Step Aside Suboxone, There's a New Treatment in Town

 Though the COVID-19 pandemic has ravaged the fabric of American society in the span of less than two years, the far more insidious opioid epidemic has been slowly picking the nation apart for much longer. Declared a public health emergency by the Department of Health and Human Services in 2017, the epidemic has claimed the lives of more than 800,000 people in the United States of America [1]. Ibogaine can not only protect the body from opioids’ dangerous physical effects, but also help break the deadly cycle of addiction. Rather than sideline its use, the neuroscience community should focus on improving ibogaine’s safety and incorporating it into current rehabilitation therapy to create holistic, augmented recovery plans.

Opioids have remained a persistent threat because of their highly potent effects and addictive nature. They act on specific receptors in the brain, attaching themselves to mu, delta, and kappa opioid receptors [2]. By activating the receptors, opioids are able to initiate a number of changes in the nervous system. One of the major effects is the blocking of pain signals, a function shared by the endorphins that are released after strenuous exercise, but amplified considerably [3]. Another effect is the release of excessive amounts of dopamine and serotonin, neurotransmitters that produce feelings of pleasure and well-being [3]. Because opioids are central nervous system depressants, they also exert a relaxing but lethal effect on the areas of the brainstem that regulate important involuntary bodily functions. These bodily functions include breathing and circulation. The corresponding declines in respiratory (bradypnea) and heart rates (bradycardia) can cause extensive damage to the brain tissue or even result in death due to inadequate oxygen supply [4].

The gold standard for opioid addiction treatment is medication assisted therapy (MAT), which rests upon three drugs: naloxone, suboxone, and methadone. While these medications are the best treatments currently available and have been proven indispensable tools in the battle against opioid addiction, none of them possess abiding potency and ease of use comparable to that of ibogaine. 

Naloxone is an opioid antagonist, which means it inhibits or dampens the effects of other opioids. While naloxone is markedly effective at restoring normal breathing, it is limited to treating opioid overdoses and counters the effects of opioids only in the short term [5]. Usually used in emergency situations when a person has overdosed and has a dangerously slow or absent breathing rate, naloxone is ill-equipped to treat the underlying addiction that causes overdoses, which is driven by neurotransmitter imbalances rather than fluctuations in vital signs. 

Methadone and suboxone are both long-term opioid agonists, which means that they provide a sustained reaction against opioids’ effects. However, these two drugs have significant drawbacks as well. Suboxone is a mix of the aforementioned naloxone and a drug called buprenorphine, which is but a partial agonist. Thus, it can only be used to treat opioid dependence by alleviating some cravings and withdrawal symptoms, but unlike ibogaine, it cannot combat a major addiction with symptoms ranging from cognitive disorientation to delirium to seizures [6].

Though methadone has shown the most promise as a potential treatment for opioid addiction, it is a full agonist, meaning that it itself is an opioid. Its use can thus be compared to “fighting fire with fire” in that there will be a real risk of simply bouncing from one opioid addiction to another [7]. Therein lies its inferiority to ibogaine; methadone could potentially start an addiction, whereas ibogaine works to end it. Methadone and suboxone must also be taken regularly, as their effects wear off, which results in a high cost of treatment for the patient, as well as room for error on the part of the patient or doctor, who can either overmedicate or overprescribe.

Originally used and marketed as a stimulant, ibogaine is a naturally-occurring psychoactive substance that has been proven to decisively reverse opioid addiction when combined with adequate and sustained rehabilitative services [8]. Ibogaine’s first major strength is its longer lasting effect in the brain. It achieves this effect by converting into noribogaine, which works to lower dopamine levels, especially around the nucleus accumbens, an area in the midbrain that acts as the brain’s reward and motivation center [9, 10]. This is accomplished by the binding of noribogaine to special receptors on the membranes of neurons. The binding blocks off those receptors from opioids, neutralizing their immediate life-threatening effects, such as respiratory depression and declining heart rate. 

Curiously, researchers have determined that a concentration of ibogaine delivered in amounts in the micromolar range can block the transport and subsequent reuptake of dopamine and serotonin [11]. This forces them to remain active in the brain and slows their removal. During opioid use, those two chemical messengers suddenly peak at extremely high levels but then drastically drop after the opioids “wear off.” This generates an intense craving in the user to obtain another dose and “chase the next high”, thus driving a strong addiction to the drug [12]. Therefore, the regulated and slowed removal of dopamine and serotonin allows the feelings of pleasure and reward created by opioids to safely dissipate over time, rather than disappear and reappear in sharp drops and spikes and precipitate the desire to take more opioids and reach the “next high.”

Ibogaine is a fascinatingly intriguing substance not simply because of its potential to counter opioid addiction, but also because of what it reveals about the connection between neuroscience and drug addiction. Though the brain is a delicate organ, composed of tissue and cells that do not recover easily from damage as other more regenerative organs such as skin, it is nevertheless equally, or perhaps even more malleable. Just as the chemistry of the brain can be significantly altered by opioids and other drugs, so too can those alterations be effectively neutralized. More research work needs to be done to investigate ibogaine’s potential to actually reverse the changes in brain chemistry caused by opioid addiction, which could support a more complete recovery. However, because the brain ultimately regulates a vast array of body functions ranging from rudimentary breathing to complex rationality and judgement, ibogaine’s role in diminishing the addictive properties of opioids is nevertheless already instrumental in easing the effects of withdrawal for former opioid users in rehabilitation therapy. 

As powerful as it is, ibogaine is currently banned from use in the United States, though it is listed as a legal or controlled substance in other countries such as New Zealand and Canada. Though it had been the subject of much research by the Food and Drug Agency, such studies were discontinued in 1995 due to the discovery of its toxic effects on the heart, resulting in cardiopulmonary arrest in multiple study participants [8]. Adding to the notoriety of ibogaine was its association with recreationally used hallucinogenic drugs such as LSD and PCP, despite having slightly different psychedelic effects, such as feelings of dissociation from reality.

Further research into how to improve the safety and efficacy of ibogaine should be conducted, rather than continuing to marginalize and stigmatize a natural substance with such potent anti-addictive properties. Ongoing research and clinical trials test the effectiveness and safety of 18-methoxycoronaridine, a derivative of ibogaine that so far has not been shown to have significant adverse effects on the heart whilst still retaining the same mechanism of action [13]. Studies have also established a correlation between the use of psychedelic substances and reduced drug consumption, possibly due to the highly insightful and introspective experiences they induce in users [14]. It is an exciting area of research -- one that may have far-reaching effects in American society, healing the wounds created by the opioid epidemic.

References:

1. Centers for Disease Control and Prevention [CDC]. (2021, February 12). Trends and geographic patterns in drug and synthetic opioid overdose deaths — United States, 2013–2019. https://www.cdc.gov/mmwr/volumes/70/wr/mm7006a4.htm?s_cid=mm7006a4_w 

2. Bovill, J. G. (1997). Mechanisms of actions of opioids and non-steroidal anti-inflammatory drugs. European journal of anaesthesiology. Supplement, 15, 9–15. https://doi.org/10.1097/00003643-199705001-00003

3. Chahl, L. A. (1996). Opioids - mechanisms of action. Australian Prescriber, 19, 63-5. https://doi.org/10.18773/austprescr.1996.063 

4. Boom, M., Niesters, M., Sarton, E., Aarts, L., Smith, T. W., & Dahan, A. (2012). Non-analgesic effects of opioids: opioid-induced respiratory depression. Current pharmaceutical design, 18(37), 5994–6004. https://doi.org/10.2174/138161212803582469

5. National Institutes of Health [NIH]. (2021, June). Naloxone drug facts. https://www.drugabuse.gov/publications/drugfacts/naloxone 

6. Substance Abuse and Mental Health Services Administration [SAMHSA]. (2021, May 14). Buprenorphine. https://www.samhsa.gov/medication-assisted-treatment/medications-counseling-related-conditions/buprenorphine 

7. Substance Abuse and Mental Health Services Administration [SAMHSA]. (2021, November 4). Methadone. https://www.samhsa.gov/medication-assisted-treatment/medications-counseling-related-conditions/methadone 

8. Corkery, J. M. (2018). Chapter 8 - Ibogaine as a treatment for substance misuse: Potential benefits and practical dangers. Progress in brain research. (pp. 217-257). Elsevier. https://doi.org/10.1016/bs.pbr.2018.08.005 

9. Maillet, E. L., Milon, N., Heghinian, M. D., Fishback, J., Schürer, S. C., Garamszegi, N., & Mash, D. C. (2015). Noribogaine is a G-protein biased κ-opioid receptor agonist. Neuropharmacology, 99, 675–688.

10. Sershen, H., Hashim, A., & Lajtha, A. (1995). The effect of ibogaine on kappa-opioid- and 5-HT3-induced changes in stimulation-evoked dopamine release in vitro from striatum of C57BL/6By mice. Brain research bulletin, 36(6), 587–591. https://doi.org/10.1016/0361-9230(94)00250-5

11. Wells, G. B., Lopez, M. C., & Tanaka, J. C. (1999). The effects of ibogaine on dopamine and serotonin transport in rat brain synaptosomes. Brain research bulletin, 48(6), 641–647. https://doi.org/10.1016/s0361-9230(99)00053-2

12. Kosten, T. R., & George, T. P. (2002). The neurobiology of opioid dependence: implications for treatment. Science & practice perspectives, 1(1), 13–20. https://doi.org/10.1151/spp021113

13. Glick, S. D., & Maisonneuve, I. M. (1998). Mechanisms of antiaddictive actions of ibogaine. Annals of the New York Academy of Sciences, 844(1), 214–226. https://doi.org/10.1111/j.1749-6632.1998.tb08237.x

14. Garcia-Romeu, A., et al. (2020). Persisting reductions in cannabis, opioid, and stimulant misuse after naturalistic psychedelic use: An online survey. Frontiers in Psychology, 10, 1-955. https://doi.org/10.3389/fpsyt.2019.00955