E-cigarette / Vapor Inhalation

Humans choose to ingest psychoactive drugs by several different routes of administration, including inhalation. Smoking combusted tobacco or cannabis has been common across history and in the present, as is the inhalation of opioids volatilized by heat. Although there have been a few limited attempts to establish inhalation models in laboratory animals over past decades, these attempts have not resulted in sustained research programs or adoption of the methods beyond the individual laboratory. This, unfortunately, constrains our ability to determine areas in which the inhalation route may entail different health consequences of a given drug relative to other routes of administration.

More recently, "vaping" has become increasingly popular with human users, in synergy with the broad availability of two distinct technologies. One method heats cannabis (or other materials) to a high temperature below the combustion threshold and collects drug-infused air into a balloon (Volcano® type devices) from which it can be inhaled. A second method uses e-cigarette technology, often termed Electronic Nicotine Delivery Systems (ENDS), which we have adapted for our research program. Human use of these technologies to ingest a wide range of drugs shows that a generic term of Electronic Drug Delivery Systems (EDDS) is perhaps more apt than ENDS. The picture to the right illustrates a standard rat cage fitted with a sealed lid. This permits the controlled airflow through the chamber and the incorporation of vapor from an e-cigarette cartridge upon demand. We are using this approach in a variety of investigations to determine the impact of drugs when inhaled, as contrasted with more typical routes of administration in laboratory model.

Additional reading can be found in the tlneuro blog Vape inhalation archive.

Cannabinoids

A primary focus of our work is on the primary active constituent of cannabis or marijuana, i.e., Δ9-tetrahydrocannabinol (THC). Growing numbers of cannabis consumers are using non-combustible techniques, based on the evidence of a plethora of Web sites advertising methods, an emerging literature showing human practices (Giroud et al, 2015, Morean et al, 2015) and from suggestions that e-cigarette delivery may offer a safer alternative for medical cannabis consumers (Varlet et al, 2016). Our first paper (Nguyen et al., 2016a) demonstrated that vapor inhalation of THC reduces body temperature, decreases locomotor activity and attenuates detection of a noxious stimulus. These are three of the four traditional behavioral measures of cannabinoid activity in a rodent and thus verify the efficacy of this approach. We next showed in further studies that male and female rats exhibited approximately the same acute effects (Javadi-Paydar et al., 2018) and that tolerance develops with twice-daily exposure for four days (Nguyen et al., 2018).

We are also interested in the effects of cannabidiol (CBD) a constituent of marijuana that does not produce the strong psychotropic effects associated with THC. Our studies seek primarily to determine how CBD may modulate the effects of THC when the two are ingested together. We have found, at least in the rat models, that CBD enhances the effects of THC (Javadi-Paydar et al., 2018). One interesting thing that has emerged is that CBD inhalation reduces the body temperature of rats while this is not observed when CBD is injected. This is a case where the route of administration produces qualitatively different drug effects and will require some additional follow up work.

Past-Month Cannabis Vaping is Rising

https://www.drugabuse.gov/drug-topics/trends-statistics/infographics/drug-alcohol-use-in-college-age-adults-in-2019

Past-Month Nicotine Vaping is Rising

https://www.drugabuse.gov/drug-topics/trends-statistics/infographics/drug-alcohol-use-in-college-age-adults-in-2019

Opioids

Inhalation has been a common route of administration for opioid drugs, with a documented history spanning back to Mediterranean antiquity, as reviewed (Kritikos, 1960). Some of the earlier modern Western opioid misuse crises occurred in the 19th century during an interval of Chinese diaspora and primarily involved the inhalation of opium vapor (Kane, 1881). Inhalation continues to be a common route of administration among individuals that abuse opioids at present (Alambyan et al., 2018) and some newer users will first choose inhalation as a means of administering opioids because of the perceived safety compared with injection (Stover and Schaffer, 2014). We are using our EDDS approach to model inhalation exposure to heroin to contrast the effects of involuntary exposure (Gutierrez et al 2022) and to determine if rats will self-administer heroin vapor (Gutierrez et al 2020) and to determine any lasting effects of repeated exposure during adolescence (Gutierrez et al., 2022). Methodological work from the laboratory models "chasing the dragon" by delivering heroin by direct volatilization of heroin HCl (Gutierrez et al 2023).

Nicotine

The primary use of e-cigarettes is for the delivery of nicotine. Work in the laboratory is interested in the antecedents that enhance the development of nicotine addiction, with a particular focus on e-cigarette use. We are also interested in the intersection of nicotine and THC in driving health effects of each drug. A substantial population of cannabis users consume it via "blunts" which are cigars hollowed out and filled with cannabis. Other individuals may ingest nicotine and THC in a sequential manner. Thus, we are developing some studies to determine how nicotine inhalation can be modeled in the rat. In our first paper, Javadi-Paydar et al. 2019a (Drug Alcohol Depend) we find that the effects of nicotine and THC are probably independent when co-inhaled in the same vapor exposure session. We then showed similarly independent effects occur with the co-inhalation of CBD and nicotine in Javadi-Paydar et al., 2019b ( Pharmacol Biochem Behav).

Psychostimulants

One of the primary interests of the laboratory is the use and abuse of psychostimulants including methamphetamine, MDMA and substituted cathinone stimulants. Inhaled use of methamphetamine is more common than other routes of administration in habitual and dependent users. Furthermore, the SAMHSA/TEDS treatment admission database for 2012 shows 4.7% of treatment seekers in the USA were admitted for smoked cocaine vs 2.2% for other routes of cocaine administration as the primary reason for treatment. Despite this, preclinical models which incorporate inhaled exposure to psychomotor stimulants are not commonly available. E-cigarette technology has further facilitated inhalation of methamphetamine (Evans 2014; Rass et al. 2015), “bath salts” (Johnson and Johnson 2014; Rass et al. 2015) and “flakka” (α-pyrrolidinopentiophenone; alpha-PVP) as reported (Anderson 2015) in one case of paranoid public behavior. Additional evidence exists in popular drug-user forums such as www.bluelight.org host sub-threads for the discussion of administering several different stimulants in e-cigarettes. We have thus been working to determine if active doses of psychostimulants can be delivered to rats using this technology. Our first publication (Nguyen et al., 2016b) showed that methamphetamine, mephedrone and MDPV increase locomotor activity when delivered with the e-vape model.

Vape Publications

Gutierrez, A., Creehan, K.M., Grant, Y., and Taffe, M.A. Adult consequences of repeated nicotine and Δ9-tetrahydrocannabinol (THC) vapor inhalation in adolescent rats. Psychopharmacology, 2024, 241:585-599. doi: 10.1007/s00213-024-06545-5

Gutierrez, A., Nguyen, J.D., Creehan, K.M., Grant, Y., and Taffe, M.A. Adult consequences of repeated nicotine vapor inhalation in adolescent rats. Nicotine & Tobacco Research, 2024, 26(6):715-723. doi: 10.1093/ntr/ntad211 [ Publisher Site ][ PubMed ][ Free Author Link ]

Gutierrez, A., and Taffe, M.A. Rats Chasing the Dragon: A new heroin inhalation method. J Neurosci Methods, 2024, 402:110013. doi: 10.1016/j.jneumeth.2023.110013 [ Publisher Site (OA) ][ PubMed ]

Kulbe, J.R., Nguyen, L., Le, A., Laird, E., Taffe, M.A., Nguyen, J.D., Fields, J.A. Nicotine, THC, and dolutegravir modulate e-cigarette-induced changes in addiction- and inflammation-associated genes in rat brains and astrocytes. Brain Sciences, 13(11): 1556. [ Publisher Link (OA)]

Gutierrez, A., Harvey, E.L., Creehan, K.M., and Taffe, M.A. The long-term effects of repeated heroin vapor inhalation during adolescence on measures of nociception and anxiety-like behavior in adult Wistar rats. Psychopharmacology, 2022, Oct 26. [ Publisher Site (OA) ][ PubMed ]

Gutierrez, A., Creehan, K.M., Turner, M., Tran, R.N., Kerr, T.M., Nguyen, J.D., and Taffe, M.A. Vapor exposure to Δ9-tetrahydrocannabinol (THC) slows locomotion of the Maine Lobster (Homarus americanus). , 2021, Pharmacol Biochem Behav, Jun 28;173222. doi: 10.1016/j.pbb.2021.173222. [Publisher Site][PubMed]

Gutierrez, A., Creehan, K.M., Javadi-Paydar, M., Grant, Y. and Taffe, M.A. Effects of combined THC and heroin vapor inhalation in rats. Psychopharmacology, 2021, Jun 23:1-15. doi: 10.1007/s00213-021-05904-w. [PublisherSite][PubMed][AuthorAccessLink(free)]

Moore, C.F., Davis, C.M., Harvey, E.L., Taffe, M.A., and Weerts, E.M. Appetitive, antinociceptive, and hypothermic effects of vaped and injected Delta-9-tetrahydrocannabinol (THC) in rats: exposure and dose-effect comparisons by strain and sex. Pharmacol Biochem Behav, 2021 Jan 22; 202:173116. [ Publisher Site ][ PubMed ]

Gutierrez, A., Creehan, K.M., and Taffe, M.A. A vapor exposure method for delivering heroin alters nociception, body temperature and spontaneous activity in female and male rats. J Neurosci Methods, 2021 Jan 159;108993. doi: 10.1016/j.jneumeth.2020.108993. (Epub 2020 Oct 29) [ Publisher Site ][ PubMed ]

Gutierrez, A., Nguyen, J.D., Creehan, K.M., and Taffe, M.A. Female rats self-administer heroin by vapor inhalation. Pharmacol Biochem Behav, Volume 199, December 2020, 173061, doi: 10.1016/j.pbb.2020.173061. [ Publisher Site ][ PubMed ]

Nguyen, J.D., Creehan, K.M., Grant, Y., Vandewater, S.A., Kerr, T.M. and Taffe, M.A. Explication of CB1 receptor contributions to the hypothermic effects of Δ9-tetrahydrocannabinol (THC) when delivered by vapor inhalation or parenteral injection in rats. Drug Alcohol Depend, 2020, DOI: 10.1016/j.drugalcdep.2020.108166 [ Publisher Site ][ PubMed ]

Taffe, M.A., Creehan, K.M., Vandewater, S.A., Kerr, T.M. and Cole, M. Effects of Δ9-tetrahydrocannabinol (THC) vapor inhalation in Sprague-Dawley and Wistar rats. Exp Clin Psychopharmacol., 2020, (Apr 16, 2020). DOI:10.1037/pha0000373 . [ Publisher Site ][ PubMed ]

Nguyen, J.D., Creehan, K.M., Kerr, T.M. and Taffe, M.A. Lasting effects of repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence in male and female rats. Brit J Pharmacol, 2020 177(1):188:203. [ Publisher Site ][ PubMed ]

Javadi-Paydar, M., Creehan, K.M., Kerr, T.M. and Taffe, M.A. Vapor inhalation of cannabidiol (CBD) in rats. Pharmacol Biochem Behav, 2019 Jul 20:172741. doi: 10.1016/j.pbb.2019.172741. [ Publisher Site ][ PubMed ]

Nguyen, J.D., Grant, Y., Creehan, K.M., Hwang, C.S., Vandewater, S.A., Janda, K.D., Cole, M. and Taffe, M.A. Δ9-tetrahydrocannabinol Attenuates Oxycodone Self-Administration Under Extended Access Conditions, 2019, Neuropharmacology, 151:127-135. [ Publisher Site ][ PubMed ]

Javadi-Paydar, M., Kerr, T.M., Harvey, E.L., Cole, M., and Taffe, M.A. Effects of Nicotine and THC Vapor Inhalation Administered By An Electronic Nicotine Delivery System (ENDS) In Male Rats. Drug Alcohol Depend, 2019 May, 198:54-62. [ Publisher Site ]

Nguyen, J.D., Grant, Y., Kerr, T.M., Gutierrez, A., Cole, M., and Taffe, M.A. Tolerance to the Hypothermic and Antinoceptive effects of Δ9-tetrahydrocannabinol (THC) Vapor Inhalation In Rats. Pharmacol Biochem Behav, 2018 Sept, 172:33-38. [ Publisher Site ][ PubMed ]

Javadi-Paydar, M., Nguyen, J.D., Kerr, T.M., Grant, Y., Vandewater, S.A., Cole, M., and Taffe, M.A. Effects Of Δ9-THC And Cannabidiol Vapor Inhalation In Male And Female Rats. Psychopharmacology, 2018 Jun 16, 235:2541-2557. [ Publisher Link ][ Free Viewable Link ][ PubMed ]

Vendruscolo, J.C.M., Tunstall, B.J., Carmack, S.A., Schmeichel, B.E., Lowery-Gionta, E.G., Cole, M., George, O., Vandewater, S.A., Taffe, M.A., Koob, G.F. and Vendruscolo, L.F. Compulsive-like sufentanil vapor self-administration in the rat, Neuropsychopharmacology, 2018, 43:801-809.

Nguyen, J.D., Bremer, P.T., Hwang, C.S., Vandewater, S.A., Collins, K.C., Creehan, K.M., Janda, K.D. and Taffe, M.A. Effective active vaccination against methamphetamine in female rats, Drug Alcohol Depend, 2017, 175:179-186. [ Publisher Site ][ PubMed ]

Nguyen, J.D., Aarde, S.M., Cole, M., Vandewater, S.A., Grant, Y. and Taffe, M.A. Locomotor stimulant and rewarding effects of inhaling methamphetamine, MDPV and mephedrone via electronic cigarette-type technology, Neuropsychopharmacology, 2016b, 41:2759-2771. [ Publisher Site ][ PubMed]

Nguyen, J.D., Aarde, S.M., Vandewater, S.A., Grant, Y., Stouffer, D.G., Parsons, L.H., Cole, M. and Taffe, M.A. Inhaled delivery of Δ9-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology, Neuropharmacology, 2016a, 109:112-120. [ Publisher Site ][ PubMed ]

Vapor inhalation research in the Taffe Laboratory was initially supported by subcontract of USPHS Grant R44 DA041967 awarded to La Jolla Alcohol Research, Inc. We continue to collaborate with the company on an ad hoc basis. Additional support has been provided by the Tobacco-Related Disease Research Program includes a prior Pilot award (T31IP1832C) and current Research award (T33IR6653), and the USPHS Grant R01 DA057423.

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