An intermediate, reduced set of items considered in the subsequent analyses are presented in Table 2. In prediction analyses with early-onset marijuana use as the outcome, the most predictive items were three externalizing characteristics: destroys things belonging to his/her family or others,steals outside the home,and lying or cheating.We used these items to construct a preliminary 3-item scale. We the determined whether we could improve upon this 3-item scale by adding each of the intermediate sets of individual items.The greatest improvement was seen with the addition of “disobedient at school”.The addition of parent smoking also improved the prediction results in all data sets. Table 3 compares the performance of this “5-item Screener” across both the construction and validation data-sets. Considerable replication of results was shown across the nine analyses. Eight of the nine AUCs showed statistically significant findings. The AUCs were moderately strong, ranging from 0.59 to 0.74. In most instances, the AUC reduction from construction to validation analyses was low in magnitude.However, in the case of the PYS boys, the validation sample result was a non-significant finding. Table 3 shows that across all analyses, almost all the results held equally well for boys and girls .Marijuana and tobacco products remain two of the most widely used substances worldwide. In the U.S., combined use of both substances is upwards of 60–70% in MJ users and more than five times as likely as measured by past month use in tobacco users. Moreover, in some countries, smoked MJ joints are almost exclusively mixed with tobacco.
Despite the widespread preva-lence of MJ and tobacco co-use, interactive effects of marijuana and nicotine are scantly characterized in the existing literature and lacking direct comparisons of separate and combined uses is a limitation in most studies of marijuana use. Individually, MJ and tobacco are associated with changes to brain structure and function. Structural neuroimaging studies in MJ users have indicated that volumes of several brain areas are smaller in heavy MJ users,ebb and flow especially in areas enriched with cannabinoid type I receptors such as medial temporal lobe structures.Of these structures, the hippocampus appears to be particularly sensitive to heavy marijuana use. Delta9- tetrahydrocannabinol,the primary psychoactive component in marijuana, which binds to CB1 receptors, is associated with cell shrinkage and damage to DNA strands in THC-treated hippocampal neuron cultures. The association ofthese alterations, such as smaller hippocampal volume with greater lifetime duration of use and cumulative amount as well as with recent use, suggest that these changes are consequences of exposure to MJ. A recent study by Smith et al. examined the interaction between cannabis use and schizophrenia on hippocampal morphology and found a main effect of cannabis use such that altered hippocampal shape was found in both cannabis users with and without schizophrenia. Moreover, these hippocampal differences were related to poorer episodic memory performance emphasizing the relationship between hippocampal morphology and memory. Taken together, smaller brain volumes in MJ users may reflect potential neurotoxic influence of exogenous cannabinoid exposure. Relative to MJ, less is known about structural brain changes specific to chronic nicotine use. However, existing studies reportlower gray matter densities across widespread areas in tobacco smokers. Animal models of rats exposed to nicotine show reduced cell numbers, increased markers of apoptosis and alterations in synaptic activity in these regions.
These regions express dense levels of acetylcholine receptors that are primary binding targets for nicotine, which further supports the potential for nicotine-related brain changes. Thus, it is likely that similar to MJ’s effects, reported morphometric changes result from nicotine-related neurotoxicity. In addition to structural changes, MJ and tobacco have also been individually associated with declines in cognitive function. Existing studies suggest that tobacco use is associated with impaired working memory, attention, and verbal abilities that map on to brain structures that undergo changes due to tobacco use.In terms of MJ’s effects on cognition, studies have reported widespread deficits across various domains such as memory, attention, and learning that are dependent on CB1 receptor activation; however, deficits in working memory appear to be the most consistent. While individual studies provide evidence for neurocognitive consequences of MJ and nicotine, the independent drug effects may not generalize to the context of combined use. Interactions between the two substances have been described at the cellular level wherein CB1 and nicotinic acetylcholine receptors are densely co-localized in hippocampal regions and both are involved in a diverse set of modulatory processes.For example, chronic nicotine treatment in rats results in altered endocannabinoid levels in the brain.Moreover, Valjent, et al. noted altered fear, withdrawal, and tolerance behaviors in rats co-treated with THC and nicotine, suggesting functional-biochemical interactions. Taken together, there is convergent evidence from human, animal and pharmacological studies supporting the potential for additional consequences on the integrity of the hippocampal structure and function with combined MJ and nicotine use.
However, to date, this has not yet been directly examined. In this study, we aimed to characterize the differential and combined impact of marijuana and nicotine on hippocampal morphometry and memory function among marijuana-only users, nicotine-only users, and comorbid marijuana and nicotine users with a non-using comparison control group. As a primary aim, we compared groups on hippocampal volume. To then further characterize any difference found in hippocampal volumes, we also compared groups on memory performance and examined relationships between morphometry, memory and substance use patterns. Given findings from existing literature, we anticipated that MJ and nicotine individually and in combination would be associated with smaller hippocampal volumes and poorer memory scores that are inversely related to substance use patterns.Participants were recruited through flyers and advertisements in the Albuquerque, New Mexico metro area. The community sub-sample used for this study originated from two larger studies conducted at the University of New Mexico.Informed consent was provided by all of the participants in accordance with the Institutional Review Board at UNM. Participants were compensated for their time. To be eligible for the study, all individuals had to meet the following criteria: be between the ages of 18 and 50 years; be right-handed;have no magnetic resonance imaging contraindications ; have no symptoms of psychosis and be fluent in both oral and written English. Furthermore, individuals with fewer than 10 years of education, IQs less than 75, or illicit drug use were excluded from our sample. We were interested in differences resulting from regular, heavy marijuana and nicotine use rather than from recreational marijuana and nicotine use.
To that end, the marijuana users were also required to report using marijuana at least 4 times per week over the past six months. Nicotine users were included if they reported nicotine use of 10 or more times daily and had less than three months of abstinence in the past year. Controls were included if they reported no marijuana use occasions and no tobacco use occasions in the preceding three months, and did not meet criteria for any drug or alcohol abuse or dependence according to the Structured Clinical Interview for DSM-IV disorders. For our study, participants were categorized into four groups based on substance use: MJ,NIC,MJ + NIC,and non-using controls.The combined chronic marijuana and nicotine smoking group was derived from the two studies, with participants having to meet criteria for both chronic marijuana and frequent nicotine use to be part of this group.The study took place over two separate visits. The first visit included assessments of substance use history and neuropsychological tests. The second visit was scheduled three days after the first visit and consisted of an MRI scan. Participants were required to abstain from MJ and illicit drugs between the two visits so that MRI and cognitive measures did not reflect effects of acute intoxication. This resulted in a ∼72-hour abstinence period confirmed by self-report. To promote compliance with the 72-hour abstinence from marijuana, we followed a bogus pipeline by collecting a urine cannabis toxicity screen before and after abstinence.While the urinalysis is insensitive to 72-hour abstinence, this method has been shown to increase accuracy of self-report.Only those who reported 72-hour abstinence were included in the study. Participants were also asked not to use caffeine or tobacco for two to four hours prior to their brain scan and neither were permitted during their MRI appointment. During session two, each participant had a head MRI scan and each was administered a brief cognitive battery including standardized tests of new learning and memory .No known studies have characterized the differential impact of independent versus combined marijuana and nicotine use on brain structure and related function. Here, dry racks we found that marijuana use individually and combined with tobacco had smaller hippocampal volumes compared to tobacco users and non-using controls.
We also found differential associations between brain and behavior such that smaller hippocampal volumes were associated with poorer memory performance for controls, while in MJ + Nic users, smaller hippocampal volumes were linked to relatively higher memory scores. Our findings of marijuana-related abnormalities in hippocampal morphology and relationship to impaired memory function is concordant with recent findings by Smith et al.. Several studies have previously reported reduced hippocampal volumes in chronic marijuana users,which may reflect a potential neurotoxic effect.However, the best evidence for direct neurotoxic influence of THC has been primarily limited to well-controlled pharmacological manipulations of hippocampal neuron cultures. Alternatively, studies of in vivo THC treatment in rodent models find reduced dendritic length and spine density, suggesting that gross volumetric deficits may reflect morphological changes to hippocampal neurons. Structural and functional abnormalities may also be obscured by THC-activation of glial cells, thereby yielding decreased neuronal densities by virtue of the presence of increased glial cells. It is of interest that the combined MJ + Nic users had the smallest hippocampal volumes. Given that MJ + Nic user hippocampal volumes were not statistically different from the MJ-only group, this finding does not support an additive detrimental effect of combined THC and nicotine exposure. However, MJ + Nic had the lowest memory performance out of all groups, thus functional interactions cannot be ruled out. Instead of a dualtoxic mechanism, it is possible that poorer memory performance in MJ + Nic users stems from a dual-withdrawal process, whereby combined withdrawal from MJ and nicotine may further weaken memory processes. There is some evidence that nicotine interferes with memory function in MJ users. For example, Jacobsen et al. found abnormal fronto-parietal brain response during a verbal working memory task in conjunction with poorer word recall in MJ + Nic users following short periods of nicotine withdrawal.Interestingly, these effects normalized without abstaining from tobacco.
In our study, however, the combined MJ + Nic using subjects were not required to abstain from tobacco for an extended period ; thus, nicotine withdrawal effects on short-term memory function would be minimal. It is possible that the functional relationship between hippo campal volume and memory in MJ + Nic users might invert during acute nicotine deprivation. Although nicotine selectively enhances memory function, we did not observe recovery of any memory function from smoking nicotine in the chronic MJ + Nic subjects. The lack of significant difference may result from heavier MJ use relative to tobacco use. Most of the MJ users in this study were heavy MJ users.THC and other cannabinoids build up and are metabolized and excreted relatively slowly, while the nicotine of a cigarette can be metabolized in ∼2–8 h. In the current study, participants were required to abstain from MJ for three days, but tobacco smokers were only abstinent for ∼3 h. As such, poorer memory performance in MJ + Nic users is not likely driven by acute nicotine withdrawal.Rather, memory functioning is more likely disrupted by chronic MJ and tobacco co-use, combined with MJ withdrawal. One of the positive acute effects of nicotine is normalization of withdrawal effects. For example, File and colleagues observed no cognitive enhancing effects of nicotine in a sample of non-smoking students. Thus, the positive effects on short-term memory after nicotine administration appear to reflect the reversal of an acute deprivation state. Nevertheless, the nicotine users had the greatest WMS scores relative to the other groups including the non-using controls suggesting underlying sub-threshold effects that parallel the existing literature.