Marijuana use in adolescence causes significant concern since marijuana use may impact the brain, which is still developing throughout adolescence. Though overall brain size stabilizes around age five , important progressive and regressive developmental processes continue throughout adolescence, including myelination , synaptic refinement , reductions of grey matter volumes and improved cognitive and functional efficiency . It is unclear how heavy marijuana use at this time could influence neural development. The long-term effects of marijuana have not yet been determined, but could potentially have major implications on social, academic, and occupational functioning. Although a good deal of research has been done on the effects of marijuana in chronic adult users, very little is known about adolescent users. Studies have shown that chronic marijuana has an influence on the neuropsychological performance of adults within a week of use. Specifically differences have been found in attention and executive functioning , memory , psychomotor speed and manual dexterity . One study demonstrated verbal learning deficits among marijuana users compared to controls 0, 1, and 7 days following use, but that these impairments subsided after a 28-day abstinence period . However, others have identified impairments in memory, executive functioning, psychomotor speed, and manual dexterity after 28 days of verified abstinence compared to published norms . Furthermore, adults who began use early in adolescence demonstrated greater decrements on verbal IQ after a 28-day abstinence period those who began late in adolescence and non-using controls,cannabis grow tent suggesting an adolescent vulnerability .
Due to its high safety profile and good spatial resolution, functional magnetic resonance imaging has become a powerful method for visualizing neural activation. More specifically, these studies have demonstrated an increase in spatial working memory brain response in marijuana users compared to normal age-matched controls in the pre-frontal cortex, anterior cingulate, and the basal ganglia . This suggests a compensatory neural response as well as recruitment of additional brain areas to achieve necessary task requirements, as seen in a recent study of task performance and brain functioning in marijuana users . However,because this study was done on adults who were abstinent for only 6-36 hours prior to the scan, it may be that these effects reflect recent use and not persisting effects . Others have characterized visuospatial attention among 12 recent marijuana users who had used 2 – 24 hours earlier, 12 abstinent users who not used for an average of 38 months, and 19 non-using controls . Both active and abstinent users showed decreased brain response in prefrontal, parietal, and cerebellar regions that normally sub-serve visual attention, and increased activation in alternate regions, suggesting brain response alterations even after extended abstinence. These adult fMRI studies point to altered neural functioning among marijuana using adults during visuospatial tasks, particularly in frontal and parietal regions. Less is known about neurocognitive functioning in adolescent marijuana users. A longitudinal study of ten adolescent marijuana users showed incomplete recovery of learning and memory impairments even after six weeks of abstinence . Recent fMRI studies of SWM involving alcohol-abusing adolescents and marijuana and alcohol-abusing adolescents have found that marijuana and alcohol were associated with greater changes than alcohol alone.
Specifically, after an average of 8 days of abstinence, adolescent marijuana users showed an increase in dorsolateral prefrontal activation and reduced inferior frontal response compared to alcohol users and non-using controls, suggesting compensatory working memory and attention activity associated with heavy marijuana use during youth . Adolescent marijuana users demonstrated increased right hippo campal activity and poorer attention and verbal working memory performance compared to demographically similar tobacco smokers and non-using controls, suggesting compensatory neural recruitment, even after a month of abstinence . In a follow-up study, marijuana using youths who were abstinent at least two weeks performed similarly as non-users on verbal working memory during ad libitum smoking and again during nicotine withdrawal, but exhibited increased parietal activation and poorer verbal delayed recall during nicotine withdrawal compared to non-marijuana users . Together, these studies suggest altered working memory functioning among adolescent marijuana users that may persist after a month of abstinence. Yet it is unclear how variability in task performance might contribute to brain activation patterns. Among normal adolescents, spatial working memory task performance is associated with activation in bilateral prefrontal and posterior parietal brain regions . Adult studies have suggested increased frontal and parietal activity associated with greater spatial working memory task difficulty . FMRI studies of adolescent and adult marijuana users have suggested that increased neural responding associated with marijuana use may be evidence of compensatory neural recruitment to maintain task performance . Therefore, the relationship between task performance and neural response may differ between marijuana users and controls, with a stronger positive relationship among marijuana users. The interaction between task performance and fMRI response to SWM has not yet been studied in adolescent marijuana users. The goal of the present study was to understand how task performance patterns contribute to neural activation in abstinent adolescent marijuana users. We studied blood oxygen level dependent fMRI neural activation during a SWM task which typically activates bilateral prefrontal and posterior parietal networks in adolescents and adults . This SWM task has been shown to be sensitive to brain response abnormalities in adolescent alcohol and marijuana users. In this study, both adolescent users and controls were required to abstain from all drugs and alcohol for 28 days prior to their fMRI scan, and all were free from psychiatric disorders and learning disabilities.
Based on our previous work we predicted that after 28 days of abstinence, marijuana users as a group would perform as well as controls; however, the task performance would vary within each group resulting in a group by task performance interaction that would be associated with brain response. Specifically, we hypothesized that there would be interactions between task performance and fMRI response in the bilateral dorsolateral prefrontal and posterior parietal cortices,grow lights for cannabis such that marijuana users show a stronger positive association between performance and brain response than controls in these regions. Flyers were distributed at local high schools, community colleges and universities to recruit 16- to 18-year-old adolescents . Adolescent participants provided written informed assent or consent for their participation, and guardians provided consent for youths under age 18, we well as consent for their own participation. This included an interview about their adolescent’s health and development history. The University of California San Diego Human Research Protections Program approved this study. Participants were initially screened for eligibility and then were given a 45-minute phone interview to collect information about general health, psychiatric disorders, and lifetime substance use. Participant parents gave consent for their own participation and were interviewed for detailed information about family health history and prenatal conditions. The computerized NIMH Diagnostic Interview Schedule for Children Predictive Scale was conducted separately with the youth and a parent to exclude adolescents with a potential psychiatric disorder . Other exclusion criteria included prenatal substance exposure, birth complications, psychotropic medication use, physical health problems, neurological dysfunction, head injury, family history of bipolar I or psychotic disorder , left-handedness, learning disability, or MRI incompatibility. Teens found to meet diagnostic criteria for alcohol use disorder were not excluded due to high comorbidity with marijuana use . Two subjects, both in the marijuana group, met criteria for alcohol abuse. Groups consisted of 17 heavy marijuana users and 17 non-using demographically similar controls. Users reported 477 episodes of lifetime marijuana use, on average, and control participants reported no more than five lifetime uses of marijuana. Groups were comparable in age, gender, ethnicity, family history of substance use disorders, and depressed and anxious mood . Marijuana users and control teens showed similar levels of IQ, as prorated by the Wechsler Abbreviated Scale of Intelligence Vocabulary and Block Design subtests , and socioeconomic status . Even though marijuana users reported more use of other drugs than controls, lifetime use of other drugs was less than 27 times across all substance types besides nicotine, alcohol, and marijuana. MJ users reported higher rates of alcohol than controls, and both groups had low rates of tobacco use . Measures Substance Use. Substance intake was assessed using the Customary Drinking and Drug Use Record .
Self-reported information was collected about lifetime and past three-month use of marijuana, alcohol, nicotine, and other drugs. Strong internal consistency, test-retest and inter-rater reliability have been shown with adolescent Customary Drinking and Drug Use Record assessments . The Timeline Follow back was used to assess drug and alcohol use for the previous 28 days. Participants were asked to point out for each day whether they used or drank. If they disclosed use, they were to indicate how many hits of marijuana or drinks of alcohol they consumed . “Drinks” were defined as one can of beer, one glass of wine or one shot of hard liquor to clarify amount of alcohol consumed. If asked, a “hit” of marijuana was defined as a puff from a pipe, bong, joint or vaporizer since smoking is the most common method of use. State Scales. The Beck Depression Inventory and the Spiel berger State Trait Anxiety Inventory measured mood prior to the time of scanning. The Stanford Sleepiness Scale determined alertness immediately before and after scanning with self-report ratings .Psychopathological Syndromes. Parents were interviewed about the child’s internalizing and externalizing behaviors via the Child Behavior Checklist . Spatial Working MemoryTask. This task consisted of 18 21-second blocks that alternated between resting fixation, vigilance, and working memory conditions . Each block began by showing a one-second word cue that prompted the upcoming block. The resting fixation block began with the cue “LOOK” and subjects were asked to look at the fixation cross. Each vigilance block was prompted by the cue “DOTS” and subjects were asked to respond with a button press to figures that had a dot above them . Before each working memory block, the cue “WHERE” appeared on the screen. During these blocks, abstract figures were individually shown in one of eight spatial locations, and subjects were instructed to respond with a button press every time a figure appeared in the same location as a previous figure had been within that block. Unknown to the subject, repeat location stimuli were 2-back, and composed 30% of stimuli. For both the vigilance and working memory conditions, stimuli were presented for 1000 ms, with an interstimulus interval of 1000 ms . All subjects were given practice with the task prior to entering the scanner and were monitored to ensure they understood the task instructions. Performance data were collected for accuracy and reaction time with a fiber optic response box. Procedures Toxicology. The toxicology procedure was designed to ensure that participants would not use substances in the 28 days prior to the fMRI scan. Cannabis metabolites can reliably remain detectible in urine for at least four days . Subjects were required to give a urine sample every three to four days each week during the 28 days prior to the fMRI session to make sure there was no recent use of cannabis, amphetamines, methamphetamines, benzodiazepines, cocaine, barbiturates, codeine, morphine, phencyclidine, and ethanol. Samples were collected and analyzed at the VA Medical Center using CEDIA DAU assays. Collections were observed to minimize the risk of participant tampering. Quantitative indices were tracked to determine if tetrahydrocannabinol metabolite levels decreased during the 28-day period. Participants who initially screened positive for cannabis were accepted and retained, as long as THC metabolite indices decreased continually throughout the 28 days. If participant’s levels increased or if a positive screen was obtained after a negative screen, the participant was given the option to restart the 28-day abstinence period or was dropped from the study. All participants produced negative urine toxicology screens at the time of scanning. Breathalyzers checked for recent alcohol use prior to the fMRI scan. Imaging. Anatomical and functional imaging data were acquired with a 1.5 Tesla General Electric Signa LX scanner . The high-resolution structural scan was collected in the sagittal plane using an inversion recovery prepared T1-weighted 3D spiral fast spin echo sequence . The functional scan was acquired in the axial plane using T2*-weighted spiral gradient recall echo imaging . Task Performance.