Similar to effects seen in adolescent rats exposed to ethanol, long-lasting effects on learning, memory, and object recognition have been shown in adolescent rats with chronic cannabis exposure , which have been attributed to a reduction in quality or efficiency of synaptic connections in the hippocampus . While most existing studies examine the impact of alcohol or marijuana use separately, understanding the impact of concomitant use is also highly relevant. One study found that use of cannabinoids in a neonatal rat brain enhanced sensitivity to damage from ethanol . The combination of THC and mildly intoxicating doses of ethanol produced widespread and severe neuronal degradation similar to levels observed from much higher doses of ethanol administration. In sum, animal literature has linked both independent and concurrent alcohol and marijuana use to microstructural and macrostructural changes that likely contribute to observed behavioral and cognitive differences, including poorer neuropsychological functioning. The extant human literature also suggests that heavy and recent alcohol exposure in adolescence is associated with poorer neuropsychological outcomes relative to those of non-drinkers . A recent study examining community youth of heavy episodic drinkers relative to their non-drinking peers found that even after one month of monitored abstinence, adolescent drinkers still showed differences in prospective memory, cognitive switching, inhibition task accuracy, verbal memory, and visuospatial construction . More specifically, cannabis trimming tray numerous studies examining neuropsychological impact of drinking among adolescents with alcohol use disorders suggest deficits in verbal memory and recognition discriminability and in recall of nonverbal information such as delayed recall of a complex figure .
Similar to alcohol use, marijuana use during adolescence may also disrupt the normal neuromaturational processes that take place during this time period . After at least three weeks of abstinence, adolescent marijuana users still show decrements in memory, attention, psychomotor speed, and planning and sequencing; increased errors on a speeded visuomotor sequencing task; and more intrusions on word list learning . One study that tested adolescent marijuana users once per week over three weeks of sustained abstinence found initial differences in verbal memory and verbal working memory that improved with three weeks of sustained abstinence, but not to levels of controls . Deficits in accuracy on a visual attention task were seen at the first assessment and across time . Another study found that MJ-using teens continued to show poorer functioning in complex attention, sequencing ability, verbal story memory, and psychomotor speed following one month of monitored abstinence . While multiple studies report neuropsychological deficits in alcohol and marijuana using teens, even after one month of abstinence, one major limitation across these studies is the high rate of comorbid substance use among participants. Many alcohol-using populations have moderate to high levels of marijuana use; similarly, many marijuana-using teens have significant exposure to heavy drinking. Therefore, much of the existing literature cannot report confidently if cognitive decrements are primarily related to alcohol, to marijuana, or to use of both substances. Additionally, few studies have directly compared alcohol-using youth and marijuana-using youth to each other. One study comparing non-using teens, alcohol users, and marijuana users used 12-hour abstinence protocols and 9th grade scores as indications of pre-morbid academic functioning ; another study used marijuana users who had consumed alcohol up to 810 times and other drugs up to 70 times . Therefore, there is a great need to distinguish the impact of alcohol, marijuana, and concomitant use on neuropsychological outcomes using extended abstinence protocols, indicators of premorbid functioning that predate initiation of substance use, and group eligibility criteria to limit exposure to other substances much more stringently.
These limitations are addressed in the current study.We examined the effects of alcohol and marijuana use during adolescence in a sample of substance using teens and demographically similar non-using teens using a neuropsychological battery after four weeks of monitored abstinence. Using strict criteria to differentiate groups, we compared neuropsychological performance among alcohol users, marijuana users, those who use both marijuana and alcohol, and non-using controls. Based on prior adolescent research, we hypothesized that even following one month of sustained abstinence, users of marijuana and alcohol would show poorer performance relative to non-users. Poorer executive functioning and visuospatial ability were expected in the alcohol group, but not in the marijuana group. Poorer task accuracy and psychomotor speed were expected to be most notable among the marijuana users. Given previous animal and human research , we expected youth who use both marijuana and alcohol to show poorest performance in the same domains as heavy users of alcohol or marijuana, while also possibly showing unique changes attributable to concomitant use.In accordance with the University of California, San Diego Institutional Review Board and high school district policies, written informed assent and consent were obtained prior to participation. The current study examined 131 adolescents who were classified into four groups using “episode” to describe the number of days on which a substance was used in a participant’s lifetime: heavy episodic drinking adolescents , protracted marijuana users , heavy alcohol and marijuana using teens , and control teens . The higher group cutoff for alcohol use among MJ youth was used because three MJ participants had 50-75 alcohol episodes; however, they had over 800 marijuana episodes, so 10-20 times more marijuana than alcohol in their lifetimes. Also, in the three months prior to starting the study, MJ youth reported 0 heavy episodic drinking episodes and 0 alcohol withdrawal symptoms. The HED and HED+MJ groups, however, reported 5-20 heavy episodic drinking episodes per month and 3-9 alcohol withdrawal symptoms in the three months prior to study initiation. All participants were drawn from the same schools, and groups were similar on socio-demographic factors including age, gender , ethnicity , grades completed, grade point average , socioeconomic status , family history of substance dependence, and 5th grade California Achievement Test, 6th Edition language arts and mathematics scores . Groups who used similar substances were matched on their common substance in the following areas: lifetime episodes, frequency of recent use , days since use at study initiation, and age of onset of regular use . HED and HED+MJ had a heavy episodic drinking experience 4.18 and 6.75 days per month, respectively; MJ and HED+MJ smoked marijuana 17.78 and 18.38 days per month, respectively .Participants were recruited from San Diego high schools and colleges via mailings and fliers that advertised an “Adolescent Development Project.” No information regarding alcohol or drug use criteria was described in the flier or discussed prior to screening. Participants responding by phone were informed of the study protocol and assessment schedule, potential risks and benefits, and the confidentiality of their participation. All interested teens and their guardians underwent an extensive screening process to determine eligibility, and those potentially eligible were mailed consent packets. After completing the assents/consents, teens and their guardians participated in more detailed, structured clinical interviews. To minimize confounds, exclusionary criteria included history of a DSM-IV Axis I disorder other than substance abuse; extensive other drug use ; head trauma ; a learning disorder; neurological dysfunction; serious medical illness; family history of bipolar I or psychotic disorder; significant prenatal alcohol or drug exposure; sensory problems; use of psychoactive medications; and substance use during the abstinence protocol.After providing their assent/consent, trimming tray for weed adolescent participants and their parents were separately administered confidential structured clinical interviews assessing demographics, social and academic functioning , family history of psychiatric disorders using the structured clinical interview of Family History Assessment Module Screener , and personal history of Axis I psychiatric disorders using the Computerized Diagnostic Interview Schedule for Children [DISC; Shaffer, Fisher, Lucas, Dulcan, & Schwab-Stone, 2000]. Parents completed the Child Behavior Checklist [CBCL; Achenbach & Ruffle, 2000] and teens completed the Youth Self Report [YSR; Achenbach & Ruffle, 2000] to assess levels of internalizing and externalizing psychopathology. Teen substance use history was documented using the Customary Drinking and Drug Use Record [CDDR; Brown et al., 1998], which assessed both lifetime and recent tobacco, alcohol, and drug use , withdrawal symptoms, DSM-IV abuse and dependence criteria, and other negative consequences associated with heavy drinking.
Good inter-rater reliability, internal consistency, and test-retest ability have been demonstrated with the CDDR among adolescent participants . The Timeline Followback [TLFB; Sobell & Sobell, 1992] modified to include other drugs was used to collect frequency and quantity of alcohol, marijuana, and other drug use for the four weeks prior to initiating protocol and for the four week duration in the study.All eligible participants who initiated the study protocol were monitored for abstinence from substance use for four weeks and then assessed using neuropsychological tests at the completion of their abstention period. Prior to the NP testing session, participants provided a urine sample, submitted a Breathalyzer reading , and completed emotional state measures. To minimize the possibility of substance use during the four-week abstention period, supervised urine and breath samples were collected three times weekly to assess for recent use of alcohol with ethyl glucuronide and ethyl sulfate metabolites and use of methamphetamines, cocaine, THC , benzodiazepines, methadone, barbiturates, MDMA , opiates, PCP, and oxycodone. We utilized an observed sample collection procedure to minimize the likelihood of participant tampering. Samples were analyzed by Redwood Toxicology using cloned enzyme donor immunoassay kits. If abstinence maintenance was confirmed via subject self report, Breathalyzer, and quantitative toxicology results, participants continued to be scheduled for appointments. Abstinence was also facilitated using a standardized Motivational Interviewing protocol demonstrated to encourage the maintenance of abstinence for adolescents in prior research . To minimize the impact of study participation on subjects’ daily lives, research staff worked closely with enrolled youth to select a one-month period that did not conflict with birthdays, school events, or breaks. As this was not a treatment-seeking sample , eligibility was not contingent upon a teen’s expressed desire to quit substance use. Instead, participants were motivated by financial compensation and the opportunity to contribute to research. HED, MJ, and HED+MJ youth started the study protocol within three weeks of exposure to the substance of interest . At the time of assessment following one month of monitored abstinence, average days since exposure to the substance of interest ranged from 31-35 days in HED, MJ, and HED+MJ youth .We used chi-square tests and Analysis of Variance to compare demographic characteristics among groups. We used Multivariate Analysis of Covariance to test for group effects on neuropsychological task performance after one month of monitored abstinence. Given that poor externalizing behavior has been linked to academic underachievement, impulsivity, poor decision making, and neurocognitive deficits , CBCL externalizing behavior was used as a covariate in the analyses since the three groups of substance using teens scored higher on this trait. Post-hoc contrasts were examined using Tukey’s HSD tests. Secondary analyses examined the associations between alcohol and marijuana use characteristics and performance on tasks of executive functioning, learning and memory, visuospatial construction, attention and psychomotor speed, and language and achievement. Due to non-normal distribution of substance use characteristics, Spearman’s correlations were calculated to describe these relationships. A False Discovery Rate correction for multiple comparisons was used to recalculate p-values from the outputs . All reported p-values were generated from the FDR correction.We examined neuropsychological differences following one month of monitored abstinence among adolescents with limited substance use history compared to those who predominantly use alcohol, marijuana, or both substances. This study features the design strengths of matching groups on premorbid academic functioning, lifetime and recent substance use characteristics, and recency of use at time of testing. While the performances for each group were predominantly in the average range and no group means suggested clinical impairment, subtle differences were evident between groups, with substance-using groups scoring lower than non-using controls in multiple domains. Importantly, these differences were observed after one month of abstinence, on average, which is sufficient time for acute withdrawal symptoms to abate and for THC to be eliminated from the body. Our results suggest that use of alcohol and/or marijuana produces unique and shared cognitive differences in teens earlier in their use continuum than shown previously. These differences seem to emerge in youth prior to the onset of clinical dependence and in the midst of ongoing brain development. Teens with histories of heavy drinking showed poorer cognitive flexibility, recall and semantic organization of verbal information, and reading achievement relative to non-using controls. Worse performance among HED youth on the D-KEFS Trail Making Number-Letter Switching task suggests poorer cognitive flexibility .