Illicit drug use and associated harms are highest among young people aged 15-24 years [1]. Globally, the onset of illicit drug use spikes around 15 years of age, a stage of high neuroplasticity, and rates climb throughout emerging adulthood (18-24 years) before dropping at approximately 25 years—after neuromaturation [2,3]. It comes as no surprise that illicit drug use during neurodevelopment is widespread; a quarter (24%) of adolescents (12-17 years) and over half (57%) of emerging adults report illicit drug use in the United States [4]. Moreover, from adolescence to emerging adulthood, lifetime methylenedioxymethamphetamine (MDMA; ecstasy) use surges from 0.8% up to 10.5% and cocaine use rises from 0.7% to 11.4% [4]. Although single-time drug use carries a small increase in morbidity and mortality, it may be the patterns of use and stage of neurodevelopment, that most influences the risk of neuronal aberrations and dependence [5]. Cannabis is the most commonly consumed illicit drug worldwide, with 5.6% of the world’s adolescent population reporting recent use, nearly one fifth (18%) of Europeans (15-24 years) reporting past-year use [6], and 10% of young Canadians reporting daily or almost daily use [7]. In Australia, around 41% of young people (14-24 years) have used an illicit drug in the past year, representing 90% of all national illicit drug users [8]. Despite risky patterns of use and the potential for ongoing harm, there is limited research investigating the ongoing impact of illicit drug use on the developing brain.

Adolescence and emerging adulthood represent a period of protracted neurobiological development marked by structural and functional remodeling, contributing to improved cognitive performance [9,10]. Structural integration occurs throughout the brain into early adulthood, with processes such as synaptic pruning (removal of unneeded neural connections), myelination (insulation and strengthening of neural messaging), and synaptogenesis (new neural connections), occurring predominantly in the prefrontal cortex [11]. These structural advances provide the underpinning of encephalization, which is the age-related transfer of function from the primitive, autonomic systems such as the hindbrain (pons, cerebellum, and medulla oblongata) and subcortical midbrain (limbic system), to the sophisticated cognitive systems of the forebrain (cerebral cortex, including the prefrontal cortex) [12,13]. Structural and functional maturation in cortical regions of the brain, specifically in the prefrontal cortex, precipitate improved cognition functioning [14], however, occur over a nonlinear trajectory. For example, neural projections between the prefrontal cortex and subcortical limbic system oscillate between regressive and progressive changes. Although development across structural, functional, and cognitive domains are inextricably linked, they are asynchronous, so one does not indicate the presence of another. Therefore, interpreting single brain outcomes during neurodevelopment is limited, particularly if assessed during a single data instance. Triangulating neurophysiological and neuropsychological studies may help to account for different trajectories of neurodevelopment and establish a more wholistic view of brain health.

The neurotoxic impact of illicit drugs on the developing brain has been studied extensively; however, a clear relationship between exposure (drug class[es] and patterns of use) and neurological sequelae is yet to be established. Sustained use of most drugs, such as cannabis inhalants, opiates, psychostimulants, and ecstasy, tends to be associated with executive dysfunction such as declines in working memory, verbal fluency, learning, and attention [15-18] and structural and functional abnormalities in the frontal cortex and limbic system [19-22]. However, the precise and quantifiable impact of different drug classes is less clear. A recent review of neuroimaging publications involving adolescent drug use showed that most focus on alcohol, only 45% focus on cannabis, less than 2% assess ecstasy/meth and inhalants, and 7% address polydrug use [23]. Untangling the impact of illicit substance use, including the difference between regular low dose use and infrequent high dose use, is challenging in part due to the limited investigation in this area [24,25]. Studies measuring the brain’s capacity to recover after abstinence are mixed [26,27], with some confirming cognitive deficits are present in the weeks after drug use [28,29], others claiming full recovery [30], and others showing persistent structural and functional changes months and years after abstinence [29,31]. Longitudinal study designs are required to discern the impact of complex patterns of illicit drug use and determine which classes carry additional risk of ongoing harm.

The age of drug use onset and corresponding stage of brain development may mediate neurophysiological and neuropsychological vulnerability to harm [32,33]. Many studies have shown a difference in harm between adolescents and adults [25], and some researchers hypothesize the brain is more protected against harm after 16 or 17 years of age [34,35]. Adding to the complexity are sex-based neurobiological factors that may subject females to higher risk than males [36-38]. Unfortunately, sex-based differences are not well understood, in part due to the underrepresentation of females in neuroimaging studies. Pressingly, the gender gap between male and female use may be closing [39-41] and could be accompanied by an increase in the number of young females presenting with neurodevelopmental aberrations. Longitudinal studies that help to untangle the relationship between pre-existing neural differences and trajectories of neurodevelopment will help elucidate individual vulnerability to harm.

Several narrative reviews have synthesized the evidence of the long-term impact of illicit drug use on the developing brain [42,43]; however, there are limited systematic reviews that can provide a complete view of the evidence. The systematic reviews are highly skewed towards cannabis use [44-46] and tend to provide insight into a single brain outcome [47]. Very few reviews harness structural, functional, and cognitive data [23,48-50], and only one incorporates findings on more than one drug [51]. Most importantly, very few reviews assess the longitudinal harms of drugs [25,52,53] and instead rely on cross-sectional data, which provide a limited assessment of change over neurodevelopment. Of these reviews, one did not include neuroimaging data [54], and the remaining three included only one brain domain [25,52,53]. To our knowledge, there has been no systematic review of longitudinal studies measuring the long-term impacts of a broad range of common illicit drugs, with findings encompassing both neurobiological and neuropsychological outcomes. To understand the neurological health burden of illicit drugs for young people and to inform policy and future prevention programs, a systematic review of the longitudinal studies assessing the impact of illicit drug use on structural, functional, and cognitive brain domains in young people will be conducted. Specifically, the main objectives of this review include:

This systematic review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020151442) and was written per the Preferred Reporting Items for Systematic Review (PRISMA) guidelines [55] as provided (see Multimedia Appendix 1).

This paper describes an ongoing review. As of February 2020, papers are in full-text screening, with results predicted to be complete by July 2020.

Accumulating research assessing the impact of illicit drug use on the developing brain underscores the need for a systematic review to assist clinicians, educators, and public health advisors in evidence-based practice. The significant consequences of illicit drug use, such as an increase in the likelihood of developing a drug use disorder or a persisting mental deficit, may be preventable [37,60]. The shifting legal landscape and subsequent liberalization of attitudes and perception of the harm of drugs make quantifying their precise neurological impact critically important. Synthesizing a current view of the evidence of illicit drug use and brain development may support the early detection and prevention of neurodevelopmental harm.