We also were unable to assess clinical data, such as HIV viral loads and CD4 cell counts among PLWH. On the other hand, the BRS and GAD-7 are highly validated and reliable instruments. In a review of resilience measures, Windle et al. identified the BRS as one of three scales with the highest psychometric properties for resilience. The generalizability of resilience among PLWH may be limited by survivorship bias. Nevertheless, resilience among PLWH was protective against adverse mental and behavioral health outcomes. There were also considerable losses to follow-up; however, a sensitivity analysis using cross-sectional data from all participants during the 1st survey wave also supported our hypotheses: PLWH had higher odds of high resilience than HIV-uninfected peers, and high resilience was associated with lower risk of substance misuse. The study is strengthened by the use of six C3PNO cohorts across the USA, consisting of marginalized and minority groups with a diverse population of PWUD, many living with or at-risk of HIV. Expansion of the use of cannabis for purported medical benefits stimulates interest in the possible opioid-sparing effects of cannabis constituents, including the primary psychoactive compound Δ9 -tetrahydrocannabinol . While opioids are effective medications, they have many limitations including the development of tolerance , the development of dependence , diversion for non-medical use, and the development of addiction. Any drugs which may act in an additive or synergistic fashion with opioids therefore have the potential to reduce opioid-related concerns. There are known interactions by which endogenous cannabinoid receptor 1 ligands may enhance signaling of mu opioid receptors,thus generating a reasonable mechanistic hypothesis for evaluating opioid-sparing effects of cannabis grow supplies constituents. Cannabis co-use triples the risk of dependence on heroin in those diagnosed with a substance use disorder and cannabis users over 50 years of age exhibit a 6.3 increased odds ratio of heroin use .
Adolescents in one urban setting who use cannabis regularly were at twice the risk for opioid misuse compared with occasional users of cannabis and age 14 onsets of frequent cannabis use increased the risk of opioid use at age 19 . Almost two-thirds of individuals in one sample first used heroin while co-using cannabis and 50–60% of individuals in heroin- and methadone-maintenance treatment for opioid use disorder were co-using cannabis . On a day-by-day basis, cannabis use doubles the risk of non-medical opioid use in adults with problematic substance use . Thus, although cannabis may have the potential to reduce opioid use in medical patients, there is also a clear risk for cannabis to increase the non-medical use of heroin from adolescence into middle age. Consideration of these phenomena spurs interest in determining the interactive effects of cannabinoids and opioids across multiple behavioral and physiological endpoints to lend greater context for “opioid-sparing” recommendations for cannabis use. We recently presented evidence that THC enhances the effects of oxycodone in an anti-nociception assay in rats and it also enhances the effects of a unit dose of oxycodone or heroin when self-administered . Maguire and France have shown that the nature of the anti-nociceptive interaction between cannabinoids and opioids may depend on the specific drugs that are involved which cautions against making generalizations across either class of substances, before specific data are available. In the case of both nociception and drug self-administration, the effects of opioids and cannabinoids are often in the same direction, i.e., antinociceptive and rewarding . This can make it difficult to determine if the outcome of co-administration is due to the additive effects of independent mechanisms or the interaction of signaling within the same mechanistic pathways . Determination of any heroin/THC interactions for in vivo endpoints that are expected to change in opposite directions after each drug is administered individually can help to further parse the specificity of any apparent additive effects.
We have identified conditions under which either inhaled or injected heroin can increase the body temperature and spontaneous locomotor activity , and conditions under which THC can decrease body temperature and locomotor activity . We have further shown that the locomotor effects of nicotine and THC on activity can oppose each other when co-administered ; the effects of each drug to decrease body temperature were also dissociated across time, after administration. This study was conducted to determine if heroin and THC interact in an additive or independent manner to alter thermal nociception, body temperature, or spontaneous locomotor activity when inhaled or injected. The recent broad availability of e-cigarette style Electronic Drug Delivery Systems supports the possibility of delivering a range of drugs other than nicotine, including opioids, via vapor inhalation. The EDDS can be used to deliver active doses of a wide range of drugs including amphetamine and cathinone derivative psychomotor stimulants , opioids , cannabinoids , and nicotine to rats and mice; for review see . Generally speaking, the effects of drugs after inhalation persist for a shorter time than when injected , and, as we have recently shown, this is certainly true for heroin and THC . This difference may impact the combined effects, and therefore, the inhalation route was contrasted with traditional injection routes used in rodent models.A preliminary dose-ranging experiment was conducted in a group of male Sprague Dawley rats used previously in investigations of the effects of inhalation of cannabidiol, nicotine, and THC as reported . The first goal was to evaluate whether heroin by vapor inhalation would alter body temperature and spontaneous locomotion, as it does when injected. These were our first attempts, conducted prior to the subsequent investigations reported here and in prior publications , critical to establishing the efficacy of drug delivery by this method. The second goal was to identify sub-maximal exposure conditions such that interactions with another drug such as THC might be detected. All animals were habituated to the procedure with one session of 30-min vapor exposure to PG followed by a 60-min recording interval. To determine the effect of heroin vapor on body temperature and locomotor activity, an initial 30-min inhalation exposure to PG and Heroin was designed. Animals were randomized to treatment conditions, and exposed, in pairs. Subsequently, the animals were evaluated after a 15-min interval of exposure to PG, heroin , THC , or heroin +THC.
The treatment conditions were again counter-balanced across exposure pairs and THC was experienced no more frequently than once per week for a given rat.Groups of male and female Sprague–Dawley rats used in studies previously reported were recorded for a baseline interval, exposed to inhalation of vapor from PG, heroin , THC , or the combination for 30 min in groups of 2–3 per exposure. These studies were conducted subsequent to a series of similar challenges with vapor inhalation of nicotine, THC, and with an injection of THC in additional studies not previously reported. The tail-withdrawal assay was conducted immediately after the vapor session and then rats were returned to their individual recording chambers for telemetry assessment. The four inhalation conditions were evaluated in a counterbalanced order across pairs/triplets, no more frequently than every 3–4 days.An opioid receptor antagonist study was included because we had not included this evidence in a prior study reporting heroin vapor effects on similar endpoints and we have reported an unusual lack of effect of cannabinoid receptor 1 antagonist/inverse agonist pre-treatment on THC vapor-induced hypothermia . This latter was observed despite efficacy against the anti-nociceptive effects of inhaled THC and the thermoregulatory effects in injected THC; thus, it was of interest to determine if a nonselective opioid receptor antagonist was effective against the effects of inhaled heroin on temperature, activity,cannabis grow facility and anti-nociceptive responses. The group of male Sprague–Dawley rats used in experiments 2–4 was recorded for a baseline interval, and then injected with either saline or naloxone 15 min prior to the start of a 30-min inhalation session of either PG or Heroin vapor. Post-inhalation, a tail-withdrawal assay was conducted and then animals were returned to their recording chambers for telemetric assessment. Inhalation was conducted in two pairs and one triplet, with the groupings changed on each test day. Pre-treatments were varied within the inhalation groupings to provide further randomization of conditions. Sessions were conducted two times per week in a counterbalanced treatment order. The female group examined in parallel with these animals in prior studies was not included because the maximum number of treatment days under the approved protocol had been used in prior experiments.
Groups of female and male Wistar rats were used in these studies. Rats had been exposed to twice daily sessions of vapor from the propylene glycol vehicle or heroin from PND 36 to PND 45 . These antinociception experiments were conducted between PND 253 and PND 275. Four treatment conditions were evaluated in counter-balanced order. Each session started with a tail-withdrawal assessment before any injections . This was followed immediately with an injection of THC or the cannabinoid vehicle . Another tail-withdrawal assessment was conducted 30 min post-injection, followed by a second injection of either heroin or saline , and then a final tail-withdrawal 30 min later. We have shown previously that anti-nociceptive effects of THC when injected at 5 or 10 mg/kg, i.p., persist essentially unchanged from 30 to 90 min after injection , justifying this sequential assessment approach. The design resulted in four replications of the pretreatment baselines, two replications of the THC or vehicle condition and then four final conditions of vehicle-saline, vehicle-heroin, THC-saline, and THC-heroin.The telemeterized body temperature and activity rate were collected on a 5-min schedule in telemetry studies but are expressed as 15-min or 30-min averages for primary analysis. The time courses for data collection are expressed relative to the initiation of vapor inhalation and times in the figures refer to the end of the interval . Due to transfer time after vapor sessions, the “60- min” interval reflects the average of collections from~40 to 60 min. Any missing temperature values were interpolated from the values before and after the lost time point. Activity rate values were not interpolated because 5 to 5-min values can change dramatically; thus, there is no justification for interpolating. Data were generally analyzed with two-way analysis of variance including repeated measures factors for the drug treatment condition and the time after vapor initiation or injection. A third factor was used for pre-treatments, adolescent exposure group, or sex in some experiments as described in the “Results” section. A mixed effects model was used instead of ANOVA wherever there were missing datapoints. Any significant main effects were followed with post hoc analysis using Tukey or Sidak procedures. The criterion for inferring a significant difference was set to p<0.05. All analyses used Prism 8 or 9 for Windows .The activity of the female rats was increased after heroin inhalation and decreased after inhalation of the THC+heroin combination. The post hoc test confirmed that activity was decreased relative to the baseline and all other inhalation conditions 60 min after the start of THC+heroin inhalation and elevated relative to the baseline and all other inhalation conditions 60 min after the start of THC. Activity was elevated compared with all other conditions 90–120 min after the start of heroin inhalation.Similarly, the post hoc test confirmed that temperature was significantly higher after inhalation of heroin 50 mg/mL and lower after inhalation of THC 50 mg/mL or the combination , compared with the PG condition. Temperature following the inhalation of both drugs in combination was significantly lower compared with heroin and higher compared with THC . The post hoc test confirmed that activity was elevated 90–120 min after the start of heroin inhalation compared with all other conditions, as well as at individual time points relative to the combination , THC , and PG . Activity differed between TH and the combined inhalation was higher than the baseline 60 min after initiation of heroin and lower than the baseline in the PG and THC inhalation conditions.The body temperature of the male rats was significantly elevated by heroin and decreased by THC .The post hoc test further confirmed a significant difference between saline injection and all three heroin doses, and between 0.32 and 0.56 mg/kg, within the THC pre-treatment condition.