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"but keep the euphoria, wouldn’t that be better?" Not if what you want is to restore people's ability to work and study as usual - it's probably easier to do those things if you can get pain relief but not feel high.
As the second in a series of two posts on how psychedelics can be beneficial to treating painful conditions:
Chronic Pain is a Massive, Debilitating Problem
“A new study by the CDC revealed that 50 million Americans (just under 20% of the age-adjusted adult population) suffered from chronic pain, which was defined as “pain on most days or every day in the past 6 months.” Nearly 20 million (about 7.5%) experienced high-impact chronic pain, defined as “limiting life or work activities on most days or every day in the past 6 months.”
– Who Is Hurting? The Prevalence Of Chronic Pain In America
Using IHME’s GBD visualization tool, about 5% of total DALYs come from conditions associated with chronic pain (back pain, neck pain and self-harm), not to mention the implications pain has in a variety of other conditions, from osteoporosis to cancer.
The Most Effective Tool for Pain Management Carries its Own Significant Burdens
Opioids are highly effective as analgesics for managing chronic and acute pain, and are the most widely used pain treatment[1]. However, consistent use of opioids results in tolerance, dependence, withdrawal and overdose, which claimed the lives of 47,600 people in 2017[2]. Furthermore, the CDC estimates the total economic burden of prescription opioid misuse in the US is $78.5 billion a year, including the costs of health care, lost productivity, addiction treatment, and criminal justice involvement.[4]
Finding a solution for opioids’ dark side would help millions enjoy life, reduce the global health burden by no less than 5%, avoid 10s of thousands of future deaths, and recover billions in lost productivity.
A solution may be to combine variable doses of Ibogaine, the active compound found in the Tabernanthe iboga shrub with safer classes of opioids.
The proliferation of opioids (specifically, full mu-opioid agonists) has this laundry list of problems: tolerance, addiction, withdrawal, overdose and euphoria (if one chooses to see it as a negative side-effect). In an effort to wean off of opioids, several groups have sought to attack these symptoms. Non-opioid therapeutics include cannabidiol (CBD) and CA-008, a TRPV-1 agonist which acts on nociceptive c-fibers in the peripheral nervous system similarly to capsaicin. These tend to be less habit-forming than opioids (attributed to their lower affinity for nuclei in the mesolimbic system), but also less effective at offering relief from intense neuropathic pain[4]. Other attempts to tame opioids have been made, most of them having the reduction of pleasure as the main target. CARA Therapeutics has created a kappa-opioid agonist which acts selectively on receptors in the peripheral nervous system to “produce little to no CNS-mediated side effects that one sees with traditional CNS-acting mu opioids like nausea/vomiting, sedation, respiratory depression, abuse, addiction or euphoria”. NKTR-181, a novel full mu-opioid agonist, is more direct: “NKTR-181, a first-in-class opioid analgesic, is a new chemical entity (NCE) that is the first full mu-opioid agonist molecule designed to provide potent pain relief without the high levels of euphoria that can lead to abuse and addiction with standard opioids”. As it turns out, addiction and pleasure have a complex relationship; one is not reducible to the other[5]. Euphoria-inducing psychedelic drugs and the jhana states of meditative absorption seem to lack the addictive profile of opioids. Pleasure and habit become decoupled over time in the path of opioid addiction as well, one fading with the other stubbornly immovable. If we can have opioids that forego tolerance, addiction, withdrawal and overdose, but keep the euphoria, wouldn’t that be better?
Ibogaine has a history of being used for the treatment of opioid addiction, but it may also have interesting properties for producing safer opioids as well. While at high doses (1g+) it creates intense psychedelic effects, it also has interesting properties at both lower doses of 500-600mg and at ‘microdoses’ of around 50mg. Ibogaine is illegal in many countries, but unregulated in Mexico, legal in Brazil, Gabon, and Costa Rica, and on the prescription drug list in New Zealand and Canada. For a more in-depth review of the history of Ibogaine and its use in treatment, read this review on Pysmposia.
In this case study, a patient who had been a long-term opioid user and recently transitioned to methadone (a replacement for harder opioids like heroin, but maintaining the full agonist mu-opioid method of action) was taken off methadone without withdrawal using increasing doses of Ibogaine (150mg, 300mg, 400mg, 500mg, 600mg). As the Ibogaine dose was increased, the methadone was halved each time. We could allow opioid users to substantially decrease their opioid intake without withdrawal, while continuing to use opioids for pain management. After a few applications at the 100-600mg level, users could be maintaining their usage at ¼ of their original intake. Then they could utilize “dirty maintenance”: taking 25-50mg of Ibogaine daily while using a much lower amount of the opioid they typically use. Microdosing ibogaine alone is also potentially mood-enhancing, and some former opioid users have employed “clean maintenance” (i.e. just Ibogaine), to reduce post-acute-withdrawal syndrome (PAWS).
The reason these solutions work is because Ibogaine acts as an ‘anti-tolerance’ drug. It potentiates the effects of opioids and prevents patterns of tolerance and dependence from forming at the neurological level. When combined with full mu-opioid agonists, even in lower doses, this can pose a risk since the dose required to overdose could be more unpredictable with Ibogaine. A ‘best of both worlds’ solution would be to continue microdosing Ibogaine in conjunction with a partial mu-opioid agonist. Partial mu-opioid agonists prevent overdose by creating an upper-bound on activity at the opioid receptor and preventing the respiratory depression that causes death in full agonists.
While existing partial mu-opioid agonists, such as the drug combo of buprenorphine and naloxone are used in opioid replacement therapy settings, they too lack euphoria-producing properties. With this new class of analgesics, patients could choose when to start, stop, and for how long to take their pain medication without fear, along with a depression-preventing hedonic enhancement. For more, see: On Hitting the Actual Target of Hedonic Tone.
A well-known example of a partial mu-opioid agonist is 7-hydroxymitragynine, the active compound in kratom. Brazil is the only country to not prohibitively schedule either kratom or Ibogaine, and so might be an option for conducting research into this new form of non-tolerance-inducing opioid mixture. In the United States, research is being done at DemeRXfor approving Ibogaine through the FDA IND process for the detoxification of people afflicted with opioid addiction. Their success would also open the door to further innovation in Ibogaine-assisted pain treatments in the US.
Risks of Ibogaine
Unfortunately, Ibogaine has a harsher risk profile than most psychedelics, and has been associated with about 30 deaths due to cardiac complications. However, many researchers who have worked with Ibogaine for decades believe that these incidents can be minimized or even eliminated by standard medical practices like employing EKG screenings. Medical screenings should not only assess current heart health, but also in-system drugs, which can be potentiated by Ibogaine use, and can lead to unexpected overdose. In a population of drug users to be treated, higher incidences of poor heart health and the presence of other drugs likely contributed to a significant number of the cases of death recorded.
Mash et al. 2018 reviewed 191 cases of ibogaine therapy (all at Dr. Mash’s clinic on Saint Kitts) and found that there were no cases of cardiac-related death at doses used for interrupting addiction. Furthermore, Clear Sky Recovery has administered 1000s of Ibogaine sessions without a single fatality.
Iboga rescheduling in the US may be far off, but its potential shouldn’t be underestimated. As Hamilton Morris notes, Ibogaine is “alien technology”, with the potential to help us humans solve some of our greatest medical mysteries. For now, it’s enough to think that it might be able to a create stable, long-term pain medication with no risk of respiratory depression, tolerance, and minimal withdrawal. Along with risk-free… risk tolerant euphoria. Whether that sustainable euphoria will be available to all, remains to be seen.
[1] https://www.mayoclinic.org/chronic-pain-medication-decisions/art-20360371
[2] https://www.hhs.gov/opioids/about-the-epidemic/index.html
[3] https://www.moveforwardpt.com/resources/detail/7-staggering-statistics-about-america-s-opioid-epi
Most people who know about drugs tend to have an intuitive model of drug tolerance where "what goes up must come down". In this piece, the author shows that this intuitive model is wrong, for drug tolerance can be reversed pharmacologically. This seems extremely important in the context of pain relief: for people who simply have no option but to take opioids to treat their chronic pain, anti-tolerance would be a game-changer. I sincerely believe this will be a paradigm shift in the world of pain management, with a clear before-and-after cultural shift around it. But before that, a lot of foundational research needs to take place. That's the stage we are at.
We anticipate and hope that the field of anti-tolerance drugs soon materializes in an academically credible way. Given how common chronic pain is, we would all benefit from its fruits in the future.