Residues of ractopamine,a livestock feed additive,in meat might alleviate misuse of cocaine,nicotine,methamphetamine,and morphine

Introduction

The global burden of disease attributable to substance misuse brings considerable negative effects on the health, economy, and social features of communities. Worldwide, in 2016, the disability-adjusted life-years (DALYs) of alcohol and drug use were estimated to be 99.2 and 31.8 million, respectively (GBD 2016 Alcohol and Drug Use Collaborators, 2018). Illicit drug use was associated with poor mental health, increased risk of cardiovascular diseases, elevated incidence of human immunodeficiency virus, and viral hepatitis C infection. Among the illicit drugs, the most recently reckoned global prevalence of cocaine use was 0.4% and amphetamine use was 0.7% with a combined use of psychostimulants and opioids another serious problem (Farrell et al., 2019). In addition to that, daily tobacco smoking with a prevalence of 15.2% among adults in 2015 has much higher estimated DALYs (170.9 million) and mortality (110.7 deaths per 100,000 people) than those of alcohol and illicit drugs (Peacock et al., 2018). Therefore, pharmacologic means for reducing substance misuse has long become an aspiring strategy in medicine. Although naltrexone is effective at reducing heavy drinking days by 17% to 25% and combination nicotine replacement therapy can successfully increase smoking abstinence rate from 10% to 20% (Klein, 2016), there is currently no satisfactory pharmacotherapies available for psychostimulant addiction, especially for cocaine and methamphetamine (Forray and Sofuoglu, 2014). Despite that agonist replacement therapies, such as methadone and buprenorphine, have proven to be effective for opioid use disorders, prevention of relapse is still a big challenge (Jordan et al., 2019). Nonetheless, in the past decade, intensive study in the molecular physiology of trace amine-associated receptor 1 (TAAR1) has brought stimulant and opioid use disorders treatment to a new horizon.

TAAR1 is widely expressed in the monoaminergic system within the brain. Growing research results reveal that TAAR1 interacts with presynaptic and postsynaptic dopamine receptor 2, modulates dopamine transmission, and synergistically controls downstream signaling transduction involved in behavior manipulation including drug addiction (Liu and Li, 2018). Despite basic and animal experiments demonstrate that TAAR1 agonists are able to inhibit the rewarding effects of some psychostimulants, promising clinical application of this novel kind of therapy in substance use disorder treatment is still far from reality (Liu et al., 2020b). Notably, ractopamine, a livestock feed additive approved for use in the United States and several other countries for two decades (Centner et al., 2014), has been identified to be a full TAAR1 agonist (Liu et al., 2014). Herein, the possible influence of ractopamine residues in meat on the prevalence trends of cocaine, nicotine, methamphetamine, and morphine misuse will be assessed based on both laboratory and epidemiology evidence to see whether a hypothetic preventive effect of ractopamine residues on a certain substance addiction could be established.

Cocaine

Although cocaine is the third most commonly used illicit drug in the United States, drug overdose death rate of cocaine remained stable from 1999 to 2015 while the overdose death rates of opioids and heroin presented contradictory climbing trends during the same time period (Ritchie and Roser, 2019). Additionally, it is surprising to know that the past-year prevalence of cocaine use among people aged 12 or older in the United States decreased significantly from 2002 to 2019 (Substance Abuse and Mental Health Services Administration, 2020).

The cause for a downward trend of cocaine misuse in the United States could theoretically be explained by the consumption of meat containing ractopamine, a full TAAR1 agonist, in the past 20 years. Astonishing supporting evidence came from experiments on rats as shown by one group that TAAR1 agonists efficiently suppressed the rewarding and reinforcing phenomenon of cocaine in self-administration and intracranial self-stimulation models (Pei et al., 2015). In another study, activation of TAAR1 by agonists attenuated extended access cocaine intake, decreased cue-induced cocaine-seeking after prolonged abstinence, and eliminated stress-induced cocaine reinstatement (Liu et al., 2020a).

Nicotine

Like what happened to cocaine, the percentage of past month cigarette use among civilians aged 12 or older in the United States dropped steadily and significantly from 2002 to 2019 (Substance Abuse and Mental Health Services Administration, 2020). Besides the contribution of regulation, policy making, and advocacy in tobacco control, the potential beneficial effects of ractopamine residues in beef and pork could not be casually disregarded.

Excellent rat experiments have disclosed TAAR1 as a crucial regulator of the neurological consequence of nicotine exposure and addiction. The researchers found that TAAR1 activation by TAAR1 agonists could weaken the development of nicotine-induced sensitization, nicotine self-administration, and the reinstatement of nicotine-seeking while TAAR1-knockout rats showed intensified cue-induced and drug-induced reinstatement of nicotine-seeking (Liu et al., 2018). Coincidentally, another study group discovered that pretreatment with a TAAR1 agonist decreased nicotine-induced hyperlocomotion in rats habituated to locomotor boxes and prevented the development of nicotine sensitization, supporting the view that TAAR1 is a promising target for the prevention and treatment of nicotine addiction (Sukhanov et al., 2018).

Methamphetamine

Similar to what we see in the cases of cocaine and nicotine, epidemiological evidence showed that the percentage of past-year methamphetamine use among people aged 12 or older in the United States remained rather stable from 2015 to 2019. Pitifully, there are no corresponding data available for comparison prior to 2015 due to different methodologies adopted in prevalence estimation (Substance Abuse and Mental Health Services Administration, 2020).

Nevertheless, the fact that both methamphetamine and ractopamine act on TAAR1 might provide meaningful implications for the constrained prevalence curve of methamphetamine misuse during the limited time period (Underhill et al., 2021). It is thus not strange to see in rat experiments that a TAAR1 agonist successfully blocked cue- and methamphetamine prime-induced reinstatement of extinguished methamphetamine-seeking behavior (Jing et al., 2014). Moreover, in another experiment, a partial TAAR1 agonist completely blocked methamphetamine-primed reinstatement of methamphetamine seeking but exhibited no apparent abuse liability for itself, hopefully making TAAR1 agonists adequate treatment agents for methamphetamine addiction (Pei et al., 2017).

Morphine

Furthermore, also notably revealed recently is that TAAR1 agonist RO5263397 could attenuate morphine-induced behavioral sensitization in mice and decrease the cue- and drug-induced morphine-seeking behavior in rats despite it did not affect morphine-induced conditioned place preference in both kinds of laboratory animals (Liu et al., 2021). Although morphine does not belong to psychostimulants and the brain mechanisms of opioid addiction are quite complex (Listos et al., 2019), epidemiologic data surprisingly showed that the incidence of the past-year opioid misuse among people aged 12 or older went in a slightly downward trend from 2015 to 2019 in the United States (Substance Abuse and Mental Health Services Administration, 2020). These interesting findings lead to a speculation that ractopamine residues in meat might lower the prevalence of opioids misuse as well. Since both opioid receptors and TAAR1 are G protein-coupled receptors, investigation of possible interactions between their downstream signal transduction pathways seems to be an attractive issue.

Discussion and conclusions

Taken together, the above information from animal studies demonstrates that TAAR1 agonists have the potential in treating and preventing misuse of cocaine, nicotine, methamphetamine, and morphine. Although the definite molecular pathophysiology mechanism underlying these effects remains unclear, cross-talk between TAAR1 and other aminergic receptors within limbic and monoaminergic areas of the brain is considered to be tightly related to mood, attention, and addiction (Rutigliano et al., 2018). The TAAR1 agonist ractopamine has been approved for use as a feed additive in finishing cattle and swine for more than two decades. Despite that ractopamine residues in meat would be at a very low concentration, TAAR1 is naturally activated by monoamines in trace levels. Consequently, it seems confident to hypothesize here that ractopamine residues in meat probably have helped a lot in lessening the prevalence trends of cocaine, nicotine, methamphetamine, and opioid misuse in the United States based on laboratory research results and the coincident epidemiologic evidence.

As we know, people are worried all the time about the drawbacks of ractopamine in regard of its possible adverse effects on cardiovascular diseases (Zaitseva et al., 2014); however, the speculative benefits of ractopamine deserve inspection as well. Certain kinds of pharmacological therapies have been developed for substance use disorders in the clinical fields but their consistent efficacy is yet to be confirmed. Accordingly, it must be very exciting if an investigation in the near future could unambiguously prove ractopamine in meat is a “nature” form of preventive modality for substance addiction. That is, although the ban on ractopamine as a feed additive has not been lifted in China and European Union due to fear of its unrecognized influence on human beings, at least the presumption raised here brings a positive point of view to the issue.

In conclusion, the potential alleviating effects of ractopamine on cocaine, nicotine, methamphetamine, and morphine misuse might open a door to further development of itself and alternative TAAR1 agonists as novel therapeutic and chemopreventive modalities in the field of substance use disorders. The assumed neurological mechanism of ractopamine in this regard is worthy of more thoroughgoing research.