Methamphetamine/amphetamine abuse and risk of Parkinson's disease in Utah: A population-based assessment
Introduction
According to the 2006 National Survey on Drug Use and Health, Utah ranks 17th among US states in reported use of methamphetamine (METH) within the previous year among those 12 years and older (0.94%; Substance Abuse and Mental Health Services Administration (SAMHSA), 2006) and nearly 4% of Utah high-school students reported using METH at least once in a recent survey (Centers for Disease Control and Prevention, 2011). Regionally, Utah is located within the western United States (US) where recent METH use rates are over twice as high as in the Midwest or the South, and 12 times as high as the Northeast; age at first use typically occurs in the late teens to early 20's (SAMHSA, 2013). The budgets of community hospitals and treatment facilities are adversely affected as visits related to METH use account for 9% of emergency department patient visits nationally (SAMHSA, 2011). The individual and public health consequences of these reports are significant, considering potential adverse health outcomes of individuals who initially engage in METH use at a young age.
Despite widespread abuse of METH and amphetamine or other amphetamine-type stimulants (AMPH), little is known about the long-term consequences of METH/AMPH abuse and dependence. Methamphetamine and its metabolite amphetamine cause release of the neurotransmitter dopamine in the dopamine-rich striatal subdivisions of the mammalian brain (Kish, 2008). Both the plasmalemmal dopamine transporter and the vesicular monoamine transporter-2 seem to play critical roles in this neurotoxicity (Hanson et al., 2004). Pre-clinical data demonstrate that METH can damage dopamine nerve terminals in the striatum, but with largely an apparent sparing of cell bodies (Fleckenstein et al., 2007). In humans, imaging and postmortem studies indicate that METH abuse causes persistent dopaminergic deficits (Wilson et al., 1996, Volkow et al., 2001, Kitamura, 2009). These neurotoxicity findings raise public health concerns that METH/AMPH may damage dopamine neurons in humans, resulting in dopamine-related disorders such as PD (Caligiuri and Buitenhuys, 2005). This concern was raised in a small clinical study in which prolonged amphetamine exposure was more frequent in PD patients ages 40–64 than in spouse controls (Garwood et al., 2006), and later in a study of California inpatient hospital and death records (1990–2005) in which researchers reported patients had a 1.8-fold risk of developing PD in comparison to appendicitis controls (Callaghan et al., 2011). To evaluate the potential link between METH/AMPH dependence and PD expression in a statewide population, we conducted a retrospective cohort study of individuals in the Utah Population Database (UPDB) with linked electronic medical records from 1996–2011. Over 85% of those with medical records in Utah link to a person in the UPDB through a birth, death, driver license, or voter registration record to provide personal medical histories on over 3 million individuals.
In 2012, 19% of patients admitted for drug dependence in Utah claimed METH as their principal drug of choice, and women were almost twice as likely as men in Utah to have a meth-related hospital admission (27% vs. 15%) second only to alcohol (Utah Department of Human Services, 2012). Widely recognized sex differences occur in all of phases of drug abuse; initiation, escalation, addiction, and relapse (Greenfield et al., 2010). Women begin regular use of illicit drugs at lower doses than do men; however, use escalates more rapidly into addiction and women are at greater risk for relapse after abstinence (Greenfield et al., 2010). In preclinical studies, female rats exhibit higher self-administration of METH and increased METH-seeking relapse relative to males (Roth and Carroll, 2004, Reichel et al., 2012). The effects of stimulants may be strongly influenced by endogenous hormones as estrogen increases and progesterone decreases the interaction of stimulants with reward-related systems in women (Anker and Carroll, 2011). Lifetime rates of mood and anxiety disorders which often co-occur with METH or AMPH abuse are significantly higher among women than men (Greenfield et al., 2010). Lower phosphocreatine levels, associated with depressive symptoms, were more pronounced in female METH users (Sung et al., 2013). Because of such gender differences, we investigated sex-specific risks of PD in the Utah population.
It is projected that the number of people with PD in the US will double over the next 25 years; thus, the potential contribution of METH/AMPH abuse to PD incidence is a significant national health issue (Dorsey et al., 2007). The objectives of our study are to assess the findings of the California report (Callaghan et al., 2011), to identify population features relevant to the association between METH/AMPH use and PD, and to enhance generalizability of results by utilizing a statewide resource. Our study is novel in many respects. Using the UPDB, we accessed a statewide pool of individuals with long-term follow up and no history of illicit drug or alcohol abuse to provide an unexposed population from which we randomly selected controls for matching to exposed individuals with an indication of METH/AMPH or cocaine use. Our exposed drug cohorts are based not only on hospitalizations, but also on comprehensive outpatient records.
Section snippets
Sources of data
Utah Population Database: The UPDB is a dynamic and rich resource located at the University of Utah that consists of computerized records for nearly eight million individuals spanning more than a century. The UPDB includes extensive genealogies, statewide vital records, driver license and voter registration records, and statewide inpatient records and links to clinic discharge records beginning in 1996. The discharge data hold up to eight fields per admission of International Classification of
Participant characteristics
Characteristics of exposed individuals in the METH/AMPH and cocaine cohorts in comparison to their respective matched population controls are shown in Table 1a. In the METH/AMPH cohort, 86% of individuals had ≥1 occurrence of ICD-9-CM code 305.7 (72%), 304.4 (23%), 969.7 (5%), or E854.2 (<0.5%) while 14% had diagnoses across multiple codes. A majority of users were diagnosed within the UUHC and IH healthcare systems (83%); the remainder were diagnosed from hospital discharge records of other
Study strengths
While confirming an earlier report of increased PD risk in a study of a northern California population, our analysis helps to further elucidate the nature of the association between METH/AMPH use and expression of PD. To our knowledge, it is the first retrospective cohort study of METH/AMPH and PD or PD/PT outcomes in the US conducted over an entire statewide population (Utah). Rather than relying on hospital-based controls, we were able to randomly select unexposed controls from the same
Conclusions
Our findings of an approximate three-fold increased risk of PD or PD/PT in METH/AMPH exposed individuals, compared to both an unexposed control cohort and a cocaine use cohort, confirm those of the California study. Our study suggests the risk in those with a history of METH/AMPH dependence may be somewhat higher than previous estimates and although power was limited to detect an interaction, suggestive differences in risk estimates between women and men merit further study. Our investigation
Ethical approval
The current study was approved by both the institutional review boards of the University of Utah and Intermountain Healthcare.
Role of the funding source
This research was supported by the University of Utah Department of Pharmacology and Toxicology, and by the National Institutes of Health, National Institute on Drug Abuse (NIDA) R01 DA031883 to G. Hanson, PI. Partial support for all datasets within the Utah Population Database was provided by the University of Utah Huntsman Cancer Institute and the Huntsman Cancer Institute Cancer Center Support grant, P30 CA2014 from the National Cancer Institute (NCI). The National Institutes of Health (NIDA
Contributors
KC conceived the study design, prepared the manuscript, and supervised all statistical analyses and preparation of study datasets; AF helped to prepare and critically revise the manuscript; RJR and MJC participated in the design of the study and helped in the preparation of the manuscript; RJR supervised data extraction efforts at Intermountain Healthcare. KRS contributed to the research design and preparation of the manuscript. GHR conceived the study question and substantially participated in
Acknowledgements
We gratefully acknowledge Alison Fraser (database management) and Yuan Wan (programming support) of the Huntsman Cancer Institute Pedigree & Population Resource, and Jef Huntington (Intermountain Healthcare) and Micky Daurelle (University of Utah Healthcare) for their efforts in the extraction of enterprise warehouse medical records.
References (39)
- et al.
Methamphetamine use behaviors and gender differences
Addict Behav.
(2004) - et al.
Extent of illicit drug use and dependence, and their contribution to the global burden of disease
Lancet
(2012) - et al.
Amphetamine exposure is elevated in Parkinson's disease
Neurotoxicology
(2006) - et al.
Substance abuse in women
Psychiatr. Clin. North Am.
(2010) Detection of methamphetamine neurotoxicity in forensic autopsy cases
Leg. Med. (Tokyo)
(2009)- et al.
Decreased frontal lobe phosphocreatine levels in methamphetamine users
Drug Alcohol Depend.
(2013) - et al.
Movement disorders and AIDS: a review
Parkinsonism Relat. Disord.
(2004) - et al.
Epidemiology and neuropsychiatric manifestations of Young Onset Parkinson's Disease in the United States
Parkinsonism Relat. Disord.
(2013) - et al.
Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones
Curr. Top. Behav. Neurosci.
(2011) - et al.
Amphetamine-induced psychosis—a separate diagnostic entity or primary psychosis triggered in the vulnerable?
BMC Psychiatry
(2012)