Psychopharmacology https://doi.org/10.1007/s00213-021-05904-w ORIGINAL INVESTIGATION Efects of combined THC and heroin vapor inhalation in rats Arnold Gutierrez1,2 · Jacques D. Nguyen1,2 · Kevin M. Creehan1,2 · Mehrak Javadi‑Paydar1 · Yanabel Grant1,2 · Michael A. Tafe1,2 Received: 27 April 2021 / Accepted: 27 May 2021 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 Abstract Rationale Opioids are efective medications, but they have several key limitations including the development of tolerance, establishment of dependence, diversion for non-medical use, and the development of addiction. Therefore, any drugs which act in an additive or synergistic fashion with opioids to address medical applications have the potential to reduce opioid- related harms. Objectives To determine if heroin and Δ9-tetrahydrocannabinol (THC) interact in an additive or independent manner to alter nociception, body temperature, and spontaneous locomotor activity when inhaled or injected. Methods Groups of female and male rats, implanted with radiotelemetry transmitters, were exposed to vapor generated from heroin (50 mg/mL in propylene glycol vehicle; PG), THC (50 mg/mL), or the combination for assessment of efects on temperature and activity. Thermal nociception was assessed with a warm water tail-withdrawal assay. Results Heroin inhalation increased temperature and activity whereas THC inhalation decreased temperature and activity in both female and male Sprague–Dawley rats. Efects of combined inhalation were in opposition, and additional experiments found the same outcome for the injection of heroin (0.5 mg/kg, s.c.) and THC (10 mg/kg, i.p.) alone and in combination. In contrast, the co-administration of heroin and THC by either inhalation or injection produced additive efects on thermal nociception in both male and female Sprague–Dawley and Wistar rats. Conclusions This study shows that additive efects of THC with an opioid on a medical endpoint such as analgesia may not generalize to other behavioral or physiological efects, which may be a positive outcome for unwanted side efects. Keywords e-cigarette · Vape · Opioid · Nociception · Locomotor activity · Thermoregulation Introduction similar efcacy), the development of dependence (which counter-indicates rapid discontinuation), diversion for non- Expansion of the use of cannabis for purported medical medical use, and the development of addiction. Any drugs benefts (e.g., for pain) stimulates interest in the possible which may act in an additive or synergistic fashion with opioid-sparing efects of cannabis constituents, including the opioids therefore have the potential to reduce opioid-related primary psychoactive compound Δ9-tetrahydrocannabinol concerns. There are known interactions by which endog- (THC). While opioids are efective medications, they have enous cannabinoid receptor 1 (CB 1) ligands may enhance many limitations including the development of tolerance signaling of mu opioid receptors (Parsons and Hurd 2015), (and the consequent need to increase the doses to obtain thus generating a reasonable mechanistic hypothesis for evaluating opioid-sparing efects of cannabis constituents. This article belongs to a Special Issue on Cannabis and Cannabis co-use triples the risk of dependence on heroin Cannabinoids in those diagnosed with a substance use disorder (Crummy et al. 2020) and cannabis users over 50 years of age exhibit a * Michael A. Tafe 6.3 increased odds ratio of heroin use (Ramadan et al. 2020). [email protected] Adolescents in one urban setting who use cannabis regu- 1 Department of Neuroscience, The Scripps Research Institute, larly were at twice the risk for opioid misuse compared with La Jolla, CA, USA occasional users of cannabis (Reboussin et al. 2020) and 2 Department of Psychiatry, University of California, 9500 age 14 onsets of frequent cannabis use increased the risk of Gilman Drive, San Diego, La Jolla, CA 92093, USA Vol.:(0123456789)1 3 Psychopharmacology opioid use at age 19 (Thrul et al. 2021). Almost two-thirds THC interact in an additive or independent manner to alter of individuals in one sample frst used heroin while co-using thermal nociception, body temperature, or spontaneous loco- cannabis (Olthuis et al. 2013) and 50–60% of individuals in motor activity when inhaled or injected. heroin- and methadone-maintenance treatment for opioid use The recent broad availability of e-cigarette style Elec- disorder were co-using cannabis (Musshof et al. 2010). On tronic Drug Delivery Systems (EDDS) supports the pos- a day-by-day basis, cannabis use doubles the risk of non- sibility of delivering a range of drugs other than nicotine, medical opioid use in adults with problematic substance use including opioids, via vapor inhalation. The use of these (Gorfnkel et al. 2021). Thus, although cannabis may have devices for the ingestion of cannabis extracts has become the potential to reduce opioid use in medical patients, there increasingly popular (Allem et al. 2019; Dugas et al. 2020; is also a clear risk for cannabis to increase the non-medical Kowitt et al. 2019; Nicksic et al. 2020; Pearson and Villanti, use of heroin from adolescence into middle age. Considera- 2020). The EDDS can be used to deliver active doses of a tion of these phenomena spurs interest in determining the wide range of drugs including amphetamine and cathinone interactive efects of cannabinoids and opioids across mul- derivative psychomotor stimulants (Nguyen et al. 2016a, tiple behavioral and physiological endpoints to lend greater 2017), opioids (Gutierrez et al. 2020a; Moussawi et al. 2020; context for “opioid-sparing” recommendations for cannabis Nguyen et al. 2019; Vendruscolo et al. 2018), cannabinoids use. (Breit et al. 2020; Freels et al. 2020; Javadi-Paydar et al. We recently presented evidence that THC enhances the 2019a, 2018; Moore et al. 2020a; Nguyen et al. 2016b), and efects of oxycodone in an anti-nociception assay in rats and nicotine (Cooper et al. 2021; Frie et al. 2020; Javadi-Paydar it also enhances the efects of a unit dose of oxycodone or et al. 2019b; Montanari et al. 2020; Ponzoni et al. 2015) to heroin when self-administered (Nguyen et al. 2019). Magu- rats and mice; for review see (Miliano et al. 2020; Moore ire and France have shown that the nature of the anti-noci- et al. 2020b). Generally speaking, the efects of drugs after ceptive interaction (supra-additive, sub-additive, additive) inhalation persist for a shorter time than when injected (i.p. between cannabinoids and opioids may depend on the spe- or s.c.), and, as we have recently shown, this is certainly true cifc drugs that are involved (Gerak et al. 2019; Maguire and for heroin and THC (Gutierrez et al. 2021; Nguyen et al. France 2018; Maguire et al. 2013) which cautions against 2016b). This diference may impact the combined efects, making generalizations across either class of substances, and therefore, the inhalation route was contrasted with tra- before specifc data are available. In the case of both noci- ditional injection routes used in rodent models. ception and drug self-administration, the efects of opioids and cannabinoids are often in the same direction, i.e., anti- nociceptive (Li et al. 2008; Lichtman and Martin, 1990; Methods Manning et al. 2001; Peckham and Traynor 2006; Wakley and Craft 2011) and rewarding (Blakesley et al. 1972; Jus- Subjects tinova et al. 2003; Killian et al. 1978; Panlilio et al. 2010; Vendruscolo et al. 2018). This can make it difcult to deter- Male (N = 15) and female (N = 7) Sprague–Dawley rats mine if the outcome of co-administration is due to the addi- (Harlan/Envigo, Livermore, CA) and male (N = 10) and tive efects of independent mechanisms or the interaction of female (N = 22) Wistar (Charles River) rats were housed in signaling within the same mechanistic pathways (Ahmad humidity- and temperature-controlled (23 ± 2 °C) vivaria et al. 2013). on 12:12-h (reversed) light:dark cycles. Rats had ad libitum Determination of any heroin/THC interactions for in vivo access to food and water in their home cages and all experi- endpoints that are expected to change in opposite directions ments were performed in the rats’ scotophase. All proce- after each drug is administered individually can help to fur- dures were conducted under protocols approved by the Insti- ther parse the specifcity of any apparent additive efects. tutional Care and Use Committees of The Scripps Research We have identifed conditions under which either inhaled Institute or the University of California, San Diego. or injected heroin can increase the body temperature and spontaneous locomotor activity (Gutierrez et al. 2021), and Drugs conditions under which THC can decrease body temperature and locomotor activity (Javadi-Paydar et al. 2018; Nguyen Heroin (diamorphine HCl) and Δ9-tetrahydrocannabinol et al. 2016b; Tafe et al. 2021). We have further shown that (THC) were administered by vapor inhalation with doses the locomotor efects of nicotine and THC on activity can described by the concentration in the propylene glycol (PG) oppose each other when co-administered (Javadi-Paydar vehicle (e.g., 50, 100 mg/mL) and duration of inhalation et al. 2019b); the efects of each drug to decrease body tem- (15, 30 min), following the methods described in prior perature were also dissociated across time, after administra- studies (Javadi-Paydar et al. 2018; Nguyen et al. 2016b). tion. This study was conducted to determine if heroin and Heroin was also administered subcutaneously. THC was 1 3 Psychopharmacology also administered intraperitoneally in a dose of 10 mg/kg, for inhalation and injection studies started with a 15-min which produces robust temperature responses (Nguyen et al. interval to ensure data collection, then a 15-min interval 2016b; Tafe et al. 2015). Naloxone was administered i.p. for baseline temperature and activity values followed by the For injection, heroin and naloxone were dissolved in physi- initiation of vapor sessions or drug injection.