After medical marijuana became legal in Massachusetts – cannabis-related poison doubled

After medical marijuana became legal in Massachusetts, cannabis-related poison control calls involving the commonwealth’s children and teenagers doubled, according to a public health investigation led by University of Massachusetts Amherst injury prevention researcher Jennifer Whitehill.

The increase in calls to the Regional Center for Poison Control and Prevention at Boston Children’s Hospital occurred despite legislative mandates for childproof packaging and warning labels, and before the recreational use of marijuana was legalized for adults.

“As states across the country enact more permissive marijuana policies, we need to do more to promote safe storage in households with children,” says Whitehill, assistant professor of health promotion and policy and lead author of the research published in JAMA Network Open.

Whitehill and former UMass Amherst graduate student Calla Harrington analyzed data from the poison control center in collaboration with staff from the center, including medical director Dr. Michele Burns and clinical fellow Dr. Michael Chary.

The research team reviewed the center’s data from 2009 through 2016—four years before and four years after medical marijuana was legalized in Massachusetts.

During the study period, the poison control center received 218 calls from Massachusetts involving cannabis exposure in children and teens, from infancy to age 19, including 98 single-substance calls and 120 polysubstance calls.

Those calls represented 0.15 percent of all poison control calls during that time period for that age group.

“While we’re pleased to see that the incidence is relatively low, we feel these cases are preventable, and the issue needs to be on the radar of policymakers and parents, particularly now that dispensaries are open for adult-use sales,” Whitehill says.

Some highlights of the findings:

• The incidence of calls for single-substance cannabis exposure increased 140 percent during the study period—from 0.4 per 100,000 population before medical marijuana was legalized to 1.1 per 100,000 population after legalization.
• Nearly 80 percent of the calls to the poison control center came from healthcare facilities, and, in terms of medical outcomes, most of the exposures resulted in moderate and minor effects. Four cases with major effects and no deaths were reported.
• A little more than a quarter of the cases were reported as unintentional, with 19.4 percent of calls involving children from infancy through age 4.
• Calls involving edible cannabis products increased for most age groups, including ages 15-19. Because other research has found that the proportion of teens using marijuana is remaining about the same even as marijuana laws are loosening, this finding suggests that teenagers may be caught off guard by the potentially potent effects of edibles and concentrated extracts, Whitehill says.

The paper concludes, “This study suggests that states liberalizing marijuana policies should consider strengthening regulations to prevent unintentional exposure among young children and enhancing efforts to prevent use by teenagers, with particular attention to edible cannabis products and concentrated extracts.”

Whitehill says the next step is to study the impact of marijuana’s legalization for adult use, which went into effect in late 2016.

Two years later, in November 2018, marijuana retail stores began opening.

“Given what we’ve seen here,” Whitehill says, “I would expect the calls to the poison control center to increase even more.”

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As of January 2018 in the United States, nine states have legalized cannabis for recreational use, with another 29 legalizing it for medical use. These policy changes have created broad interest in understanding the effects on public health and the healthcare system.

The Colorado Department of Public Safety report, “Impacts of Marijuana Legalization in Colorado: A Report Pursuant to Senate Bill 13-283,” includes a timeline for marijuana legalization in Colorado with five distinct periods in both the legal status and commercial availability of marijuana in Colorado.¹ These include the following:

• Prior to 2000: It is illegal to possess or grow marijuana.
• 2000–2009: Amendment 20 is approved and medical marijuana is legalized. The Colorado Department of Public Health and Environment (CDPHE) issues registry identification cards to individuals who have received recommendations from a doctor that marijuana will help a debilitating medical condition. No regulated market exists. Individual grow operations or caregiver grow operations limited to five patients are allowed.
• 2010–2012: Medical marijuana is commercialized and regulated with licensed dispensaries, grow operations, and product manufacturers open in jurisdictions allowing these types of businesses. This corresponded with the Ogden memorandum issued in October 2009, which instructed U.S. Attorneys not to “focus federal resources in your States on individuals whose actions are in clear and unambiguous compliance with existing state laws providing for the medical use of marijuana.”² The commercialization of medical marijuana followed and the number of patients registered with CDPHE increased dramatically from about 5000 in 2009 to almost 119,000 in 2011.
• 2013: Amendment 64 takes effect. Personal possession and grow limits for recreational marijuana are in place but sales are not commercialized. Medical continues as a regulated, commercial market.
• 2014 to present: Recreational and medical marijuana is fully regulated and commercialized. Licensed retail stores open January 1, 2014. This corresponded with the Cole memorandum, which gave further guidance to U.S. Attorneys: “[I]n jurisdictions that have enacted laws legalizing marijuana in some form and that have also implemented strong and effective regulatory and enforcement systems to control the cultivation, distribution, sale, and possession of marijuana, conduct in compliance with those laws and regulations is less likely to threaten federal priorities… [E]nforcement of state law by state and local law enforcement and regulatory bodies should remain the primary means of addressing marijuana-related activity.”³ This memorandum was widely interpreted to mean that the federal government would not interfere with state marijuana laws;⁴ however, in January 2018 the Cole memorandum was rescinded by then U.S. Attorney General Jeff Sessions.⁴

Changes in past-month cannabis use by year and age group for Colorado and Kansas (non-legalized state) are shown in Figures 1 and ​and2.2. (Kansas was chosen for proximity; other non-legalized states in proximity, including Wyoming and Idaho, had similar graphs to Kansas.)⁵

Over this time span cannabis potency has increased. Current commercialized cannabis is near 20% tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, while in the 1980s concentration was <2%. This 10-fold increase in potency does not include other formulations such as oils, waxes, and dabs, which can reach 80–90% THC.⁶

This general increase in cannabis use and increase in cannabis potency has led to cannabis-related presentations to emergency departments (ED) and hospitalizations across the state. This review will focus on negative health and safety effects Colorado has experienced with inclusion of relevant peer-reviewed literature. It will conclude with a short review of the medicinal use of cannabis products.

Population Health Research Capsule

What do we already know about this issue?

Legalized cannabis has led to increased cannabis related presentations to emergency departments (ED).

What was the focus of this review?

The negative impacts to EDs, particularly in the state of Colorado, following cannabis legalization.

What was the conclusion of this review?

Cannabis legalization has been correlated with multiple adverse outcomes that impact EDs.

How does this improve population health?

Healthcare policy makers may take the adverse outcomes described into consideration when considering if and/or how to legalize cannabis.

Cannabis Effects on Healthcare Resources in Colorado

ED visits and hospitalizations with marijuana-related billing codes have increased following legalization. Mental illness represents a concerningly large number of marijuana-related visits. A retrospective review by Wang et al. reported Colorado Hospital Association hospitalizations and ED visits with marijuana-related billing codes.

Between 2000 and 2015, hospitalization rates increased 116% from 274 to 593 per 100,000 hospitalizations. For primary diagnosis categories, the prevalence of mental illness was five-fold higher (5.07; 95% confidence interval [CI], 4.96 – 5.09) for ED visits and nine-fold higher (9.67; 95% CI, 9.59 – 9.74) for hospital admissions for patients with marijuana-related billing codes compared to those without.⁷ This data compared diagnostic categories between patients with a marijuana-related diagnostic code and those without.

Subsequent data by the CDPHE show significant increases in hospitalizations in each phase of marijuana legalization, increasing from 575 per 100,000 hospitalizations in 2000 to 2413 in the 2014–June 2015 period, as displayed in Figure 3.⁸ There are differences in incidence between the Wang study and the CDPHE report because the Wang study only included a patient’s healthcare event if a marijuana code was among the first three diagnostic codes, while the CDPHE study included marijuana diagnostic codes within the top 30.

ED and urgent care (UC) visits with cannabis-associated International Classification of Diseases (ICD) codes or positive urine drug screens for teenagers and young adults have increased since legalization, and the majority require behavioral health evaluation. A subsequent retrospective review by Wang et al. from 2005–2015 identified 4202 such visits for patients 13 to <21 years old to a tertiary-care children’s hospital system. Behavioral health evaluation was obtained for 2813 (67%) and a psychiatric diagnosis was made for the majority (71%) of the visits. ED/UC visits with cannabis-associated ICD codes or positive urine drug screens of all types increased 2.7-fold from 1.8 per 1000 in 2009 to 4.9 per 1000 in 2015 (N = 161 in 2005 to 777 in 2015). Behavioral health consultations increased 2.7-fold from 1.2 per 1000 in 2009 to 3.2 per 1000 in 2015 (N = 84 in 2005 to 500 in 2015). These data indicate that despite national survey data suggesting the rate of adolescent marijuana use is flat, there has been a significant increase in adolescent ED/UC visits with cannabis-associated ICD codes or positive urine drug screens.⁹ Figure 4 displays these visits by year.

Cannabis Effects on Mental Health

Psychosis and Schizophrenia

Previous studies, including large reviews by the World Health Organization (WHO) and the National Academies of Sciences, Engineering, and Medicine (NASEM), have found substantial evidence of a statistical association between cannabis use and the development of schizophrenia or other psychoses, with the highest risk among the most frequent users.^6,10 In a study of 45,570 Swedish men drafted into the military, the authors found that the men who had tried cannabis by age 18 were 2.4 times (95% CI, 1.8–3.3) more likely to be diagnosed with schizophrenia over the next 15 years than those who had not.¹¹ A follow-up study found a dose-response relationship between frequency of cannabis use at the age of 18 and the risk of schizophrenia. This effect persisted after controlling for confounding factors such as psychiatric diagnosis at enlistment, IQ score, personality variables concerned with interpersonal relationships, place of upbringing, paternal age, cigarette smoking, disturbed behaviors in childhood, history of alcohol misuse, family history of psychiatric illness, financial situation of the family, and father’s occupation. (The enlistment procedure included intelligence tests and non-anonymous, self-reported questionnaires on family, social background, behavior during adolescence, and substance use – including first drug used, drug most commonly used, frequency of use, and direct questions regarding use of a list of specified drugs.) The researchers estimated that 13% of cases of schizophrenia could have been averted if no one in the cohort had used cannabis.¹² These findings have been reproduced repeatedly and across the world.^13–20

Depression, Anxiety, and Suicide

Cannabis use is associated with increased rates of depression, anxiety, and suicide. The NASEM found that there is a moderate statistical association between cannabis use and an increased risk for the development of depressive disorders (odds ratio [OR] = 1.17; 95% CI, 1.05–1.30) and this increases with increased frequency of use (OR = 1.62; 95% CI, 1.21–2.16).^10,21 There was also moderate evidence of a statistical association between regular cannabis use and increased incidence of social anxiety disorder (OR = 1.28; 95% CI, 1.06–1.54).^10,22 The NAESM found that there was moderate evidence of a statistical association between cannabis use and the incidence of suicidal ideation (OR = 1.43; 95% CI, 1.13–1.83 with any cannabis use, OR = 2.53; 95% CI, 1.00–6.39 with heavy cannabis use) and suicide attempts (OR = 2.23; 95% CI, 1.24–4.00 for any cannabis use, OR = 3.20; 95% CI, 1.72–5.94 with heavy cannabis use), and increased incidence of suicide completion (OR = 2.56; 95% CI, 1.25–5.27 for any cannabis use).^10,23

The NASEM reviewed multiple studies to come to the summary conclusions, and the odds ratios represent the most compelling systematic review for the conclusions. However, there were many more studies used to reach the stated conclusions. The data reviewed by the World Health Organization also demonstrate similar results for depression, anxiety, and suicide.⁶ Both the NASEM and the WHO reviews acknowledge that reverse causation and shared risk factors cannot be ruled out as explanations of these statistical associations and acknowledge that further research is needed.

In the most recent data on Colorado adolescent suicides, marijuana was the most common substance present for ages 10–19 in 2016. Of 62 suicides with toxicology data available, marijuana was present in 30.6% (n = 19) compared to 9.7% (n = 6) for alcohol.²⁴ This trend has been increasing since liberalization of marijuana policy in 2010. This is more concerning as suicide is currently the leading cause of death of adolescents in Colorado.²⁵ For all age groups in Colorado, in the five-year period from 2004–2009 there were 4822 suicides and 7.1% (n = 303) of those were marijuana positive on toxicology analysis (538 did not have toxicology data available). In the subsequent five-year period of marijuana legalization, 2010–2015, there were 5880 total suicides (22% increase), and 12.6% had a positive toxicology for marijuana (n = 601; 1,120 did not have toxicology data available). This represents a statistically significant 77.5% increase in the proportion of suicide victims with toxicology positive for marijuana (an absolute difference of 5.5%) for which toxicology data were reported (chi square 77.2884, p<0.0001). Suicides with marijuana toxicology by year and overall suicide by year data are displayed in Figure 5.

Social Outcomes

Cannabis has been associated with adverse social outcomes which may impact EDs and patient health. The large (N = 49,321) cohort study of Swedish men drafted at age 18–20 and followed to age 40 showed increased risk of unemployment and need for welfare assistance in those using cannabis greater than 50 times (risk ratio [RR] = 1.26; 95% CI, 1.04–1.53 for unemployment), (RR = 1.38; 95% CI, 1.19–1.62 for welfare assistance).²⁶ These results were repeated in a longitudinal birth cohort study in New Zealand to 25 years old, which found high levels of cannabis use correlated with statistical significance to poorer educational outcomes, lower income, greater welfare dependence and unemployment, and lower relationship and life satisfaction.

This cohort was classified into six levels of cannabis use, and found that as cannabis use increased, the odds ratio of adverse outcome increased.^27,28 Both of these studies adjusted for confounding factors including socioeconomic background of the family, family functioning and exposure to adversity, exposure to child sexual and physical abuse, childhood and adolescent adjustment, academic achievement in early adolescence, comorbid mental health disorders, and other substance use.

A prospective cohort study from upstate New York (N = 548) found that, compared with cannabis nonusers or minimal users (a few times a year or less), chronic users and users who began use in early adulthood and then tapered off use into later adulthood, had a significantly higher likelihood of unemployment at mean age 43 (adjusted OR = 3.51; 95% CI, 1.13–10.91), even after controlling for covariates.²⁹ 

The NASEM review stated that there was a limited level of evidence of impaired academic achievement and education outcomes, increased rates of unemployment and/or low income, and impaired social functioning or engagement in developmentally appropriate social roles.¹⁰ 

The report stated that although there was evidence to suggest these outcomes, it was difficult to document a direct link between cannabis use and these outcomes because other variables played a role. Social outcome data for cannabis users specifically in Colorado are currently unavailable and could be an area for further research.

Structural, Functional, and Chemical Brain Changes in Cannabis Users

A number of review articles on cannabis have described adverse effects on brain imaging.^6,30–33 

These findings may help establish a mechanistic link between the epidemiological studies on the adverse effects of cannabis.

Structural, functional, and chemical changes to the brain have been established. These include both the gray matter (neuronal cells) and white matter (nerve axons responsible for communication).^34,35

 Structural changes to the brain include reductions in the hippocampus^34–38 (12.1% in the left and 11.9% in the right, relative to controls)³⁸ and amygdala^37,38 (6.0% in the left and 8.2% in the right, relative to controls)³⁸ volumes in cannabis users.

Several studies also identified reductions in volume of specific areas of the prefrontal cortex,^39–41 as well as functional magnetic resonance imaging (fMRI) studies demonstrating reduced functional connectivity in the prefrontal networks responsible for executive function (including inhibitory control) and the subcortical networks, which process habits and routines.^30,42–25

Other fMRI studies show reduced connectivity in the fimbriae of the hippocampus and commissural fibers extending to the precuneus, and suggest that this disturbed brain connectivity in cannabis users may underlie cognitive impairment and vulnerability to psychosis, depression, and anxiety disorders.⁴⁶ 

Multiple other areas of the brain have also been shown to demonstrate changes on fMRI studies in response to cannabis and include the orbitofrontal cortex, anterior cingulate cortex, striatum, amygdala, hippocampus, and cerebellum.³⁷ In general, these changes on both structural and functional MRI studies corresponded with frequency of use and earlier age of onset of use (although several studies identified these changes in adult users as well).^34,35

Other fMRI studies show reduced connectivity in the fimbriae of the hippocampus and commissural fibers extending to the precuneus, and suggest that this disturbed brain connectivity in cannabis users may underlie cognitive impairment and vulnerability to psychosis, depression, and anxiety disorders.⁴⁶ 

Multiple other areas of the brain have also been shown to demonstrate changes on fMRI studies in response to cannabis and include the orbitofrontal cortex, anterior cingulate cortex, striatum, amygdala, hippocampus, and cerebellum.³⁷ In general, these changes on both structural and functional MRI studies corresponded with frequency of use and earlier age of onset of use (although several studies identified these changes in adult users as well).^34,35

Changes to neurotransmitters in the brain have also been well described in systematic reviews and include disruptions in glutamate,⁴⁷ dopamine,⁴⁸ N-acetylaspartate,⁴⁹ myo-inositol,⁴⁹choline,⁴⁹ and γ-aminobutyric acid (GABA).^33,49

Taken together, these changes may underlie the clinical features being observed in observational and epidemiological studies demonstrating increases in psychosis, impulsivity, depression, anxiety, suicidality, decreases in cognition, IQ, and executive function, abnormalities in habits, routines, decision-making capacity, and deficits in learning, memory, attention, and social interaction.^6,30,31

Link to Other Substance Abuse

Cannabis use has also been associated with abuse of other illicit substances. According to the NASEM report, there is a moderate level of evidence of a statistical association between cannabis use and the development of substance dependence and/or substance abuse disorder for alcohol, tobacco, and illicit drugs.¹⁰ Multiple cohort studies have demonstrated these results.^50–52

 Four separate discordant twin studies have found that the twin who used marijuana was more likely to use other substances even after controlling for environmental and genetic influences.^53–56 Although some studies reported that medical cannabis has resulted in improvements in opiate-related deaths,^57,58 Colorado has had an increase in poisoning and deaths from opiates and methamphetamines since 2010, with the highest in 2017. These rates have increased nationwide as well and the influence of cannabis in Colorado is difficult to discern. Nevertheless, the increase in overdose deaths in Colorado is alarming. These data are shown in Figure 6.²⁵

Although animal studies do not consistently translate to human effects, rat studies can provide some mechanistic clues.

After exposure to tetrahydrocannabinol (THC), rats have an increased behavioral sensitization response to not only THC but also opiates and nicotine.^59–61 Studies also demonstrate that these behavioral changes in rats correspond to neuronal activity changes in mesolimbic dopamine neurons in the ventral tegmental area and nucleus accumbens and that cross-tolerance results with exposure to morphine, amphetamines, and cocaine.^61,62 

Repeat morphine self-administration has been shown to be significantly lower in CB₁ knockout mice (CB₁ receptors are the among the most predominant G protein-coupled receptors in the brain and mediate most of the psychotropic effects of THC) and opiate withdrawal symptoms significantly less when the knockout mice are administered naloxone.⁶³

Cannabis Dependence/Withdrawal Symptoms

Cannabis use may result in dependence and cessation may result in withdrawal symptoms. Dependence rates are reported at one in 10 among those who ever use cannabis, one in six among adolescent users, and one in three among daily users.^6,64–67 Withdrawal symptoms may include anxiety, insomnia, appetite disturbance, and depression. These symptoms are sufficient to impair everyday functioning and are markedly attenuated by doses of an oral cannabis extract.⁶

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More information:JAMA Network Open (2019). DOI: 10.1001/jamanetworkopen.2019.9456

Journal information: JAMA Network Open
Provided by University of Massachusetts Amherst