There were no effects of heroin dose in the vehicle pretreatment conditions confirmed in this analysis.This study first confirms that THC enhances the antinociceptive effect of heroin when the drugs were administered by vapor inhalation via an electronic drug delivery system , in a manner similar to the effects observed when the drugs were delivered by parenteral injection . This outcome is consistent with a prior demonstration that THC enhances the effects of another opioid, oxycodone, on anti-nociception when drugs are delivered either by inhalation or injection . Thus, the routes of administration, and the doses used in this study, are those which are effective at demonstrating the “opioid-sparing” effects of THC when it comes to one desired medical benefit of both opioids and THC, i.e., analgesia. In contrast, the effects of each drug on thermoregulation and locomotor activity when co-administered appear to be independent. That is, when doses of heroin that increase body temperature are combined with doses of THC that decrease body temperature, the net effect is an intermediate response, indistinguishable from the response to vehicle in some cases. Interpretation of the effects of co-administration on activity is complex because the effects of higher doses of heroin are biphasic with time after dosing. Still, at a time post-administration when hyperlocomotive effects of heroin are observed, the combination with hypolocomotor doses of THC results in an intermediate effect on activity. There is a biphasic dose-dependent effect of heroin on body temperature with lower exposures producing small, but reliable, increases in temperature and higher doses/exposures reducing body temperature, as with the first experiment and in female rats in a prior report . Here,cannabis grow system we selected parameters of exposure to heroin anticipated to increase body temperature in both male and female rats and a parameter of THC exposure anticipated to lower body temperature.
The results show that the co-administration produces an intermediate phenotype, consistent with independent effects. This was the case in two cohorts of male rats as well as in the female rats, illustrating the robustness of the observation. There was a slight disconnect in that inhalation of vapor from heroin 50 mg/mL for 30 min was the higher exposure in the first group and constituted a lower exposure in the second group of males. It is likely that the slight change in methods across studies produced the difference, i.e., we used multiple inhalation chamber setups. This further underlines the necessity for validation studies to hone exposure conditions when using this method, even when the same canister/ atomizer and power supply configurations are used. We have previously shown that heroin vapor exposure produces anti-nociceptive effects in male and female Wistar rats and that is herein extended to Sprague–Dawley rats. We also show here that the competitive, non-selective opioid receptor antagonist naloxone attenuates the anti-nociceptive effects of inhaled heroin . It also blunted the thermoregulatory and locomotor stimulant responses to heroin inhalation . This is a novel observation since we did not include this in our prior study which was the first to show the efficacy of EDDS vapor delivery of heroin. While the effect of naloxone is perhaps expected, we have reported an unanticipated lack of effect of CB1 antagonist/ inverse agonist pre-treatment on THC vapor–induced hypothermia , so it was important to confirm opioid antagonist efficacy in this model. The failure to achieve a statistically reliable additive anti-nociceptive effect of THC+heroin inhalation in the female group is likely due to a slightly more robust response to the heroin inhalation condition, compared with the males. We then went on to expand this experiment to a broader range of conditions in female Wistar rats, using drug injection to afford tighter dose control . These studies demonstrated that a 0.56 mg/ kg, s.c., dose of heroin combined with a 5.0 mg/kg, i.p. dose of THC appears to approximate the threshold for observable interactions.
After demonstrating that the 0.1–0.32 mg/kg, s.c., doses of heroin produce minimal effect administered alone, we then went on to show in the complex design that only 0.56 mg/kg produced a significant increase in nociception beyond that induced by 5.0 mg/kg, i.p., THC. The 5.0 and 10.0 mg/kg THC doses appear to produce approximately the same magnitude of effect in the tail withdrawal assay at 52 °C as illustrated here and in prior work , suggesting an asymptote in the dose–response curve for this drug when administered alone. It is therefore intriguing that the addition of 0.5 mg/kg heroin to 10 mg/kg THC had a greater additive anti-nociceptive effect than the addition of 0.56 mg/kg heroin to 5 mg/kg THC. This hints at a more than the additive interactive effect that would need to be explored with additional experimental designs to confirm. As one minor caveat, although the two female groups were well age-matched, the second group was experimentally naïve and the first group had received prior drug exposure. Overall, these results confirm the so-called opioid-sparing effects of THC in the context of thermal analgesia. The translational potential is that by taking lower doses of each drug the consequences of higher doses might be partially avoided. This may be important for slowing the development of tolerance to the therapeutic benefits of either drug independently and thereby slow the need for increasing doses. In a more general sense, this study further confirms the utility of the EDDS approach for the investigation of poly-substance use. Patterns of poly drug use in humans via simultaneous vaping are already being described in the epidemiological literature , which tends to lag real-world practices by months to years; thus, it is a critical advance to be able to study such practices in a controlled laboratory model. As outlined in the Introduction, EDDS models for the inhalation delivery of a range of drugs in laboratory rodents are being rapidly developed and reported. This technique for laboratory rodent research is flexible in terms of drug substances and doses and is therefore capable of supporting poly-drug investigations.
We have previously used this model to explore interactive effects of nicotine with THC and of nicotine with cannabidiol , as well as the effects of combined inhalation of these two cannabinoids . As a minor caveat, we did not examine both sexes in every experiment. In the studies that did examine the sexes in parallel, the effects appeared to be qualitatively similar, albeit there may be minor differences in dose–effect curves. Thus, although there is support for the conclusion that studies conducted in one sex would generalize, a firm conclusion would await future verification in direct sex comparisons. In conclusion, THC can reduce the dose of heroin necessary for a given analgesic effect. However, the effects of combined THC and heroin on activity and thermoregulation show, critically, that the inference that THC universally enhances the effects of heroin, or vice versa, is not supported. When the effects of each drug in isolation are in the same direction, due to either dose or the in vivo endpoint, they can appear to have interactive effects. However, when the effects are in the opposite direction, such as with body temperature and activity at specific doses, then the combination produces an intermediate phenotypic outcome.While a super-additive interaction might appear beneficial for medical applications the limitation would be that any tolerance to one or the other drug that appears would also have interactive, rather than merely subtractive effects. Additional study would be required to determine whether combinations of cannabinoid and opioid drugs used chronically result in less rapid tolerance compared with equipotent therapeutic regimens of each drug taken alone. Relatedly, it remains to be determined if the ability to more closely titrate dose to effect can be obtained with the inhaled route of administration of THC or an opioid.Tobacco use remains high among people with substance use disorders .Prevalence of cigarette smoking in this population is approximately 60-90%, which is 3-4 times higher than that in the general population.Notably,cannabis grow lights prevalence of tobacco-related mortality among people in SUD treatment is nearly double that in the general population.Cigarette smoking is also associated with poorer SUD treatment outcomes and smokers with SUD are more likely to die from tobacco-related causes than from other substance-related causes.Thus, addressing tobacco use and promoting tobacco cessation among people in SUD treatment are needed. In the past decade, use of non-cigarette tobacco products has increased in the US.5 The 2019 national data showed that 20.8% of US adults currently used any tobacco product, with cigarettes being the most common tobacco product among adults , followed by e-cigarettes , cigars/cigarillos , smokeless tobacco , and hookah .However, e-cigarette vaping surpasses cigarette smoking among young adults.Notably, multiple tobacco use is increasingly popular,with the most common pattern being dual use of cigarettes and ecigarettes.In response to these changes, research focusing on multiple tobacco use in the general population has increased.Existing evidence shows that younger age, male sex, use of cannabis, and tobacco use initiation with a noncombustible product were associated with multiple tobacco use in the general population.Furthermore, compared to single tobacco product users, multiple tobacco users have higher exposure to harmful constituents,greater nicotine dependence,and decreased intention to quit.
Given their high prevalence of cigarette smoking, people in SUD treatment may be at greater risk for multiple tobacco use and its health–related harms as compared to the general population. However, little is known about multiple tobacco use in this understudied population.To date, the preponderance of literature in this area has focused on use of traditional combustible cigarettes, which may lead to under-estimates of tobacco use in this population and limit tobacco intervention strategies to a single product. To our knowledge, only two studies explored the use of alternative tobacco products in this population,and only one of those examined multiple tobacco use.Guydish et al. examined the weekly use of different tobacco products among clients from SUD treatment programs in the National Institute on Drug Abuse Clinical Trials Network during 2014-2015. This study found multiple tobacco use was prevalent but less than single product use , and that multiple tobacco users smoked more cigarettes per day, were more likely to try to quit smoking, and had greater susceptibility to advertising for non-cigarette products.12 Given the recent increasing use of non-cigarette tobacco products, more data are needed to understand the current status of tobacco use, particularly multiple tobacco use, among people in SUD treatment, ultimately inform policy and intervention efforts targeting this population. To address these gaps, we examined multiple tobacco use among clients in residential SUD treatment programs in California. In addition, as available tobacco services in the treatment programs focus primarily on cigarette smoking cessation, comparing characteristics of dual- and poly tobacco users and single tobacco users can help tailor interventions to reduce all types of tobacco use in this high-risk group. Thus, we examined the associations between tobacco-related and health-related factors and tobacco use patterns. We hypothesized that dual and poly tobacco users would have greater nicotine dependence, less quitting motivation, and lower health status compared to single tobacco users. The current study is a secondary analysis of baseline data from three ongoing projects. These projects aimed to reduce tobacco use and promote wellness among clients at 20 residential SUD treatment programs in California, US.One project aimed to support seven treatment programs in implementing tobacco-free policies. The second project aimed to improve tobacco interventions in four treatment programs. The third project aimed to understand existing tobacco policies and interest in implementing tobacco-free policies in nine treatment programs. The 20 programs were located in 11 of California’s 58 counties. All were publicly funded and state licensed to provide residential SUD services, although some programs treated clients with both SUD and mental health problems. Residential SUD programs are those where clients live while receiving SUD treatment. Medicaid pays for residential SUD program in California, reimbursing up to 90 days of residential treatment services.16 Programs sometimes have additional contracts with local public health or criminal justice departments, or with state prisons for rehabilitation of inmates pre- or post-release. California law prohibits indoor smoking in public spaces, including residential treatment. Nearly all California SUD residential treatment programs have a policy concerning e-cigarette use, either restricting use to the same times and places as use of combustible cigarettes or, less often, banning e-cigarettes from use on program property.