Although the proportion of male and female participants was balanced in the control arm, the proportion of male participants was higher in the drug arms. This outcome highlights an important issue because, at least for nicotine use, sex-specific associations with D2-type receptor availability have been suggested. Nevertheless, the main results on nicotine were confirmed in a sensitivity analysis without the Chinese studies that almost exclusively included male smokers. Another important limitation concerns the exposure. In the ‘cannabis and nicotine’ subgroup studies, controls were allowed to smoke in most studies, but only a few studies documented the amount of tobacco used or the severity of dependence. However, since no association with negative symptoms was found in the ‘nicotine only’ subgroup, the impact of this limitation seems weak. Other limitations need to be considered, such as the absence of a generally accepted definition for heavy smoking and very scarce information on the content of nicotine, the potency or the amount of THC and cannabidiol consumed as well as even the intensity of inhalation. Furthermore, limitations regarding the outcome measurements must be considered. Most importantly, very little information was available on the apathy and diminished expression dimensions of negative symptoms. Therefore, the findings reported have to be interpreted with caution. It was not possible to conduct a meta-analysis on the five domains of negative symptoms. In addition, there were limitations in the data for secondary outcomes, such as depression and antipsychotic treatment. Therefore, we cannot determine the extent to which our findings are related to an association of drug use with negative symptoms secondary to depression or medication side-effects. Finally, it must be emphasized that the cross-sectional approach of this meta-analysis does not allow for a causal interpretation of the observed associations. Post-traumatic stress disorder is a disorder of recovery following the experience of a traumatic event, characterized by alterations in arousal and reactivity including irritability, sleep disturbances, and hypervigilance; intrusion symptoms including intrusive distressing memories, flash backs, and nightmares; persistent avoidance of stimuli associated with the traumatic event; and disturbances in cognition and mood .
Lifetime prevalence of PTSD has been estimated to be around 6.8% to 8.7% of the U.S. population , with past-year prevalence of approximately 3.5% . Epidemiological studies have demonstrated an over two-fold greater lifetime prevalence of PTSD among women compared to men. While a number of effective behavioral treatments are available for individuals with PTSD , pharmacological interventions typically involve the use of selective serotonin re uptake inhibitors which generally have small effect sizes and have been associated with various undesirable side effects, marijuana grow system low rates of symptom remission, and high rates of dropout . As such, many organizations and these deficiencies have been associated with more severe symptoms of PTSD including anxiety and extinction of aversive memories . Indeed there is now solid evidence that cannabinoids reduce responses to conditioned fear cues, impair retrieval of emotionally aversive memories, and promote the extinction of fear memories suggesting that targeting the endocannabinoid system may hold promise for reducing PTSD-related intrusions and flashbacks. Indeed, a recent double-blind placebo-controlled trial found that inhibition of fatty acid amide 31 hydrolase increased levels of anandamide in healthy adults which in turn enhanced fear extinction and attenuated autonomic stress reactivity . Consistent with this largely preclinical evidence, an open label clinical trial provided evidence that nabilone reduced nightmares, improved sleep, and reduced flashbacks in patients diagnosed with PTSD . Similarly, a retrospective study indicated that nabilone is effective in reducing insomnia, nightmares, and other PTSD symptoms . Moreover, the results of a double blind placebo-controlled cross-over study indicated that nabilone significantly reduced nightmares, improved PTSD symptom severity, and enhanced general well being in 10 men with PTSD . However, the sample sizes used in these studies are modest and most of the aforementioned studies relied on synthetic THC or other cannabinoids rather than examining the potential therapeutic effects of whole plant cannabis or phytocannabinoids . Nevertheless, a growing number of individuals with PTSD are using cannabis , with both trauma exposure and PTSD diagnosis having been associated with increased odds of cannabis use in nationally representative samples .
Indeed, cannabis appears to be used by this population, specifically, to cope with negative affect and sleep difficulties . A recent study that utilized ecological momentary assessment to determine the antecedents and consequences of cannabis use among trauma-exposed young adults exhibiting PTSD symptoms demonstrated that PTSD hyperarousal symptoms were predictive of subsequent cannabis use, which in turn was associated with reductions in state anxiety . However, the cannabinoid content of the cannabis used by participants was not assessed and ratings were not taken immediately prior to and following use of cannabis, preventing the analysis of acute, within moment effects . Another major limitation of the body of research on PTSD and cannabis/cannabinoids has been the paucity of longitudinal data which has obscured understanding of whether cannabinoids need to be administered chronically, or if acute doses are sufficient to reduce PTSD symptoms . Failures to consider long-term effects of cannabis use on PTSD is particularly concerning given that the chronic cannabis use is associated with a broad range of negative outcomes . Therefore, two recent studies have extended prior work by examining the short- and long-term effects of cannabis with different ratios of THC and cannabidiol on PTSD symptomatology . Findings suggest that THCdominant, CBD-dominant, and balanced THC:CBD cannabis preparations were associated with short-term reductions in PTSD symptoms, though none separated from placebo . However, long-term use of primarily THC-dominant cannabis was associated with lower PTSD symptomatology as well as a greater than two-fold reduction in the likelihood of PTSD diagnosis at 12 months, relative to non-users . The present study was designed to address the limitations of the extant literature by using a very large dataset to examine changes in PTSD symptomatology from immediately before, to shortly after, cannabis use as well as potential predictors of these symptom changes including gender, dose, THC concentrations, CBD concentrations, and THC x CBD interactions. We further sought to explore potential long-term consequences of repeatedly using cannabis to manage symptoms of PTSD by investigating changes in the efficacy of cannabis, changes in dose, and changes in baseline PTSD symptoms across cannabis use sessions over a 31-month time period.Archival data were obtained from Strainprint®, a medical cannabis technology platform with a journaling app that allows users to track changes in symptom severity as a function of their cannabis use. Immediately prior to engaging in medical cannabis use, Strainprint® users can select the specific condition/symptom they are using cannabis to manage and rate their severity from 0 to 10 .
For instance, users preparing to self-medicate for anxiety would be asked to respond to the question “How bad is your anxiety?” by rating the severity of this symptom on a 0 to 10 scale. Users are then prompted to indicate their method of administration . Next, they indicate the strain of cannabis that they are about to use as well as the producer/distributor of that strain by choosing from a selection of over 3,000 cannabis products sold in Canada. Lab verified cannabinoid content is pre-populated within the app using data from the websites of cannabis distributors in Canada. Alternatively, if a particular product is not pre-populated within the app, Strainprint® users can manually enter the strain name and cannabinoid content of the product they are about to use. After rating their initial symptom severity and identifying their cannabis product and method of administration, app users then indicate the dose taken during their medical cannabis use session. After an onset period determined by the method of administration chosen , the app provides a push notification reminder to prompt users to re-rate the severity of their symptom. For this study, we obtained anonymous data from Strainprint® for users who self-identified as having PTSD and who used the app to track symptoms of intrusive thoughts, flashbacks, irritability, and anxiety. More specifically, the obtained data included anonymous ID codes, cannabis treatment session numbers, gender, age, symptoms, self-reported symptom severity before and after each tracked session of medical cannabis use, cannabinoid content for the cannabis used in each session, the method of obtaining the cannabinoid content data , as well as the method of administration and dose for each cannabis use session. The Office of Research Assurances deemed this anonymous archival study exempt from the need for IRB review.Due to potential discrepancies in the efficacy and onset of different routes of administration of cannabis , we included only tracked sessions in which individuals indicated that they used an inhaled method of administration . Sessions involving other methods of administration were not included in the present study. Furthermore, only tracked sessions in which individuals re-rated their symptoms within 4 hours of cannabis use were included in the present study, given that the acute effects of inhaled cannabis are known to peak within 10-30 minutes of ingestion, and dissipate after 3-4 hours . Finally, due to concerns with the reliability and validity of self-reported cannabinoid content information, we also opted to only include sessions for which lab-verified cannabinoid content data were obtained directly from the websites of producers by Strain print® and to exclude session for which users manually inputted information on THC and CBD concentrations.To examine change in symptom severity from before to after cannabis use, two-time points latent change score models were used.
This approach allowed us to examine changes in PTSD symptoms within subjects across time and as a function of specific predictors of interest . For each symptom of PTSD, three LCS models were estimated. The baseline unconditional LCS models contained no predictors and were used to describe the nature of symptom change following cannabis use. These models provided a mean of the latent change factor, which is an estimate of average change in symptom severity over time. A negative value on this change factor is indicative of improved symptom severity following cannabis use, while a positive value is indicative of a worsening of symptoms following cannabis use. These unconditional models also provided an estimate of the extent to which change in symptom severity covaried with symptom severity scores before cannabis use. A negative covariance value between the latent change factor and symptom severity before cannabis use indicates that, on average, greater symptom severity prior to cannabis use is associated with greater relief following cannabis vertical farming use. Finally, these baseline models also provided an estimate of the variance of this latent change factor, which describes the extent to which symptom change following cannabis use varied across individuals .The second and third LCS models estimated were conditional models which included predictors of the latent change factor. First, conditional LCS models were used to estimate the influence that time/ cannabis use session, gender, dose , THC and CBD concentrations had on the latent change factor. Subsequent conditional LCS models estimated the influence of the same set of predictor variables, as well as the effect of the interaction of THC x CBD on the latent change factor. Estimates for each of these predictors can be interpreted as beta coefficients which describe the average influence of the predictor variable on the change factor. Positive beta coefficients indicate that higher levels of the predictor variable are associated with smaller decreases in symptom severity ratings following cannabis use. In contrast, negative coefficients indicate that higher values of the given predictor are associated with greater decreases in symptom severity from before to after cannabis use. All LCS models were fit using Mplus version 8.3 . Finally, separate repeated measures multilevel models were used to describe changes in baseline PTSD symptom severity across time/cannabis use sessions and dose of cannabis used over time/cannabis use sessions. In these unconditional models, which contained no predictors, cannabis use session was centered at Time 1 so that the intercept represented the first session of cannabis use in each model. The fixed and random linear effects of time/cannabis use session on baseline severity and dose were estimated using SAS Proc Mixed, with maximum likelihood estimation and incomplete data treated using missing at random assumptions.