SCRA consumption and their interaction with other co-administered substances are contributory factors to the occurrence of SCRA-related mortalities in an increasingly deprived demographic.

The International Cannabis Toolkit (iCannToolkit): a multidisciplinary expert consensus on minimum standards for measuring cannabis use.

BACKGROUND: The lack of an agreed international minimum approach to measuring cannabis use hinders the integration of multidisciplinary evidence on the psychosocial, neurocognitive, clinical and public health consequences of cannabis use. METHODS: A group of 25 international expert cannabis researchers convened to discuss a multidisciplinary framework for minimum standards to measure cannabis use globally in diverse settings. RESULTS: The expert-based consensus agreed upon a three-layered hierarchical framework. Each layer-universal measures, detailed self-report and biological measures-reflected different research priorities and minimum standards, costs and ease of implementation. Additional work is needed to develop valid and precise assessments. CONCLUSIONS: Consistent use of the proposed framework across research, public health, clinical practice and medical settings would facilitate harmonisation of international evidence on cannabis consumption, related harms and approaches to their mitigation.

Lack of evidence for the effectiveness or safety of over-the-counter cannabidiol products.

Over the past 5 years, public interest in the potential health benefits of cannabidiol (CBD) has increased exponentially, and a wide range of over-the-counter (OTC) preparations of CBD are now available. A substantial proportion of the population appears to have used these products, yet the extent to which they are effective or safe is unclear. We reviewed the evidence for whether CBD has significant pharmacological and symptomatic effects at the doses typically found in OTC preparations. We found that most of the evidence for beneficial effects is derived from studies of pure, pharmaceutical grade CBD at relatively high doses. Relatively few studies have examined the effect of OTC CBD preparations, or of CBD at low doses. Thus, at present, there is little evidence that OTC CBD products have health benefits, and their safety has not been investigated. Controlled trials of OTC and low-dose CBD preparations are needed to resolve these issues.

Does cannabis complement or substitute alcohol consumption? A systematic review of human and animal studies.

BACKGROUND: Whether alcohol and cannabis complement or substitute each other has been studied for over two decades. In the changing cannabis policy landscape, debates are moving rapidly and spill-over effects on other substances are of interest. AIMS: update and extend a previous systematic review, by: (a) identifying new human behavioural studies reporting on substitution and/or complementarity of alcohol and cannabis, and (b) additionally including animal studies. METHODS: We replicated the search strategy of an earlier systematic review, supplemented with a new search for animal studies. Search results were crossed checked against the earlier review and reference lists were hand searched. Findings were synthesised using a narrative synthesis. RESULTS: Sixty-five articles were included (64 in humans, one in animals). We synthesised findings into categories: patterns of use, substitution practices, economic relationship, substance use disorders, policy evaluation, others and animal studies. Overall, 30 studies found evidence for substitution, 17 for complementarity, 14 did not find evidence for either, and four found evidence for both. CONCLUSIONS: Overall, the evidence regarding complementarity and substitution of cannabis and alcohol is mixed. We identified stronger support for substitution than complementarity, though evidence indicates different effects in different populations and to some extent across different study designs. The quality of studies varied and few were designed specifically to address this question. Dedicated high-quality research is warranted.

Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials.

Cannabidiol (CBD) is being investigated as a treatment for several medical disorders but there is uncertainty about its safety. We conducted the first systematic review and meta-analysis of the adverse effects of CBD across all medical indications. Double-blind randomized placebo-controlled clinical trials lasting ≥7 days were included. Twelve trials contributed data from 803 participants to the meta-analysis. Compared with placebo, CBD was associated with an increased likelihood of withdrawal for any reason (OR 2.61, 95% CI: 1.38-4.96) or due to adverse events (OR 2.65, 95% CI: 1.04-6.80), any serious adverse event (OR 2.30, 95% CI: 1.18-4.48), serious adverse events related to abnormal liver function tests (OR 11.19, 95% CI: 2.09-60.02) or pneumonia (OR 5.37, 95% CI: 1.17-24.65), any adverse event (OR 1.55, 95% CI: 1.03-2.33), adverse events due to decreased appetite (OR 3.56, 95% CI: 1.94-6.53), diarrhoea (OR 2.61, 95% CI: 1.46-4.67), somnolence (OR 2.23, 95% CI: 1.07-4.64) and sedation (OR 4.21, 95% CI: 1.18-15.01). Associations with abnormal liver function tests, somnolence, sedation and pneumonia were limited to childhood epilepsy studies, where CBD may have interacted with other medications such as clobazam and/or sodium valproate. After excluding studies in childhood epilepsy, the only adverse outcome associated with CBD treatment was diarrhoea (OR 5.03, 95% CI: 1.44-17.61). In summary, the available data from clinical trials suggest that CBD is well tolerated and has relatively few serious adverse effects, however interactions with other medications should be monitored carefully. Additional safety data from clinical trials outside of childhood epilepsy syndromes and from studies of over-the-counter CBD products are needed to assess whether the conclusions drawn from clinical trials can be applied more broadly.

Real-world digital implementation of the Psychosis Polyrisk Score (PPS): A pilot feasibility study.

BACKGROUND: The Psychosis Polyrisk Score (PPS) is a potential biomarker integrating non-purely genetic risk/protective factors for psychosis that may improve identification of individuals at risk and prediction of their outcomes at the individual subject level. Biomarkers that are easy to administer are direly needed in early psychosis to facilitate clinical implementation. This study digitally implements the PPS and pilots its feasibility of use in the real world. METHODS: The PPS was implemented digitally and prospectively piloted across individuals referred for a CHR-P assessment (n = 16) and healthy controls (n = 66). Distribution of PPS scores was further simulated in the general population. RESULTS: 98.8% of individuals referred for a CHR-P assessment and healthy controls completed the PPS assessment with only one drop-out. 96.3% of participants completed the assessment in under 15 min. Individuals referred for a CHR-P assessment had high PPS scores (mean = 6.2, SD = 7.23) than healthy controls (mean = -1.79, SD = 6.78, p < 0.001). In simulated general population data, scores were normally distributed ranging from -15 (lowest risk, RR = 0.03) to 39.5 (highest risk, RR = 8912.51). DISCUSSION: The PPS is a promising biomarker which has been implemented digitally. The PPS can be easily administered to both healthy controls and individuals at potential risk for psychosis on a range of devices. It is feasible to use the PPS in real world settings to assess individuals with emerging mental disorders. The next phase of research should be to include the PPS in large-scale international cohort studies to evaluate its ability to refine the prognostication of outcomes.

Changes in the composition of cannabis from 2000-2017 in Denmark: Analysis of confiscated samples of cannabis resin.

Globally, recent studies report increases in Δ-9-tetrahydrocannabinol (THC) concentration in seized samples of cannabis for human consumption. This is important, because use of cannabis with a high concentration of THC has been linked to a number of adverse health outcomes. The objective of this study was to assess recent changes in the composition of seized cannabis resin in Denmark by (a) examining THC concentration in samples from Danish forensic laboratories from 2000 to 2017 (N = 430) and (b) examining cannabidiol (CBD) concentration and the THC:CBD concentration ratio in samples from the forensic laboratory in Western Denmark from 2008 to 2017 (N = 147). Cannabis resin samples were analyzed using a gas chromatographic analysis with flame ionization detection quantifying the total THC and CBD concentration. Results showed that the THC concentration increased 3-fold from 2000 (mean: 8.3%) to 2017 (mean: 25.3%). Significant increases occurred in all areas of Denmark. After 2011, we found a dramatic increase in cannabis resin samples with high THC concentration and the near disappearance of cannabis resin samples with medium- and low THC concentration. Furthermore, the THC:CBD concentration ratio increased significantly from 1.4 in 2008 to 4.4 in 2017. Whereas THC concentration increased, CBD concentration remained stable at ∼6%. In conclusion, the THC concentration of cannabis resin, and THC:CBD concentration ratio, have increased dramatically in Denmark, potentially leading to higher risk of harm to users. Policymakers, treatment professionals, and educators should be aware of this change. (PsycINFO Database Record (c) 2019 APA, all rights reserved).