Using Ibogaine to Create Friendlier Opioids

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?


Cap­saicin

[https://​​com­mons.wiki­me­dia.org/​​wiki/​​File:Cap­saicin_chem­i­cal_struc­ture.png]

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.


Par­tial vs full ag­o­nists [https://​​en.wikipe­dia.org/​​wiki/​​Par­tial_ag­o­nist]

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

[4] https://​​www.ncbi.nlm.nih.gov/​​pmc/​​ar­ti­cles/​​PMC1920543/​​

[5] https://​​www.ncbi.nlm.nih.gov/​​pmc/​​ar­ti­cles/​​PMC3782756/​​