Findings suggest a need to thoroughly and accurately assess and address cannabis use among HIV positive individuals who are prescribed antiretroviral medication. Indeed, it may not be enough to assess whether an individual simply uses cannabis, but also the frequency and duration of use, as well as problems associated with use, tolerance, and withdrawal, so as to be able to accurately determine dependence. Second, and related, findings suggest the potential need for specific interventions for HIV positive individuals with cannabis dependence. Cannabis dependent individuals in the present study had between 74 % and 93 % adherence, and evidence of poorer viral suppression. Though pill count data revealed higher adherence for non-dependent cannabis users, both pill count and self-report data on adherence was also lower than 95 %, on average, for this group as well. Existing brief interventions that can be used in primary care and specialty care settings may be useful in terms of reducing problematic cannabis use and increasing antiretroviral adherence among these individuals. Finally, as some data suggest that even low levels of cannabis use are associated with psychological problems , the lack of differences between cannabis non-users and non-dependent users provide some initial doubt as to the clinical utility of recommending cannabis for those with HIV. Though the present study provides a more detailed picture of the relations between cannabis use and antiretroviral adherence and HIV symptoms/ART side effects, it is not without limitation. First, the present study was cross sectional and thus unable to determine the prospective association between varying degrees of cannabis use and adherence or symptoms. Indeed, it remains unclear whether cannabis dependence led to poor adherence and symptoms or whether more severe HIV symptoms resulting from poor adherence led to cannabis grow equipment dependence via coping-oriented use. Related, though the employed measurement design was a study strength, we were not able to discern pill count or self-reported adherence as well as would have been possible with multiple assessments to establish a stable baseline level of adherence .
Future studies would benefit from examining the studied associations longitudinally, and conducting blood draws at the same time as the other assessments. Such improvements in design and measurement would also warrant more advanced methods of statistical analysis , where multiple observed variables could serve as indicators of an overarching latent ‘‘adherence’’ variable. Though the present study was quite ethnically diverse, almost 80 % of the sample was male. Though the present study had a higher percentage of females with HIV than is represented in the San Francisco bay area , future work would benefit from recruiting a more gender-diverse sample from different geographic areas. Finally, though cannabis dependence was assessed using the most current and rigorous criteria, the collection of additional contextual information related to cannabis use may help improve our understanding of the differences observed in the present study. Related, the collection of additional information on factors such as substance use motivation, emotion regulation, and cognitive functioning, in future prospective studies, would allow for the determination of malleable mechanisms that may underlie the observed relations, providing a more nuanced understanding of the association between cannabis use and antiretroviral medication adherence and HIV symptoms/ ART side effects.Cannabis and synthetic cannabinoid agonists can produce certain therapeutic effects, but they can also produce adverse side effects including dependence and memory impairment. They produce these effects by activating cannabinoid CB1 receptors, mimicking the effects of endogenous cannabinoid substances . The two main endocannabinoids, anandamide and 2-arachidonoylglycerol , are produced on demand and are rapidly degraded by fatty acid amide hydrolase and monoacylglycerol lipase , respectively. Since CB1 receptors have two separate endogenous ligands, it is likely that the brain circuits involving anandamide and 2-AG underlie distinct sets of neuro behavioral processes that can be selectively targeted for therapeutic purposes. This can be accomplished by administering inhibitors of FAAH or MGL, thereby increasing the effects of anandamide or 2-AG when and where they are released. This amplification of natural endocannabinoid signaling could potentially produce beneficial effects without the adverse side effects associated with exogenous cannabinoid agonists, which directly activate CB1 receptors throughout the brain .
In preclinical testing, URB597 does not produce classical THC-like effects such as catalepsy, hypothermia, and hyperphagia . URB597 also shows no signs of abuse potential in animal models of cannabis abuse; it does not have THC-like effects in rats trained to detect the interoceptive effects of THC , and it is not self-administered by squirrel monkeys that have extensive experience self-administering anandamide and other cannabinoid agonists . However, other FAAH inhibitors, including URB694 , PF-04457845 , and AM3506 , have shown moderate to strong reinforcing effects when offered as an intravenous solution to squirrel monkeys. These findings indicate that FAAH inhibitors can vary considerably in their effect profiles and should be evaluated individually for specific therapeutic and adverse effects. Delta-9-tetrahydrocannabinol impairs learning and memory in humans and animals , with working memory being particularly sensitive. In rodents, memory has also been shown to be impaired by administration of exogenous anandamide, but only when its degradation by FAAH is prevented . Surprisingly, inhibition or genetic deletion of FAAH, which substantially increases endogenous levels of anandamide, has been found to enhance rather than impair memory in rodents trained with procedures involving aversively motivated behavior . However, memory-related studies with appetitively motivated procedures have mostly shown impairment rather than enhancement after treatment with a FAAH inhibitor . There have been fewer studies involving MGL inhibition. The MGL inhibitor JZL184 did not affect memory in an object recognition procedure , but JZL184 and a dual FAAH-MGL inhibitor both impaired memory in a repeated acquisition water-maze procedure in mice . In the present study, we focused on the effects of FAAH inhibitors on working memory in rats, using a food-based procedure known to be sensitive to impairment by THC . We tested five different FAAH inhibitors at doses sufficient to substantially increase levels of anandamide . We found that only one of these compounds, the FAAH inhibitor AM3506, impaired working memory at the doses tested.
Since pharmacological doses of anandamide may activate alpha-type peroxisome proliferator-activated receptors and vanilloid transient receptor potential cation channels , and since FAAH inhibition increases endogenous levels of not only anandamide but also other fatty acid amides that are ligands for PPAR-alpha and TRPV1, we explored the mechanism of AM3506’s effects by giving AM3506 in combination with a CB1 antagonist , a PPAR-alpha antagonist , or a TRPV1 antagonist . These tests indicated that the memory impairment induced by AM3506 was mediated by CB1 receptors.Twelve experimentally naive male Sprague–Dawley rats were maintained in individual cages on a 12-h light/dark cycle with lights on starting at 0645 hours. Procedures were conducted Monday through Friday between 1000 and 1400 hours. Rats were fed approximately 15 g of food per day to maintain stable body weights. The facilities were fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care , and all experiments were conducted in accordance with the guidelines of the Animal Care and Use Committee of the National Institute on Drug Abuse Intramural Research Program and the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research .The preliminary training procedures, including magazine training with food, shaping of nosepoke responding, and response-chain training were described in detail previously . Under the nonmatching-to-position task used for baseline and test sessions in the present study , there were repeated trials in which either the left or right nosepoke hole was illuminated as a sample; two responses in the sample hole extinguished the sample hole light and turned on the center hole light,cannabis cultivation technology starting the delay period; after a delay of 0, 7, 14, 21, or 28 s, the next response in the center hole extinguished the center hole light and illuminated both side holes, starting the choice phase of the trial; during the choice phase, a response in the side hole opposite to the sample constituted a correct response and produced a food pellet, extinguished the hole lights, and started a 15-s intertrial period with only the house light on; alternatively, during the choice phase, a response in the same hole in which the sample had been presented constituted an incorrect response and did not produce a food pellet, but extinguished the hole lights and caused the house light to flash at 5 Hz for 5 s, followed by a 15-s intertrial period with only the house light on; regardless of whether the choice response had been correct or incorrect, the house light was extinguished and a sample hole was illuminated after the intertrial period, starting a new trial. The side of the sample hole in each trial was drawn without replacement from a list in which each side appeared twice. Similarly, the value of the delay was drawn without replacement from a list in which each of the five possible values appeared once. When either list was depleted, it was replenished before the next trial. Sessions were conducted Monday through Friday and lasted for 90 min or until 100 food pellets had been delivered.Tests were conducted up to two times per week, usually on Tuesday and Friday, if the accuracy of choice responding was over 90% correct at the 0-s delay and there was <10 percentage points difference in accuracy at a given delay over the two previous baseline sessions. The FAAH inhibitors were first tested in the following order: URB694, AM3506, URB597, PF-04457845, ARN14633. The monoacylglycerol lipase inhibitor, JZL184, was tested after ARN14633. For each test drug, the vehicle and two doses were tested in a counterbalanced order across subjects. This counterbalancing was intended to avoid artifacts due to potential confounding of shifts in baseline performance and the order in which the drugs were tested, by allowing each drug treatment to be compared to a contemporaneous vehicle control session. After this single-drug testing, the effects of treatment with AM3506 and its vehicle were tested in combination with a pretreatment injection of rimonabant , MK886 , capsazepine , or vehicle, with the order of combinations counterbalanced across subjects.Analyses were performed with Proc Mixed , using the Tukey–Kramer procedure to maintain a 0.05 significance level for paired comparisons. For figures showing delay curves, simultaneous confidence intervals with a Bonferroni-corrected 95% confidence level were determined for all points within each experiment, and gray bands were included in the figures such that points falling outside the band were significantly higher than 50%.
The percentage of trials with a correct response was analyzed as a function of the pretreatment dose , the treatment dose, and the delay value. All percentage measures were arcsine root transformed for analysis. Responding during the delay period was also analyzed using procedures to assess the role of mediating behavior in performance of the matching task. Briefly, logistic regression was used for each subject to determine whether responding in either the to-be-correct hole or the to-be-incorrect hole during the delay period influenced the accuracy of the choice response; based on this regression, each rat was categorized according to whether responding in the to-be-correct hole or the to-be incorrect hole was Bappropriate; each trial from each test session was then categorized according to whether side-hole responding occurred during the delay period only in the appropriate hole, only in the inappropriate hole, both, or neither. To obtain sufficient samples for the logistic regression used to categorize each rat, data were combined from all the baseline sessions that preceded treatment sessions.Accuracy under the non matching-to-sample task was high at the 0-s delay and decreased monotonically as a function of delay under baseline conditions and after treatment with vehicle . Even at the longest delay, accuracy was well above chance level after treatment with vehicle. During drug testing , the accuracy curves continued to show a general downward slope. The data in each frame in Fig. 2 were analyzed separately, and in each case, the main effect of delay was highly significant [F ranging from 24.0 to 46.0, all p values <.0001]. The main effect of AM3506 on accuracy was significant [F=30.2, p<.0001], but the other treatment drugs had no significant main effects or interaction effects .