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Ibogaine For Opiate Addiction & Withdrawal

Ibogaine is a psychoactive indole alkaloid derived from plants of the Apocynaceae family, including:  Tabernanthe iboga, Voacanga africana and Tabernaemontana undulata.  When ingested by humans, ibogaine induces a psychedelic response with dissociative and opioidergic properties.  The [subjective] experience of ibogaine is often described as biphasic such that the first phase (4 to 6 hours) is “visionary” characterized by psychedelic dreamlike visuals, and the second phase is “introspective” characterized by the resurfacing and processing of memories, emotions, and/or traumas.

Historically, ibogaine-containing plants (collectively referred to as “iboga”) were first reported in botanical literature as being utilized by African tribes in Gabon throughout the 19th century as part of medicinal and spiritual ceremonies.  In the year 1864, French botanists had published the first descriptions of the Tabernanthe iboga plant, and in 1901, ibogaine alkaloids were isolated and crystallized from root bark of the Tabernanthe iboga plant by Dybowski and Landrin.  Thereafter, between 1939 and 1966, an extract of the Tabernanthe manii plant (containing ibogaine) was marketed as a neuromuscular stimulant and sold throughout France (in 8 mg tablets) under the brand name “Lambarène.”

Although Lambarène gained popularity in France, particularly among athletes, the French government banned retail of all ibogaine-containing products in 1966.  Less than 1-year prior to the aforementioned ban of ibogaine products, chemist G. Büchi achieved total synthesis of ibogaine in 1965 – a feat that hadn’t been accomplished.  As of 1967, the United States FDA formally classified ibogaine as a “Schedule I” controlled-substance, implying that it has no acceptable medical use, high abuse potential, and may endanger human health.

Despite lacking FDA approval for the treatment of medical conditions in the United States, preliminary evidence suggests that ibogaine may be effective for the treatment of drug dependence and addition, particularly to opiates/opioids.  When administered at therapeutic dosages, ibogaine allegedly decreases opiate/opioid cravings and the severity of withdrawal symptoms.  Anecdotal accounts from many individuals cite ibogaine usage as the chief reason they were able to overcome refractory opiate/opioid addiction and maintain long-term sobriety.

Benefits of Using Ibogaine for Opiate Withdrawal (Possibilities)

There are many potential benefits to be attained from using ibogaine for the treatment of opiate/opioid addiction.  The most notable potential benefit is that a single dose of ibogaine could lead to long-term suppression of opiate/opioid cravings such that former opiate/opioid users are able to maintain abstinence for an indefinite duration.  Other possible advantages associated with using ibogaine to treat opiate/opioid addiction include its: ability to be used on an “as-needed” basis, low cost, and tolerability.

  • Craving suppression: One way in which ibogaine seems to be effective as a treatment for opiate/opioid addiction is through craving suppression. Most individuals report substantial suppression or reduction of opiate/opioid cravings in the days and/or weeks after ibogaine administration – as compared to pre-treatment.  In some cases, the mitigation of cravings persists for an even longer-term (e.g. months).  The suppression of cravings makes it easier for persons recovering from an addiction to maintain abstinence.
  • Estimated success rates: According to some ibogaine clinics, over 80% of patients treated with ibogaine for a substance addiction derive significant therapeutic benefit. Because these statistics are provided by ibogaine clinics themselves rather than independent third-parties, it’s possible that they are biased.  Perhaps the clinics cherry-picked their data from particular samples or intentionally fabricated their findings to increase business.  However, assuming the reported success rates are accurate, this would suggest that ibogaine is effective for a majority of individuals.
  • Evidence-based: Nearly all data derived from trials in which ibogaine has been tested as an intervention for opiate/opioid addiction – in humans and animal models of opiate/opioid addiction – are consistent in suggesting that ibogaine is an efficacious treatment.  Though stronger evidence is needed before ibogaine can be endorsed as a clinically-relevant treatment for opiate/opioid addiction, preliminary studies are nearly unanimous in showcasing its therapeutic benefit.  Compared to most alternative interventions for the treatment of opiate/opioid addiction that lack FDA approval, ibogaine is more evidence-based.
  • Long-term effect: Another advantage associated with using ibogaine to treat an opiate/opioid addiction and/or manage withdrawal symptoms is that a single treatment delivers a sustained, long-term effect. Pharmacokinetic research suggests that noribogaine metabolites can remain in systemic circulation for a span of 1 to 2 weeks post-ibogaine administration, indicating that noribogaine may continue modulating physiology for a fairly long-term post-ibogaine ingestion.  Moreover, even after noribogaine metabolites have been cleared from systemic circulation, favorable neuroadaptive changes that are conducive to opiate/opioid abstinence are thought to linger.  The lingering of favorable neuroadaptive changes may be retained for months, years, or in some cases, indefinitely.  For this reason, many will perceive the long-term effect of a single ibogaine treatment as advantageous to conventional treatments for opiate/opioid addiction that require daily dosing.
  • Long-term abstinence: Though not everyone will derive therapeutic benefit from ibogaine in terms of treating an opiate/opioid addiction, many ibogaine recipients are able to maintain abstinence over an extremely long-term after treatment.  In the literature, there is a case of a woman with a 19-year history of severe opioid use disorder who was able to maintain abstinence from opioids for an 18-month duration following a 4-day ibogaine treatment.  In online forums [unaffiliated with ibogaine clinics], there are testimonials from individuals claiming that a single ibogaine treatment resulted in abstinence for upwards of 8-year and 10-year durations.  Moreover, many individuals who’ve attained long-term abstinence from opiates/opioids as a result of ibogaine believe that they’ll likely be able to maintain abstinence for the rest of their lives (i.e. indefinitely).  Other anecdotes report that ibogaine treatment resulted in abstinence from opiates/opioids for months and/or much longer durations than they had ever been able to accomplish with conventional interventions.
  • Fair cost: If a person were to utilize ibogaine without medical supervision or therapeutic guidance, he/she could do so for a relatively fair cost. While using ibogaine without medical supervision is not recommended, anyone who does so could save a significant amount of money compared to conventional treatments for opiate/opioid addiction and the corresponding medical bills.  When purchased in bulk from an online vendor, ibogaine hydrochloride can be attained at a price of $1,165 for 10 grams.  Assuming a 200 lb. person administers a dose of 20 mg/kg to treat his/her opiate/opioid addiction, this would cost less than $300 for a single treatment.  If the therapeutic effect of ibogaine treatment persists for an extended duration, this may be a bargain compared to conventional opiate/opioid replacement therapies such as methadone and/or buprenorphine-based medications.  To put things in perspective, outpatient methadone maintenance programs cost approximately $18 per day, and buprenorphine-based medications cost upwards of $65 per month plus doctor visits [required for refills].  If 2 ibogaine treatments are required per year for an individual to manage an opiate/opioid addiction, the person could save nearly $6,000 compared to conventional pharmaceutical approaches.  Even if a person enlisted the help of an inpatient ibogaine clinic with professional monitoring, costs may be comparable or lesser (on an annual basis) than those associated with conventional pharmaceutical treatments.
  • Negligible abuse potential: Despite ibogaine’s classification as a “Schedule I” controlled-substance, research in humans and animal models of substance addiction suggests that it has extremely low, arguably nonexistent, abuse potential. The negligible abuse potential associated with ibogaine has to do with the fact that the principal action of its chief metabolite, noribogaine, involves agonizing kappa-opioid receptors.  Agonism of kappa-opioid receptors decreases dopaminergic firing in the mesolimbic reward pathways of the brain such that users will not derive any substantial pleasure from ibogaine administration.  Other actions of noribogaine and ibogaine that may further downregulate reward center activity include: NMDA antagonism, delta-opioid receptor agonism, and modulation of GDNF (glial-derived neurotrophic factor).  The net decrease in reward center activity after ibogaine administration means that most recipients will not be motivated to abuse or become addicted to it.  Moreover, compared to conventional opiate/opioid replacement therapies such as methadone and buprenorphine, each of which activate the reward center, ibogaine has a far lower abuse potential.
  • Non-replacement therapy: Another appealing aspect of using ibogaine to treat an opiate/opioid addiction is that it’s not a replacement therapy. In other words, ibogaine is not ingested with an intent to replace the physiologic effect (e.g. mu-opioid receptor agonism) that was previously derived from an illicit and/or more potent opiate/opioid.  Instead, ibogaine is administered once or twice over an extended duration to profoundly modulate neurochemistry in ways that are conducive to the long-term maintenance of opiate/opioid abstinence.  Furthermore, because ibogaine is not an opiate/opioid replacement therapy, users don’t need to worry about regularly picking up ibogaine prescriptions from a pharmacy nor routinely visiting the doctor for check-ups.  Comparatively, opiate/opioid replacement therapies are often: expensive, prescribed and utilized indefinitely (e.g. for years), and are difficult to discontinue [in that they are only slightly less addictive than the opiates/opioids that a person is attempting to quit].
  • No tolerance onset: If administered on a daily basis for an extended duration, it’s logical to expect that ibogaine users would become tolerant to its therapeutic effects (e.g. craving suppression) in the treatment of opiate/opioid addiction. That said, because ibogaine is typically administered on an infrequent basis to treat addiction – such as: every 6 months, once a year, once every few years, etc. – users do not develop physiologic tolerance to its action.  Lack of tolerance onset should be regarded as favorable when compared to conventional treatments for opiate/opioid addiction (e.g. replacement therapies).  Those who use conventional opiate/opioid replacement therapies will likely become tolerant to ongoing mu-opioid receptor agonism or partial agonism, thereby resulting in dosage increases and corresponding greater difficulty with future cessation.
  • Other addictions: Not only does ibogaine appear efficacious as an intervention for opiate/opioid addiction, but it seems promising as a treatment for a host of other addictions to substances such as: alcohol, amphetamines, and cocaine. Assuming you’re addicted to other substances besides opiates/opioids, it may be possible to overcome all of your addictions simultaneously with ibogaine treatment.  For most, using a single substance such as ibogaine to treat multiple addictions would be preferable over administering a drug for each condition.  Moreover, it makes logical sense that ibogaine could prove therapeutic for nearly all major substance addictions based on its ability to modulate activity in the reward center of the brain.
  • Refractory cases: Evidence suggests that a subset of patients with opiate/opioid addiction fail to derive adequate benefit from conventional interventions (e.g. opioid replacement therapies). Moreover, even when conventional interventions are combined with psychotherapy, outpatient sobriety programs, and/or lifestyle changes – a subset of individuals will derive insignificant benefit, and predictably, will relapse whereby they revert back to illicit opiate/opioid administration.  The aforementioned subset of patients who seemingly don’t respond to any conventional medication, medication combination, and/or therapy – may need to pursue alternative unconventional treatments such as ibogaine.  In the literature, there is a report of a woman with a 19-year history of opiate/opioid addiction who derived significant long-term benefit from ibogaine treatment after previously responding poorly to all conventional treatments.  There are also anecdotal reports online from persons with refractory opiate/opioid addictions who claimed to have benefitted from ibogaine when no other treatments worked.
  • Single treatment: Another benefit associated with using ibogaine for the treatment of opiate/opioid addiction is that, for many individuals, only a single treatment is needed to maintain abstinence or overcome an addiction.  In some cases, a single series of treatments administered over a period of several consecutive days (e.g. 2 to 5 days) may be necessary.  Nonetheless, if a single treatment or series of treatments with ibogaine yields sustained long-term opiate/opioid abstinence, most would consider this favorable as compared to ongoing [daily] treatment with opioid/opiate replacement therapies.
  • Tolerability: Most research suggests that, when administered to healthy adults at therapeutically-relevant dosages for the treatment of opiate/opioid addiction, ibogaine is well-tolerated. Following its administration, most ibogaine recipients experience side effects, however, the side effects are generally transient and easily managed.  Though it’s unclear as to how ibogaine’s tolerability compares to conventional opiate/opioid replacement therapies, ibogaine seems to be tolerable among a majority of recipients.
  • Withdrawal symptom reduction: One major reason persons with opiate/opioid addiction continue to seek out opiates/opioids and reinforce their addictions is because they don’t want to deal with the severe withdrawal symptoms that emerge following opiate/opioid discontinuation. Acute symptoms associated with opiate/opioid cessation can include: vomiting, diarrhea, nausea, sweating, aches/pains, etc.  The aforestated acute symptoms can last weeks, yet even when these end, post-acute symptoms (e.g. depression) can linger for months.  Though withdrawal symptoms can be averted with strategic administration of opioid replacement therapies like buprenorphine or methadone, or attenuated with medications like clonidine and gabapentin, the fact that withdrawal symptoms are severe is a major roadblock to complete abstinence.  Favorably, in addition to suppressing cravings, research suggests that ibogaine attenuates opiate/opioid withdrawal symptoms.  Though ibogaine may not eliminate every opiate/opioid withdrawal symptom, it usually symptom severity enough that a person is able to maintain abstinence.

Drawbacks of Using Ibogaine for Opiate Withdrawal (Possibilities)

While there are clearly potential benefits to be attained from ibogaine in the treatment of opiate/opioid addiction and/or withdrawal symptoms, there are also some potential drawbacks worthy of contemplation.  Perhaps the most serious of all potential drawbacks is that ibogaine treatment may provoke a life-threatening adverse reaction.  Other potential drawbacks to consider in regards to ibogaine treatment include its: cost, long-term complications, ineffectiveness, legal status, and untargeted physiologic action.

  • Adverse reactions: A subset of individuals will experience severe adverse reactions following ibogaine administration. Among the most common adverse reactions to ibogaine are said to include: ataxia (difficulty coordinating muscle motion), xerostomia (dry mouth), nausea, and vomiting.  These adverse reactions can persist for hours or days after administration.  Other more serious adverse reactions may include: cardiotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, and/or neuropsychiatric events (e.g. seizures, psychosis, depression, anxiety, etc.).  Compared to conventional treatments for opiate/opioid addiction, risk of the aforementioned adverse reactions with ibogaine is much greater.
  • “Bad trip”: It is understood that ibogaine induces profound psychedelic effects in which users might experience emotional lability, delusions, hallucinations (visual and auditory), and other perceptual changes. While a majority of ibogaine users will describe their psychedelic experience as positive or neutral, others may endure a nightmarish experience, usually referred to as a “bad trip.”  A bad trip may lead to self-harm, injury, property damage, and/or death.  Moreover, it’s possible that a terrifying psychedelic experience may yield deleterious long-term psychologic effects and/or fail to help the ibogaine user overcome an opiate/opioid addiction.  Though likelihood of a bad trip may be low with professional support, bad trips may still occur, possibly leading some to regret the decision to administer ibogaine.
  • Cardiotoxicity: Koenig and Hilber (2015) investigated the effect of ibogaine within the cardiovascular system and discovered that it: reduces heart rate, interacts with cardiac ion channels, and can provoke cardiotoxicity.  Specifically, ibogaine is thought to block repolarizing hERG potassium channels, inhibit repolarization phase of ventricular action potential, and prolong the QT interval to induce [life-threatening] arrhythmia.  In a majority of individuals who died following the ingestion of ibogaine, cardiotoxicity was the cause.  Moreover, it is estimated that cardiotoxicity can occur for days after ibogaine administration due to lingering concentrations of its metabolite, noribogaine.  The possibility of cardiotoxicity makes ibogaine extremely unappealing as a therapeutic intervention among persons with opiate/opioid addiction.  (Source: https://www.ncbi.nlm.nih.gov/pubmed/25642835).
  • Cognitive deficits: Treatment with ibogaine can result in significant cognitive deficits such as attentional deficits, memory impairment, poor judgment, etc.  Although cognitive deficits resulting from ibogaine are transient, they may persist for weeks or months after treatment.  Moreover, if the cognitive deficits are severe, they may interfere with occupational and/or academic performance.  Conventional treatments for opiate/opioid addiction probably won’t disturb cognitive function as much as ibogaine.
  • Contraindications: Like most drugs, ibogaine’s usage for the treatment of opiate/opioid addiction is contraindicated among persons with various medical conditions. Examples of conditions that are contraindicated with ibogaine include: cardiovascular disorders, hepatic dysfunction, neuropsychiatric disorders, and renal impairment.  Ibogaine may also be contraindicated among persons with abnormal CYP2D6 expression.  These contraindications may be perceived as a drawback such that they limit the number of persons who can safely utilize ibogaine to overcome opiate/opioid addictions.  For a complete list of ibogaine contraindications, consult a medical professional with preexisting ibogaine knowledge.
  • Death: A subset of ibogaine recipients will experience life-threatening reactions, some of which are fatal. As of 2016, a total of 27 deaths have been documented among ibogaine users, mostly attributable to ibogaine-mediated cardiotoxicity.  Although death is regarded as an unlikely outcome among healthy ibogaine recipients, deaths have been reported in the literature.  For example, a paper by Meisner, Wilcox, and Richards (2016) discussed the death of a 40-year-old man who died following the ingestion of ibogaine to treat heroin withdrawal.  In this particular case, the cause of death was ibogaine-induced cardiac arrest, which led to cerebral edema and brain death.  A paper by Papadodima, Dona, Evaggelakos, et al. (2013) highlighted a different death in which a man died after using ibogaine to treat alcohol addiction.  Considering that ibogaine usage could prove fatal, this may be reason enough to avoid it.  (Source #1: https://www.ncbi.nlm.nih.gov/pubmed/27141291; Source #2: https://www.ncbi.nlm.nih.gov/pubmed/24112325).
  • Dosing guidelines: While various dosages of ibogaine appear efficacious in case reports and preclinical trials for the treatment of opiate/opioid addiction, no large-scale trials have been conducted to establish professional dosing guidelines. Unestablished professional dosing guidelines makes it difficult to ensure the safety of ibogaine recipients, as well as to maximize the likelihood that ibogaine will effectively treat an opiate/opioid addiction.  Until professional dosing guidelines are established, there will be a greater number of safety risks for patients and a lower likelihood that the dosage administered will effectively treat opiate/opioid addiction.  Moreover, because ibogaine undergoes extensive first-pass biotransformation via the CYP2D6 enzyme, anyone with abnormal CYP2D6 expression may be especially prone to adverse reactions.
  • Exacerbation of addiction (?): Though nearly all preclinical studies are unanimous in suggesting that ibogaine appears therapeutic in the treatment of opiate/opioid addiction, a study by Maisonneuve, Keller, and Glick (1992) highlights the possibility that ibogaine could exacerbate addiction to psychostimulants such as amphetamine.  The aforementioned study discovered that if rats receive ibogaine prior to dextroamphetamine, more significant dopamine increases are observed within the striatum and nucleus accumbens – as compared to those observed following standalone dextroamphetamine administration.  Additionally, ibogaine pretreatment bolstered the motor effects of dextroamphetamine, leading researchers to note that ibogaine may enhance the reinforcing effect of dextroamphetamine.  Assuming ibogaine enhances the reinforcing effect of dextroamphetamine in humans, it could exacerbate a preexisting stimulant addiction – even if it treats an opiate/opioid addiction.  (Source: https://www.ncbi.nlm.nih.gov/pubmed/1623410).
  • Hallucinogen persisting perception disorder (HPPD): Like other hallucinogens, ibogaine could cause a condition known as hallucinogen persisting perceptual disorder (HPPD).  Hallucinogen persisting perceptual disorder is a condition characterized by permanent (or protracted) alterations in perceptions of sensory information following the administration of a hallucinogenic agent.  In many cases, the perceptual abnormalities are milder versions of certain hallucinatory events that occurred while under the influence of the hallucinogen.  Furthermore, most claim that hallucinogen persisting perceptions typically consist of visuals such as: auras or halos (around objects), shifting colors in the environment, or trails following moving objects.  Although the condition may be caused by a disruption of sensory gating after the administration of hallucinogens, there is currently no cure.  Knowing that ibogaine could cause a permanent, untreatable hallucinogen persisting perceptual disorder, this may be reason enough for some to avoid it.
  • High cost: Another drawback associated with using ibogaine for the treatment of opiate/opioid addiction is its relatively high cost. If purchased in bulk on the internet, 10 grams of ibogaine hydrochloride (HCl) runs around $1,165 – bringing the price per gram to approximately $165.  (Understand that if ibogaine hydrochloride isn’t purchased in bulk, the price per gram is generally more expensive).  Research suggests that the therapeutic range of ibogaine dosages for the treatment of opiate/opioid addiction are from 6 mg/kg to 29 mg/kg.  As a hypothetical example, let’s say that a dosage of 20 mg/kg is utilized for treatment (as this was a dose reported as successful in a case study of a woman with severe opiate/opioid addiction).  Assuming a prospective user is 200 lbs., he/she would necessitate an ibogaine dosage of ~1.81 grams, bringing the price of a single treatment to $200.  Many may not perceive a price of $200 as being very expensive given the fact that ibogaine could potentially attenuate severe withdrawal symptoms and yield long-term abstinence.  That said, to some individuals, $200 may be too large of an upfront cost – especially persons living paycheck to paycheck.  Moreover, assuming the individual undergoing ibogaine treatment wants medical supervision and psychotherapy [to ensure his/her safety], the price will be even greater.  Professional ibogaine clinics can cost between $1800 and $2500 per week, and in some cases, up to $10,000 for a series of treatments with supervised recovery.  While some may derive good return on investment from the ibogaine treatment as a result of protracted opiate/opioid abstinence (saving in spending on opiates/opioids and/or bolstered occupational productivity), others will find ibogaine clinics to be downright unaffordable.  Moreover, because ibogaine is deemed an illicit substance in the United States, treatment will not be covered by health insurance plans.  In fact, individuals with quality health insurance plans may actually save themselves a significant amount of money by utilizing conventional treatments for opiate/opioid largely because expenses will be picked up by insurance.
  • Impaired motor skills: After using ibogaine, individuals may exhibit impaired motor skills for days or weeks. While it is recommended to avoid operating motor vehicles, heavy machinery, and any activities that require peak coordination in the days following ibogaine treatment, not everyone will follow this recommendation.  Failure to abstain from the operation of a motor vehicle or machinery in the acute aftermath of ibogaine treatment will increase risk of injury and/or death for the user, as well as others in his/her environment.  For this reason, some may argue that motor function impairment is a drawback of ibogaine treatment.
  • Ineffective: Both human and animal studies reveal that not every ibogaine recipient derives therapeutic benefit from its administration for the treatment of opiate/opioid use disorders. Based on these findings, it’s reasonable to suggest that, like any drug, ibogaine is not universally effective for the treatment of opiate/opioid addiction.  Additionally, even if a subset of individuals finds ibogaine to be highly effective for the treatment of opiate/opioid addiction and/or withdrawal symptoms, others will derive insignificant therapeutic benefit or find it to be completely ineffective.  Assuming you use ibogaine with the hopes of overcoming an addiction, you may be disappointed to find out that it doesn’t work.  As of 2016, there’s no evidence from large-scale randomized controlled trials to support ibogaine’s efficacy in the treatment of opiate/opioid addiction and/or withdrawal symptoms in humans.  The lack of quality data from randomized controlled trials means that we cannot be sure as to whether ibogaine is legitimately more effective than a placebo in the treatment of opiate/opioid addiction.  It’s possible that future randomized controlled trials may show that ibogaine is of no substantial therapeutic value.  Moreover, the lone randomized controlled trial conducted with noribogaine (ibogaine’s metabolite) discovered no significant therapeutic benefit for the treatment of opiate/opioid withdrawal symptoms – as compared to a placebo.
  • Interactions: It is logical to suspect that ibogaine interacts with a host of other substances such as: dietary supplements, pharmaceutical medications, and illicit drugs. Anyone who uses ibogaine along with another substance may be at risk of experiencing severe interaction effects, which could result in permanent physiologic damage and/or death.  Substances may interact with ibogaine’s pharmacokinetics, pharmacodynamics, or a combination of both.  Pharmacokinetic interactions will likely occur if ibogaine is administered along with (or within proximal time of taking) a substance that induces or inhibits CYP2D6 enzymes.  Because ibogaine undergoes extensive CYP2D6 metabolism, if CYP2D6 enzymes were already inhibited or induced by another substance, the: speed of ibogaine’s metabolism, significance of ibogaine-mediated physiologic modulation, and duration of its action – will be subject to alteration.  Moreover, co-administration (or recent administration) of substances that undergo metabolism via CYP450 enzymes may increase risk of hepatotoxicity due to increased hepatic burden.  Pharmacokinetic interactions may be especially significant among persons with preexisting hepatic impairment and/or individuals exhibiting abnormal CYP2D6 function (e.g. poor CYP2D6 metabolizers).  It’s also necessary to mention that ibogaine plus another substance may significantly increase renal burden such that nephrotoxicity occurs.  In addition to pharmacokinetic interactions, substances may interact with ibogaine via potentiation of its pharmacodynamic and/or physiologic effect.  For example, someone taking an SSRI may develop “serotonin syndrome” due to the synergistic inhibition of serotonin reuptake and corresponding high serotonin levels.  Given ibogaine’s action, it may interact with a host of other medications involved in modulation of blood pressure, cardiac function, and/or neuropsychiatric status.
  • Lack of medical supervision: Because ibogaine is classified as an illicit substance in the United States, persons who pursue ibogaine treatment generally do so without professional medical consent and supervision. Without seeking professional medical consent prior to receiving ibogaine, individuals may remain unaware of the fact that they have a medical condition with which ibogaine administration is contraindicated (e.g. hepatic impairment, long QT syndrome, schizophrenia, etc.).  Individuals may also be unaware that medications and/or supplements they’re using could provoke a serious interaction if administered on the same day as ibogaine.  Furthermore, even if a person is completely healthy and isn’t using medications or supplements prior to receiving ibogaine, there’s no telling whether they’re going to administer a safe and/or effective dose (dosing guidelines haven’t been established).  Additionally, even if a dose of ibogaine is posited to be safe and/or effective, patient safety cannot be maximized post-ibogaine treatment unless a medical professional is present.  The presence of a medical professional post-ibogaine treatment can help prevent death resulting from adverse reactions such as cardiotoxicity.  In sum, lack of professional medical consent to receive ibogaine treatment and supervision could have disastrous consequences for certain persons.
  • Legality: Despite the fact that ibogaine may be effective for the treatment of opiate/opioid addiction, it’s classified as a “Schedule I” controlled substance in the United States, making it illegal to buy, possess, distribute, and/or ingest. If caught in possession or under the influence of ibogaine by law enforcement, you may receive a hefty fine and a lengthy prison sentence.  For many, the potential legal consequences resulting from getting caught with ibogaine may be enough to dissuade you them from its usage.  Those who wish to use ibogaine legally without facing penalization will need to visit a country in which ibogaine is classified as legal or unregulated.
  • Long-term complications: While side effects resulting from ibogaine are often transient, some individuals may experience unwanted long-term and/or permanent complications after treatment. Examples of potential long-term complications that may result from ibogaine administration include: brain damage (from neurotoxicity), cardiovascular damage (from cardiotoxicity) or cardiac irregularities, cognitive deficits, hallucinogen persisting perceptual disorder (HPPD), long QT syndrome, mood disturbances, and sleep problems.  These complications may last for weeks, months, or in rare cases, indefinitely after ibogaine treatment.  Though risk of unwanted long-term and/or permanent complications is thought to be low among healthy adults, this risk is yet another drawback associated with using ibogaine to treat addiction.
  • Mania-inducing: Mania is characterized as an extreme elevation in mood (i.e. euphoria) that’s accompanied by accelerated thoughts, high arousal, rapid speech, and impulsive behavior.  A case series by Marta, Ryan, Kopelowicz, and Koek (2015) indicates that ibogaine may induce mania in a subset of recipients.  In the case series, several individuals were noted to have developed mania following the administration of ibogaine.  It is unclear as to whether ibogaine caused mania, and if it did, whether the mania was a transient reaction to ibogaine or a permanent consequence of its administration.  Because mania can lead to regrettable decision making (e.g. shopping sprees, sexual promiscuity, etc.), this would be considered an unwanted adverse reaction if caused by ibogaine.  Moreover, considering the possibility of mania from ibogaine, persons with bipolar disorder may be suboptimal candidates for ibogaine treatment due to preexisting susceptibility. (Source: https://www.ncbi.nlm.nih.gov/pubmed/25877487).
  • Neurotoxicity: Another potential drawback associated with using ibogaine to treat opiate/opioid addiction is that it may induce neurotoxicity whereby it kills brain cells and/or damages brain structures.  According to an investigation of ibogaine’s toxicity by Litjens and Brunt (2016), ibogaine appears to stimulate the inferior olive within the brains of rats which induces excitotoxicity among Purkinje neurons in the cerebellum.  This excitotoxicity yields neuronal death and regional degeneration, and may produce long-term deficits in motor function associated with the head and upper extremities.  Though it’s unclear as to whether neurotoxicity occurs among humans using ibogaine at dosages utilized for the treatment of opiate/opioid addiction, it’s a possibility to consider.  Because most individuals won’t like the idea of [potentially] sacrificing their brain cells and/or brain structures to attain sobriety, ibogaine may be perceived as a suboptimal intervention.  (Source: https://www.ncbi.nlm.nih.gov/pubmed/26807959).
  • Psychotomimetic effects: It should be known that not everyone attempting to overcome an opiate/opioid addiction is willing to endure psychotomimetic effects in the process.  For those who wish to avoid psychotomimetic effects while recovering from an addiction, ibogaine is a poor treatment option.  Ibogaine is understood to induce psychotomimetic effects via action upon 5-HT2A, 5-HT2C, sigma, and NMDA receptors.  Examples of psychotomimetic effects that can occur while under the influence of ibogaine include: auditory hallucinations (e.g. hearing voices), delusions (e.g. believing with full conviction in things that have no basis in reality), dissociation (e.g. feeling disconnected from your body), and visual hallucinations (e.g. seeing creatures, shapes, etc.).  Though some ibogaine users won’t mind psychotomimetic effects, others will dislike them and/or have trouble coping with them.  Furthermore, it’s possible that the psychotomimetic effects of ibogaine may yield protracted drug-induced psychosis such that a user exhibits psychotic symptoms for days or weeks post-ibogaine administration, possibly requiring antipsychotic intervention.  It’s also likely that psychotomimetic effects induced by ibogaine could be especially problematic for persons with preexisting neuropsychiatric disorders such as schizophrenia – due to the fact that they may exacerbate symptoms.  For example, a case report presented by Houenou, Homri, Leboyer, and Drancourt (2011) documented pathological wandering, rambling, carelessness, delusions of persecution, and psychomotor agitation in a 26-year-old male with schizophrenia – following the ingestion of ibogaine powder.  It was further noted that the patient’s first psychotic episode occurred after the initiation of ibogaine usage.  Considering this case, it’s reasonable to speculate that ibogaine might:  accelerate schizophrenia onset, induce schizophrenia, and/or exacerbate symptoms – in vulnerable populations.  (Source: https://www.ncbi.nlm.nih.gov/pubmed/21881451).
  • Residual effects: It is known that there’s a “residual phase” of ibogaine treatment that can last between several days and several weeks post-ibogaine ingestion. During this residual phase, individuals may experience a host of unwanted effects such as: agitation, anxiety, appetite changes, cognitive deficits, emotional fluctuations, insomnia, mild psychotomimetic effects, and restlessness.  Some document the experience of “Gray Day” after ibogaine administration, characterized by: apathy, body image problems, depression, negativity, sadness, self-criticism, and/or suicidal thoughts.  While not everyone will experience severe residual effects nor “Gray Day,” those that do may have a difficult time coping and reverting back to physiologic homeostasis.  Though the residual effects generally diminish over the course of a few weeks, others may linger and become longer-term effects.
  • Seizure-inducing: There’s some evidence to suggest that ibogaine could induce seizures in a subset of recipients. For example, a case report presented by Breuer, Kasper, Schwarze, et al. (2015) documented the occurrence of tonic-clonic and grand mal seizures in a 22-year-old male who ingested 38 grams of ibogaine (divided into 2 doses).  Although the 38 grams of ibogaine was divided into 2 doses, this is still an extreme supraphysiologic dosage – far greater than the amount needed to treat opiate/opioid addiction.  That said, acknowledging this case report, it’s possible that ibogaine could provoke seizures among individuals with a history of seizures and/or who use relatively large doses to treat opiate/opioid addiction.  (Source: https://www.ncbi.nlm.nih.gov/pubmed/26518760).
  • Short-term therapeutic effect: Research in humans and animal models suggests that the duration of ibogaine’s therapeutic effect is subject to significant individual variation. It is known that not every ibogaine recipient derives therapeutic benefit from its administration.  However, even among those who derive significant therapeutic benefit from its administration, the duration of therapeutic effect will be highly variable among users.  Some may claim that their cravings only remain suppressed for a short-term such as a few days or weeks – after ibogaine administration.  Those who only derive a short-term therapeutic effect may be prone to reinstatement of opiates/opioids – and may be better suited to receive opiate/opioid replacement therapies.
  • Side effects: In addition to serious adverse reactions, ibogaine can induce a host of general side effects. While most will find the side effects of ibogaine to be tolerable and manageable, others may dislike ibogaine’s side effect profile, especially when compared to opiate/opioid replacement therapies.  Common ibogaine side effects include: dissociation, dizziness, emotional upheavals, headache, heart rhythm abnormalities, and various perceptual changes.  Some also believe it’s fairly common to experience electric shock sensations, also known as “brain zaps.”
  • Superior options: Due to the fact that ibogaine’s safety and efficacy for the treatment of opiate/opioid addiction remain unknown, it’s necessary to acknowledge that, as of present, there are superior treatment options available.  Superior treatment options should be considered any substances that have a proven track-record of safety and efficacy in the treatment of opiate/opioid addiction and/or withdrawal symptoms in large-scale randomized controlled trials.  Unlike ibogaine, both methadone and buprenorphine have proven safe and effective enough to receive FDA approval for the management of opiate/opioid dependence.  Moreover, there are a myriad of other pharmaceutical medications such as clonidine and gabapentin that have stronger evidence to support their usage in the treatment of opiate/opioid withdrawal symptoms – as compared to ibogaine.  Although ibogaine may turn out to be as safe and/or effective as FDA approved or evidence-based treatments for opiate/opioid dependence and/or withdrawal symptoms, presently there’s insufficient data to elucidate ibogaine’s safety and efficacy.  For this reason, until more ibogaine trials are conducted, it should be considered inferior treatment compared to clinically-endorsed options.
  • Tolerance onset: When utilized for the treatment of opiate/opioid addiction, ibogaine is generally administered in a single dose or a single series of doses. After the single dose or series of doses, most responders to ibogaine will experience protracted suppression of opiate/opioid cravings and/or withdrawal symptoms.  That said, some individuals may only derive a short-term therapeutic effect and require relatively frequent re-dosing with ibogaine.  Others have reported using small doses of ibogaine on a daily basis to avert its psychedelic effect and for an ongoing anti-addiction effect.  Those who use ibogaine frequently such as on a daily basis will run the risk of developing tolerance to its physiologic influence.  Once tolerance is established, it’s possible that users will resort to using higher doses of ibogaine to suppress their cravings, which might provoke adverse reactions.  Moreover, those who’ve developed tolerance to ibogaine after a long-term of regular usage may experience severe withdrawal symptoms upon cessation.
  • Toxicity: There are numerous reports of ibogaine toxicity among persons who use it for the treatment of substance addictions. Researchers Litjens and Brunt (2016) investigated the toxicity of ibogaine and discovered that it can induce cardiotoxicity, neurotoxicity, and interaction-related toxicity if administered with other drugs.  Cardiotoxicity is thought to be caused by modulation of peripheral potassium ion channels, leading to QT interval prolongation.  Neurotoxicity is thought to result from excessive excitatory transmission in which brain cells die from overstimulation.  Due to reports of toxicity, researchers consider ibogaine to be extremely risky as a treatment for opiate/opioid addiction without medical supervision.  (Source: https://www.ncbi.nlm.nih.gov/pubmed/26807959).
  • Traumatic experience: For a small percentage of individuals, being under the physiologic influence of ibogaine will prove to be traumatic.  Certain individuals have reported being traumatized by an unfavorable psychedelic experience (i.e. “bad trip”) such as one with disconcerting physical sensations (e.g. electrical shocks) and nightmarish hallucinations (e.g. demons attacking).  In addition to a potential “bad trip,” others may end up traumatized from lingering adverse effects that persist long after ibogaine treatment such as altered perception of visual inputs.  Moreover, persons with post-traumatic stress disorder (PTSD) may experience the resurfacing of repressed memories while under the influence of ibogaine, potentially reactivating their old trauma.  The potential induction or reactivation of trauma by ibogaine may lead some to regret using it as a treatment for opiate/opioid addiction.
  • Untargeted action: While it’s possible that the entirety of ibogaine’s pharmacodynamic action is needed to elicit a therapeutic effect for the treatment of addictions, it’s more likely that only a subset of its actions are relevant to the treatment of opiate/opioid addiction. Because ibogaine’s action is highly untargeted, users are prone to adverse effects (e.g. cardiac complications) and possibly unnecessary psychoactive effects.  If researchers are able to elucidate the specific mechanism(s) of ibogaine’s action that are most relevant to the generation of its anti-addiction effect, safer substances could be synthesized to generate a central anti-addiction effect without the risk of serious adverse reactions.

How Ibogaine Treats Opiate/Opioid Addiction (Potential Mechanisms of Action)

There are numerous potential mechanisms by which ibogaine and its chief psychoactive metabolite noribogaine may modulate physiology to reduce opiate/opioid cravings and discontinuation symptoms.  Binding assays suggest that ibogaine exhibits highest affinity for the following receptor sites (listed in order of hierarchy):  sigma-2, mu-opioid, kappa-opioid, sigma-1, 5-HT3, NMDA, 5-HT2A, delta-opioid, and 5-HT2C receptors.  Comparatively, noribogaine metabolites exhibit affinity for the following receptor sites (listed in order of hierarchy):  kappa-opioid, mu-opioid, delta-opioid, sigma-1, NMDA, sigma-2, 5-HT2C, 5-HT2A, and 5-HT3 receptors – differentiating its effect from the parent compound.

Considering the host of receptor sites upon which ibogaine and noribogaine interact, it’s reasonable to speculate that all receptor site interactions contribute (in varying amounts) to the generation of a therapeutic effect.  That said, it’s possible that one specific mechanism or multiple mechanisms of ibogaine’s and/or noribogaine’s action is of greater therapeutic relevance than others for the treatment of opiate/opioid addiction and/or discontinuation symptoms.  Included below is a description of each mechanism of ibogaine’s action along with speculation as to how it may aid in the treatment of opiate/opioid addiction.

Sigma-2 opioid receptor agonist: Of all receptors in the CNS, ibogaine exhibits highest binding affinity for sigma-2 receptors upon which it acts as an agonist.  Despite ibogaine’s significant interaction with sigma-2 receptors, it is unclear as to how this particular mechanism of action might aid in the treatment of opiate/opioid addiction or withdrawal symptoms.  It is known that the sigma-2 receptors are most densely located in regions of the brain associated with motor functions and emotional responses.

Furthermore, the sigma-2 receptors appear to play a role in calcium signaling, hormone signaling, and neuronal signaling.  Preliminary research has linked activation of sigma-2 receptors to altered cerebral blood flow and the generation of: antipsychotic, anxiolytic, and dystonic effects.  A paper by Guo and Zhen (2015) also reveals that sigma-2 receptors can influence dopaminergic transmission and behaviors associated with cocaine addiction in animal models.

The fact that sigma-2 receptors have been linked to behaviors associated with cocaine addiction in animals suggests that they might be a useful pharmacological target for the treatment of substance addictions.  Additionally, because sigma-2 receptors are densely located in regions of the brain associated with emotional responses, their agonism may alter emotionality of ibogaine users in ways conducive to overcoming an addiction and/or managing withdrawal symptoms.  It’s also possible that sigma-2 receptor-mediated changes in cerebral blood flow, calcium signaling, hormone signaling, and/or neuronal signaling – are conducive to the suppression of cravings for opiates/opioids and/or the attenuation of discontinuation symptoms.

Moreover, the specific means by which ibogaine interacts with sigma-2 receptors may yield downstream modulation across other neurotransmitter systems in ways that are conducive to suppression of opiate/opioid cravings.  It’s also fair to speculate the sigma-2 receptor agonism may be of limited relevance (or irrelevant) in the therapeutic effect of ibogaine for the treatment of opiate/opioid addiction.  In fact, some speculate that neurotoxicity resulting from ibogaine administration may be attributable to the stimulation of sigma-2 receptors whereby glutamatergic responses are amplified and excitotoxicity occurs.  Nevertheless, because the sigma-2 receptors are the principal target of ibogaine, their potential importance in the facilitation of a therapeutic effect should not be dismissed.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/25620095

Mu-opioid receptor agonist:  For context, the mu-opioid receptors [and upwards of 30 genes with which they interact] mediate positive reinforcement following the administration of opiates/opioids – as well as other substances (e.g. alcohol, cannabinoids, nicotine).  Although its affinity for mu-opioid receptors is nearly 5-fold lesser than its affinity for sigma-2 receptors, it’s necessary to underscore that the action of ibogaine upon mu-opioid receptors appears significant.  Because opiates/opioids exert physiologic effects predominantly via activation of the mu-opioid receptor, most persons with preexisting opiate/opioid addictions will report fewer cravings and/or reduced withdrawal symptoms from agents that modulate activity at mu-opioid receptor sites.

For example, the opioid-replacement medication buprenorphine partially agonizes mu-opioid receptors to help with the management addictions to more potent or illicit opiates/opioids (e.g. heroin) and/or opiate/opioid detoxification symptoms.  Assuming ibogaine exerts a significant effect upon central mu-opioid receptors as an agonist, this action would explain noticeable reductions in opiate/opioid cravings and withdrawal symptoms reported by persons with opiate/opioid addictions who use ibogaine.  Evidence to support the idea that ibogaine interacts with mu-opioid receptors is derived from research by Codd (1995) in which ibogaine administration was found to potentiate morphine-induced analgesia and attenuate naltrexone-precipitated withdrawal [in animal models].

Research by Cao and Bhargava (1997) documented that ibogaine (administered at high doses) to Swiss-Webster mice inhibited tolerance to the antinociceptive effect of morphine.  Because antinociceptive effects of morphine are mediated by the mu-opioid receptor, it’s possible that ibogaine’s short-lived interaction with the mu-opioid receptor yields neurochemical changes that reduce or reverse preexisting opiate/opioid tolerance.  If this is a legitimate mechanism, it would explain why individuals experience fewer and/or less severe opiate/opioid withdrawal symptoms following ibogaine administration.

That said, animal model research by Antonio, Childers, Rothman, et al. (2013) suggested that ibogaine’s action as a mu-opioid receptor agonist does not appear to facilitate the attenuation of opiate/opioid withdrawal symptoms.  The aforementioned researchers concluded that ibogaine’s ability to attenuate opiate/opioid tolerance and withdrawal is mediated by a novel mechanism of action – rather than its interaction with mu-opioid receptors.  Nonetheless, because the data are mixed [as to whether ibogaine’s interaction with mu-opioid receptors plays a role in attenuation of opiate/opioid withdrawal symptoms] and all investigations thus far involved animal models, it’s difficult to know whether mu-opioid receptors are definitively implicated in the therapeutic effect of ibogaine among persons with opiate/opioid addictions.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/7475926
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/9106464
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/24204784

Kappa-opioid receptor agonist: To a slightly lesser extent than its affinity for mu-opioid receptors, ibogaine interacts with kappa-opioid receptors as a “biased agonist.”  Kappa-opioid receptor activity is known to play a significant role in the development of addiction and can affect mood, pain perception, and stress levels.  Because the endogenous kappa-opioid receptor agonist dynorphin serves as the body’s natural addiction control mechanism, researchers speculate that kappa-opioid receptor agonists may prove efficacious in the treatment of substance addictions.

Agonism of kappa-opioid receptors is understood to attenuate the rewarding effects of opiates/opioids by decreasing the release of dopamine in the nucleus accumbens following their administration.  In other words, someone who administered a kappa-opioid agonist followed by an opiate/opioid would probably derive less reward (or perhaps no reward) from the opiate/opioid.  Moreover, ongoing agonism of kappa-opioid receptors upregulates mu-opioid receptors and D2 (dopamine) receptors, each of which are commonly downregulated among persons with opiate/opioid addictions.

Research by Wang, Sun, Tao, et al. (2010) suggests that kappa-opioid receptor activation yields analgesic effects devoid of a reward response and may reverse deleterious effects of mu-opioid receptor agonists such as: tolerance onset, reward, and impaired cognition.  Oppositely, it appears as though kappa-opioid receptor antagonists can induce and/or exacerbate addictions via upregulation of the reward response.  For example, a study by Mitchell, Liang, and Fields (2005) reported substantial and protracted increases in self-administration of alcohol among rats following the administration of a kappa-opioid receptor antagonist.

Knowing that ibogaine transiently agonizes kappa-opioid receptors, and that kappa-opioid receptor agonists may yield protracted neurobiologic effects [whereby cravings, physiologic dependence, and/or detoxification symptoms associated with opiates are attenuated], it’s likely that this mechanism of action is plays a critical role in facilitating therapeutically-relevant responses to ibogaine among persons with opiate/opioid addiction.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/16001119
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/20729876

Sigma-1 receptor agonist: Though ibogaine exhibits highest affinity for sigma-2 receptors, it also interacts – to a lesser extent – with sigma-1 receptors.  In the central nervous system, sigma-1 receptors are densest within the cerebellum, cerebral cortex, and nucleus accumbens.  It is known that sigma-1 receptors influence a variety of physiologic processes including:  intracellular calcium ion signaling, dopaminergic transmission, glutamatergic transmission, NMDA receptor activation, and voltage-gated potassium channel activation.

Research suggests that modulation of sigma-1 receptors can affect:  cardiovascular activity, cognitive function, and mood.  Abnormalities associated with sigma-1 receptors have been observed among individuals with: anxiety disorders, cancers, cardiovascular disorders, major depression, schizophrenia, and substance use disorders.  For this reason, some have proposed targeting the sigma-1 receptor for the treatment of neuropsychiatric disorders – including substance use disorders.

For example, a paper by Robson, Noorbakhsh, Seminerio, and Matsumoto (2012) outlined the fact that sigma-1 receptor ligands ameliorate certain behavioral effects associated with addictive drugs and noted that modulation of sigma-1 receptor activity may be helpful in the treatment of substance use disorders.  This considered, it’s possible that ibogaine’s transient agonism upon sigma-1 receptors is somehow useful for the treatment of opiate/opioid addiction and/or discontinuation symptoms.  That said, it’s also possible that sigma-1 receptor agonism plays minimal or no significant role as a mechanism of ibogaine’s therapeutic action among persons with opiate/opioid addictions.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/22288407
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/23632394

5-HT3 receptor modulator: According to animal model research by Sershen, Hashim, and Lajtha (1995), ibogaine interacts with presynaptic 5-HT3 receptors positioned atop striatal dopamine terminals.  As of current, it is important to emphasize that the precise modulatory action of ibogaine upon 5-HT3 receptors remains unclear.  That said, it is known that significant modulation of 5-HT3 receptor activation yields changes in dopaminergic signaling within the nucleus accumbens.

Some have speculated that ibogaine transiently modulates 5-HT3 receptors in a way that inhibits or downregulates their activation.  If this is the case, this mechanism of its action should yield downstream reductions in dopaminergic signaling in the nucleus accumbens, which in turn, would attenuate the psychologic reward (i.e. pleasure) derived from opiate/opioid administration, possibly helping users overcome preexisting opiate/opioid addictions.  In addition to attenuating psychologic reward derived from opiate/opioid administration, 5-HT3 receptor inactivation might aid in the suppression of opiate/opioid cravings.

In animal models of opiate addiction, the administration of 5-HT3 antagonists appears to decrease morphine self-administration, indicating an anti-addictive effect.  Though large-scale human trials haven’t evaluated 5-HT3 antagonists for the treatment of opiate/opioid addiction, it’s fair to hypothesize similar effects in humans.  Human studies indicate that 5-HT3 receptor activity influences intake of alcohol such that the suppression of 5-HT3 activation (following the administration of a 5-HT3 receptor antagonist) leads to decreased alcohol intake.

While 5-HT3 receptor modulation may be especially relevant for the treatment of alcohol addiction, there’s a chance that this action could also prove therapeutic for the treatment of opiate/opioid addiction.  Moreover, some speculate that ibogaine’s interaction with 5-HT3 receptors may be synergistic with its action upon kappa-opioid receptors, in that together, the combination of these actions yields far greater suppression of dopaminergic signaling in the nucleus accumbens compared to either action in isolation.  Finally, even if ibogaine’s transient interaction with 5-HT3 receptors is unable to decrease opiate/opioid cravings, there’s a chance that it might play a role in reducing certain opiate/opioid withdrawal symptoms.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/7757494

NMDA receptor antagonist: Ibogaine binds with relatively high affinity to the NMDA receptor upon which it acts as a noncompetitive antagonist.  The action of ibogaine as an NMDA receptor antagonist likely facilitates significant therapeutic benefit in terms of helping individuals overcome opiate/opioid dependence and/or withdrawal symptoms.  It is known that glutamatergic interactions with NMDA receptors contribute to the maintenance of opioid dependence [and other addictions].

When this glutamatergic transmission is disrupted via administration of an NMDA receptor antagonist, cravings for opioids decrease.  For example, a study by Bisaga, Comer, Ward, et al. (2001) shows that the drug memantine, an NMDA antagonist, attenuates physical dependence to heroin in 8 humans.  Other animal studies show that NMDA antagonists (especially selective for NR2B-containing NMDA receptors) prevent morphine dependence by attenuating reward center activation.

It is also thought that, during opioid withdrawal, excessive excitatory neurotransmission upon NMDA receptors is culpable for the induction and/or exacerbation of withdrawal symptoms.  Somewhat predictably, when an NMDA receptor antagonist is administered to patients following opioid discontinuation, withdrawal symptoms are attenuated.  For example, a trial by Amiri, Malek, and Tofighnia (2014) indicates that augmentation of clonidine with the NMDA receptor antagonist amantadine attenuates opioid withdrawal symptoms to a greater extent than standalone clonidine.  Other NMDA receptor modulators also appear promising in the treatment of substance dependence and/or discontinuation such as: acamprosate and d-Cycloserine.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/11512037
  • Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277803/

5-HT2A receptor agonist:  Ibogaine is understood to interact with the 5-HT2A receptor as an agonist.  Researchers Helsley, Rabin, and Winter (2001) suggest that ibogaine’s 5-HT2A receptor agonism induces hallucinogenic effects, likely in conjunction with its agonism of sigma-2 and 5-HT2C receptors.  It is necessary to underscore that, in many cases, hallucinatory events occurring under the influence of ibogaine are transformative such that they evoke intrinsic motivation to discontinue an addictive substance and/or maintain abstinence post-cessation.

Knowing this, it’s fair to suggest that 5-HT2A receptor agonism is an important mechanism of ibogaine’s action insofar as it aids in the generation of a transformative hallucinatory experience that leads to opiate/opioid cessation and abstinence.  That said, there may be other ways in which ibogaine’s 5-HT2A receptor agonism is of therapeutic benefit among persons attempting to overcome opiate/opioid addictions.  For example, because 5-HT2A receptors influence reward center activity, it’s possible that ibogaine’s transient agonism of 5-HT2A receptors yields protracted signaling alterations within the mesolimbic dopamine pathway that are conducive to the suppression of cravings and/or the attenuation of specific discontinuation symptoms.

Then again, it’s possible that 5-HT2A receptor agonism is of limited therapeutic value in the treatment of opiate/opioid addiction beyond its contribution to a transformative hallucinatory experience.  Moreover, while most evidence supports the idea that ongoing 5-HT2A receptor antagonism can help treat addiction [via inhibition of mesolimbic dopamine signaling], further research is needed to elucidate whether the transient 5-HT2A receptor agonism resulting from ibogaine is of legitimate relevance among persons with opiate/opioid addictions.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/11705117

Other potential mechanisms of ibogaine’s action…

In addition to its most prominent pharmacodynamic interactions with sigma, mu-opioid, kappa-opioid, 5-HT3, and NMDA receptors – ibogaine exhibits interactions with other neurochemical targets including: nicotinic acetylcholine receptors, delta-opioid receptors, 5-HT2C receptors, voltage-gated sodium channels, muscarinic receptors, the serotonin transporter, and the dopamine transporter.  Though these additional mechanisms of ibogaine’s action may yield modest or negligible physiologic effects, each warrants consideration as potentially contributing to its alleged efficacy in the treatment of addiction and withdrawal.  Of these additional mechanisms, many suspect that nicotinic acetylcholine receptor antagonism may be most implicated in the treatment of opiate/opioid dependence and discontinuation symptoms.

NAChR antagonist: Although unobserved in binding assays, functional analyses indicate substantial interaction between ibogaine and nicotinic acetylcholine receptors (NAChRs).  More specifically, it appears as though ibogaine acts as a noncompetitive antagonist at alpha(3)beta(4) nicotinic acetylcholine receptor subtypes.  An investigation conducted by Arias, Rosenberg, Targowska-Duda, et al. (2010) reported that ibogaine binds with high affinity to a single site in the alpha(3)beta(4) nicotinic acetylcholine receptor – between “position 6” and “position 13” rings, thereby altering its degree of sensitization for a prolonged duration.

Protracted alterations in the degree of alpha(3)beta(4) nicotinic acetylcholine receptor sensitization may be among the chief mechanisms by which ibogaine treats opiate/opioid addictions.  Research by Muldoon, Jackson, Perez, et al. (2014) reported that the degree of alpha(3)beta(4) nicotinic acetylcholine receptor activation exhibited in humans or animal models of addiction influences the severity of morphine dependence and withdrawal symptoms.  It was further noted that alpha(3)beta(4) nicotinic acetylcholine receptor antagonists appear to dose-dependently reduce morphine withdrawal symptoms.

Moreover, prior research by Pace, Glick, Maisonneuve, et al. (2004) demonstrated that the iboga alkaloid 18-methoxycoronaridine inhibits alpha(3)beta(4) nicotinic acetylcholine receptors, which leads to decreased self-administration of opiates (e.g. morphine) in animal models of opiate addiction.  The aforementioned researchers concluded that modulation of activity at alpha(3)beta(4) nicotinic acetylcholine receptors may prove therapeutic for the treatment of addiction.  Overall, there’s convincing evidence to suggest that modulation of alpha(3)beta(4) nicotinic acetylcholine receptor activity may aid in the treatment of opiate/opioid addiction and withdrawal symptoms.

That said, further research is necessary to understand the duration over which alpha(3)beta(4) nicotinic acetylcholine receptor sensitization remains altered post-ibogaine administration.  If alpha(3)beta(4) nicotinic acetylcholine receptor sensitization remains altered for a protracted duration following ibogaine administration, this may explain why individuals experience fewer opiate/opioid cravings and have an easier time coping with the physical symptoms of opiate/opioid withdrawal.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/20684041
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/24750073
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/15178360

Delta-opioid receptor agonist: To a lesser extent than its interactions with mu-opioid and kappa-opioid receptors, ibogaine binds to delta-opioid receptors upon which it acts as an agonist.  For reference, delta-opioid receptors are densest within the basal ganglia and neocortical areas of the brain and are thought to influence arousal, mood, nociception, and regulate aspects of drug reward.  In animal studies, the administration of delta-opioid receptor agonists yields a combination of antinociceptive, antidepressant, and anxiolytic effects.

Assuming similar effects occur in humans from delta-opioid receptor agonism, this mechanism of ibogaine’s action may increase pain tolerance, enhance mood, and/or reduce anxiety during treatment.  Moreover, it is known that delta-opioid receptors are implicated in the assignment of hedonic values to addictive drugs, which may influence drug-seeking behavior.  With this considered, it’s possible that ibogaine’s transient agonism of delta-opioid receptor activity yields a protracted neuroadaptive response such as to disturb preexisting hedonic attributions to opiates/opioids, ultimately leading to reductions in cravings.

That said, because ibogaine’s action upon delta-opioid receptors is modest, the physiologic responses resulting from this action are unlikely to be noticeable unless a large dose is administered.  Still, ibogaine’s more prominent actions at other receptor sites may be augmented by delta-opioid receptor agonism.  If this is the case, delta-opioid receptor agonism could make a modest contribution to ibogaine’s overall therapeutically-relevant neuroadaptive response.

5-HT2C receptor agonist: The exact degree to which ibogaine interacts with 5-HT2C receptors is unclear, however, its binding affinity for 5-HT2C is relatively low.  Still, it is suspected that 5-HT2C receptor agonism contributes to the induction of ibogaine’s hallucinogenic effects along with 5-HT2A and sigma receptor agonism.  As was already discussed, hallucinatory events occurring while under the influence of ibogaine may be regarded as highly transformative, serving as the principal impetus to discontinue an addictive substance and maintain abstinence.

For this reason, it’s necessary to suggest that 5-HT2C receptor agonism is a therapeutically relevant mechanism of ibogaine’s action insofar as it aids in the generation of a transformative experience that prompted the decision to discontinue opiates/opioids.  Furthermore, it’s possible that transient 5-HT2C receptor agonism is of therapeutic benefit in ways beyond augmenting the induction of psychologically-transformative hallucinations.  It is apparent that 5-HT2C receptors regulate the signaling of dopaminergic neurons in the reward pathway (ventral tegmental area and nucleus accumbens).

Research by Canal and Murnane (2017) suggests that administration of 5-HT2C receptor agonists appear to counteract the addictive properties of numerous drugs.  In brief, when 5-HT2C receptors are activated on the nucleus accumbens shell, GABAergic activity within the nucleus accumbens is enhanced, leading to inhibition of Kv1.x potassium channels and a therapeutically relevant anti-addiction effect.  Still, it remains unclear as to whether the transient 5-HT2C receptor agonism facilitated by ibogaine yields or contributes to a long-term neuroadaptive response such as to help individuals overcome opiate/opioid addictions.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/27903793

SERT inhibitor:  Another mechanism of ibogaine’s action that may prove useful in the treatment of opiate/opioid addiction and/or withdrawal symptoms involves inhibition of the serotonin transporter (SERT).  Inhibition of the serotonin transporter is known to increase serotonin concentrations in the synaptic cleft, which in turn, bolsters serotonergic signaling to postsynaptic receptor sites.  Bolstered stimulation of postsynaptic serotonin receptor sites has been hypothesized by some researchers to interfere with substance cravings and improve mood during drug withdrawal.

For example, research by Mash, Staley, Baumann, et al. (1995) reported that the ibogaine metabolite, 12-hydroxyibogamine, exhibits high affinity for the serotonin transporter upon which it acts as an inhibitor.  The researchers hypothesized that inhibition of the serotonin transporter by 12-hydroxyibogamine may explain reductions in drug cravings and/or drug-seeking behavior following ibogaine administration.  Moreover, a study by Wells, Lopez, and Tanaka (1999) suggested that while ibogaine’s inhibition of the serotonin transporter appears to be modest, this action could play a role in the generation of an anti-addictive effect.

Overall, it’s possible ibogaine-mediated serotonin transporter inhibition yields neuroadaptive changes that are conducive to addiction recovery.  Nevertheless, because ibogaine’s interaction with the serotonin transporter is transient [and possibly modest], it’s fair to question the relevance of this mechanism of action as it pertains to the treatment of opiate/opioid addictions.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/7596224
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/10386845

Voltage-gated sodium channel inhibitor: Although ibogaine is known to modulate voltage-gated ion channels throughout the peripheral nervous system, it also binds to voltage-gated sodium channels in the brain.  In fact, Koenig and Hilber (2015) report that ibogaine likely interacts with Nav1.5 sodium channels in the brain to a greater extent than with Nav1.5 sodium channels in the peripheral nervous system.  While no experiments have elucidated the exact function of ibogaine at Nav1.5 sodium channels in the brain, researchers hypothesize that it exerts an inhibitory effect whereby it downregulates channel activation.

For reference, sodium channels are implicated in the conduction of sodium ions (Na+) through neuronal membranes and influence action potentials to determine whether neurons are: inactive, resting, or active.  Though not much research has been conducted to determine whether voltage-gated sodium channel modulation might aid in the treatment of a substance addiction, particularly to opiates/opioids, it’s possible that it could.  Support for this possibility is derived from a study by Vengeliene, Heidbreder, and Spanagel (2007) in which lamotrigine, an inhibitor of sodium channels, was discovered to be effective for the treatment of alcohol addiction in animal models.

When administered to animal models of alcohol addiction, lamotrigine significantly reduced likelihood of alcohol relapse and reinstatement.  The researchers hypothesized that lamotrigine-mediated voltage-gated sodium channel inhibition leads to a downstream reduction in glutamate release, and alters monoaminergic signaling.  Because glutamate and monoamines are implicated in opiate/opioid cravings and relapse, their indirect modulation via inhibition of voltage-gated sodium channels may help treat substance addiction in humans.

Although ibogaine’s action upon voltage-gated sodium channels in the brain is transient and modest, especially if compared to the action of lamotrigine, it’s possible that transient inhibition of voltage-gated sodium channels disrupts downstream neurochemical signaling (e.g. glutamate, monoamines, etc.) implicated in opiate/opioid cravings.  It’s also possible that inhibition of voltage-gated sodium channels counteracts excessive excitatory neurotransmission that occurs during opiate/opioid withdrawal, which is likely to attenuate withdrawal symptoms.  That said, more research is needed to determine whether the action of ibogaine at central voltage-gated sodium channels is relevant among users hoping to overcome an opiate/opioid addiction.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/25642835
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/17976664/

M1 & M2 muscarinic receptors:  Multiple studies suggest that ibogaine exhibits binding affinity for M1 and M2 muscarinic acetylcholine receptors, with a slightly higher affinity for M2 than M1.  The function of ibogaine at M1 and M2 receptor sites remains somewhat unclear in that some data report its action as a muscarinic receptor agonist, whereas other data report its action as a weak, nonselective, noncompetitive receptor inhibitor.  Though further research is needed to determine the specific effect exerted by ibogaine upon muscarinic receptors, it’s possible that modulation of M1 and M2 receptor activity could prove therapeutic in the treatment of opiate/opioid addiction.

It has been hypothesized that ibogaine’s action upon M1 and M2 receptors might alter the downstream release and reuptake of catecholamines, particularly dopamine, which may help attenuate opiate/opioid cravings.  Moreover, even if the transient action of ibogaine upon M1 and M2 receptors is irrelevant in terms of reducing opiate/opioid cravings, there’s a chance that it may help treat opiate/opioid withdrawal symptoms.  For example, researchers Zhang and Buccafusco (1998) noted that the administration of anticholinergics to animal models of opiate/opioid dependence can help reduce precipitated withdrawal symptoms.

Furthermore, the aforementioned researchers reported that regular ingestion of opiates/opioids alters the dynamics of cholinergic systems in the brain, and that modulation of cholinergic activity via M2 receptors may attenuate physical dependence to opiates/opioids.  It’s also reasonable to mention that many individuals claim to derive significant therapeutic benefit from the utilization of anticholinergics for the treatment of opiate/opioid withdrawal symptoms.  At this time, more research is needed to understand the effect of ibogaine at M1 and M2 receptors, as well as the extent to which muscarinic receptor interactions may induce neuroadaptive changes needed to overcome an opiate/opioid addiction.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/9729319

DAT modulator: Binding studies suggest that while ibogaine does not interact with any of the major dopamine receptors, it acts as a competitive modulator of the dopamine transporter (DAT).  If compared to its inhibition of the serotonin transporter (SERT), ibogaine’s modulation of the dopamine transporter is thought to be between 10-fold and 50-fold less significant.  In any regard, competitive modulation of the dopamine transporter by ibogaine has been shown to significantly alter dopaminergic signaling within various regions of the animal brain.

For example, some research has shown substantial increases in the firing rates of dopaminergic neurons [in the ventral tegmental area] of animal brains following intravenous ibogaine administration.  Nonetheless, other forms of ibogaine administration do not appear to increase firing rates of dopaminergic neurons in the same manner as intravenous administration.  Additionally, most evidence indicates that ibogaine administration lowers dopamine but increases concentrations of its metabolites.

An increased ratio of dopamine metabolites to dopamine is thought to result from ibogaine’s interaction with the dopamine transporter whereby it inhibits movement of dopamine into synaptic vesicles, which leads to the redistribution of dopamine from vesicles to the cytoplasm.  Next, monoamine oxidase enzymes metabolize the redistributed dopamine, leaving lower concentrations of dopamine and higher concentrations of dopamine metabolites post-ibogaine administration.  Interestingly, researchers Ghosh, Patel, Cousins, and Grasing (1998) report that, during morphine withdrawal, the opposite effect is observed such that dopamine metabolites (e.g. DOPAC) are reduced and dopamine is elevated [in regions of the brain such as the lateral striatum and nucleus accumbens].

This finding considered, one might surmise that ratio of dopamine metabolites (e.g. DOPAC) to dopamine influences the severity or occurrence of certain withdrawal symptoms.  Perhaps the transient modulation of dopamine transport facilitated by ibogaine alters dopamine and dopamine metabolite concentrations in a way conducive to the attenuation of opiate/opioid withdrawal symptoms.  Another possibility is that transient modulation of dopamine transport yields a protracted neuroadaptive response aiding in the suppression of opiate/opioid cravings.

Moreover, dopamine is understood to influence prolactin secretion such that elevated dopamine decreases prolactin secretion.  Because some research suggests that prolactin levels may dictate the severity of certain opiate/opioid withdrawal symptoms, it’s possible that ibogaine’s interaction with the dopamine transporter leads to changes in prolactin secretion conducive to the attenuation of opiate/opioid withdrawal symptoms.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/9572677

Neurotrophic factor modulator: It is unclear as to whether the effect of ibogaine upon the expression of neurotrophic factors is direct or indirect.  In other words, it’s difficult to know if ibogaine directly influences neurotrophic factor expression or whether its influence within other neurotransmitter systems generates downstream signaling cascades that modulate levels of neurotrophic factors.  Nevertheless, modulating the expression of neurotrophic factors may be a significant mechanism by which ibogaine effectively treats opiate/opioid addiction.

Two neurotrophic factors that ibogaine is thought to modulate include: BDNF (brain-derived neurotrophic factor) and GDNF (glial-derived neurotrophic factor).  Each of the aforestated neurotrophic factors regulate: the production and growth of neurons, the survival and function of adult neurons, cognitive function (learning and memory), and synaptic plasticity.  What’s more, there’s evidence to suggest that BDNF and GDNF are implicated in the neuroadaptive and behavioral responses to addictive drugs, including opiates/opioids.

Studies by He, McGough, Ravindranathan, et al. (2005) show that ibogaine administration increases GDNF expression in the ventral tegmental area (VTA) and that this increase in GDNF expression leads to decreased alcohol intake in rats. Moreover, the administration of anti-GDNF antibodies with ibogaine prevents reductions in alcohol intake, suggesting that enhancement of GDNF expression in the ventral tegmental area (VTA) may be an important mechanism of ibogaine’s action in the treatment of substance addiction.  Though we cannot assume that increased expression of GDNF in the ventral tegmental area occurs among humans after ibogaine ingestion, nor that this mechanism would automatically decrease opiate/opioid cravings, it’s something to consider based on data from preclinical animal models.

Moreover, while Litjens and Brunt (2016) report an effect of ibogaine on BDNF expression, the specific areas of the brain in which BDNF is subject to modulation remain unknown.  It is known that BDNF signaling influences many facets of substance addiction including: reward, motivation, learning, and memory – as well as that modulation of BDNF expression in certain areas of the brain may help treat addictions.  All this considered, it’s not farfetched to assume that the modulation of BDNF and/or GDNF by ibogaine is useful in the treatment of opiate/opioid addiction and/or withdrawal symptoms.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/19914287
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/15659598/
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/26807959

Gene expression modulator: Another potential mechanism by which ibogaine may treat opiate/opioid addiction and/or withdrawal symptoms is via the modulation of gene expression.  Research by Ali, Thiriet, and Zwiller (1999) indicates that, in animals, ibogaine significantly upregulates the expression of egr-1 and c-fos throughout the brain in regions such as the:  nucleus accumbens (NAcc), caudate-putamen (CPu), frontal cortex (FC), dentate gyrus (DG), and hippocampus – and upregulates the expression of c-fos in many similar regions.  It is also understood that both egr-1 and c-fos expression can be altered with the ongoing administration of opiates/opioids.

For example, research by Kuntz, Patel, Grigson, et al. (2008) suggests that egr-1 and c-fos expression [in the medial prefrontal cortex and nucleus accumbens] influences heroin-seeking behavior in rats following 14 days of abstinence.  Furthermore, the researchers mentioned that changes in gene expression following opiate abstinence may determine susceptibility to relapse.  This considered, some may suspect that egr-1 and/or c-fos expression might also influence opiate/opioid-seeking behavior and relapse susceptibility in humans.

If egr-1 and/or c-fos expression influences opiate/opioid-seeking behavior in humans, it’s possible that the modulatory effect of ibogaine upon the expression of each could aid in the attenuation of opiate/opioid cravings and relapse prevention.  That said, at this time it remains unclear as to how ibogaine precisely affects egr-1 and c-fos in humans, as well as whether its modulation of these genes may be of therapeutic value for persons attempting to overcome opiate/opioid addiction.  Moreover, one might consider that egr-1 and c-fos expression could influence the severity of opiate/opioid withdrawal symptoms, as well as that modulation of each with ibogaine could mitigate certain discontinuation symptoms.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/10640697
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/18466961

Substance P system modulator:  Research by Alburges, Ramos, Bush, and Hanson (2000) suggests that ibogaine modulates activity within substance P systems throughout the brain.  Specifically, ibogaine appears to increase concentrations of substance P-like immunoreactivity in the striatum and substantia nigra for over 12 hours post-administration.  Based on this finding, researchers suspect that ibogaine’s interaction with substance P systems might contribute to its hypothesized efficacy in the treatment of opiate/opioid addiction.

According to research by Commons (2010), substance P systems are implicated in the development of opiate/opioid addiction.  It is thought that substance P and its primary receptor neurokinin 1 (NK1) influence behavioral responses to opiates/opioids and the stress that’s associated with the maintenance of opiate/opioid addictions.  Moreover, neurokinin 1 is required for opiates/opioids to facilitate rewarding effects and also plays a role in opiate/opioid sensitization.

For this reason, Commons noted that activity within substance P systems may influence the development of opiate/opioid tolerance and determine one’s vulnerability to opiate/opioid relapse.  Even if ibogaine transiently modulates substance P systems in certain areas of the brain, it’s possible that this may yield a protracted neuroadaptive effect that reduces opiate/opioid cravings and/or attenuates withdrawal symptoms.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/10708715
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/19913520

Brain energy metabolism modulator: A plausible mechanism by which ibogaine may help treat opiate/opioid addiction is through the modulation of brain energy metabolism.  To be clear, alterations in brain energy metabolism that are observed post-ibogaine administration are likely a secondary or downstream effect stemming from its primary interactions with neurotransmitter systems.  In other words, when ibogaine interacts with neurotransmitter systems throughout the CNS, the cumulative set of interactions yields altered brain energy metabolism.

Nonetheless, according to some researchers, altered brain energy metabolism may be among the most relevant of protracted physiologic adaptations to ibogaine ingestion with regard to generating a long-term anti-addiction effect.  Researches note that, because the anti-addiction effect of ibogaine lasts longer than its presence within the body, protracted changes in brain energy metabolism may account for ongoing craving suppression and/or withdrawal symptom attenuation – among ibogaine recipients.

A study by Paskulin, Jamnik, Zivin, et al. (2006) investigated the effect of ibogaine on brain energy metabolism of rats.  To track brain energy metabolism, the researchers assessed protein expression within the rats’ brains at via matrix-assisted laser desorption/ionization-time of flight mass spectrometry – at 24-hours and 72-hours post-ibogaine administration.  Assessments revealed significant changes in protein expression following ibogaine administration, indicative of higher metabolic turnover following ibogaine administration.  Because individuals with substance addictions tend to exhibit abnormalities in brain energy metabolism, and because ibogaine appears to modulate brain energy metabolism, it’s reasonable to consider that this action yields therapeutic benefit in the treatment of opiate/opioid addiction.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/17054944

Note: The significance of physiologic effect derived from ibogaine and noribogaine, respectively, will be subject to variation based upon CYP2D6 function.  Persons with poor CYP2D6 function will incur substantial physiologic modulation from ibogaine and minimal modulation from noribogaine.  On the hand, persons with rapid CYP2D6 function will be subject to greater physiologic modulation from noribogaine and less modulation from the parent (ibogaine).  Because comparative research hasn’t been conducted, it remains unclear as to whether the specific effect of ibogaine is superior to that of noribogaine (or vice-versa) for the treatment of addiction and/or withdrawal symptoms.  Also, while most individuals administer ibogaine orally, alternative modes of administration (e.g. intravenous, subcutaneous, etc.) will likely alter its pharmacodynamics as compared to oral administration, potentially influencing its efficacy in treating opiate/opioid addiction and/or withdrawal symptoms.

How does the mechanism of action of ibogaine compared to noribogaine?

Because no comparative research has been conducted, it’s unclear as to how the mechanism of action associated with ibogaine differs from that of its chief metabolite noribogaine.  Assays suggest that ibogaine binds with highest affinity to sigma-2, mu-opioid, kappa-opioid, sigma-1, and 5-HT3 receptors – whereas noribogaine binds with highest affinity to kappa-opioid and mu-opioid receptors.  Based on respective binding affinities, it’s logical to suspect that noribogaine exerts a physiologic effect primarily via opioid receptors, whereas ibogaine exerts a physiologic effect primarily via sigma, opioid, serotonin, and NMDA receptors.  That said, high binding affinities do not always indicate function – nor relevant function.

Is ibogaine or noribogaine more effective in the treatment of opiate/opioid addiction?

At this time, there are no head-to-head studies comparing the efficacy of ibogaine to that of noribogaine for the treatment of opiate/opioid addiction, thereby making it difficult to determine whether ibogaine or noribogaine is of greater therapeutic relevance in the treatment of opiate/opioid addiction.  Nevertheless, pharmacokinetic studies reveal that, post-administration, ibogaine undergoes extensive first-pass biotransformation via CYP2D6 isoenzymes to form noribogaine.  Due to the extensive first-pass biotransformation of ibogaine, peak plasma concentrations of noribogaine should far exceed those of ibogaine post-administration.

Markedly greater systemic concentrations of noribogaine as compared to ibogaine should yield more substantial physiologic modulation by comparison, and thus, greater therapeutic effect in the treatment of opiate/opioid addiction.  Not only is the degree of physiologic modulation resulting from noribogaine likely greater than that of ibogaine, but so is the duration.  In most humans, the half-life of ibogaine is estimated to range from 4 to 7 hours, whereas the half-life of noribogaine is estimated to range from 28 to 49 hours.

Considering the half-lives of each, we could estimate that physiology would be under the influence of ibogaine and noribogaine for up to 1.6 days and up to 11.23 days, respectively, post-administration.  A longer duration of physiologic influence associated with noribogaine would lead many to hypothesize that noribogaine is of greater importance than the parent compound ibogaine in the treatment of opiate/opioid addiction.  Moreover, if the binding affinities of ibogaine and noribogaine accurately reflect the hierarchy of their physiologic action, a case could be made that the physiologic action of noribogaine would yield more substantial anti-addictive effects than that of its ibogaine parent.

Reflecting upon the fact that noribogaine exerts a more potent, longer-lasting physiologic effect than ibogaine, as well as the fact that it probably exhibits more relevant pharmacodynamics for the treatment of opiate/opioid addiction – most would suspect that noribogaine is of greater importance for the treatment of opiate/opioid addiction as compared to ibogaine.  The only time in which ibogaine may be of greater therapeutic relevance than noribogaine for the treatment of opiate/opioid addiction is among persons with suboptimal CYP2D6 function [in which the CYP2D6-mediated first-pass biotransformation of ibogaine to noribogaine is impaired].  In this case, concentrations of ibogaine would far exceed those of noribogaine (due to lack of noribogaine formation), yielding more substantial and longer-lasting physiologic modulation from ibogaine.

How does a single treatment with ibogaine generate a protracted anti-addiction response?

Due to lack of research, it remains somewhat unclear as to how a single dose of ibogaine could generate a protracted anti-addiction response that persists for days, weeks, months, or years after treatment.  Currently, studies in humans and animal models of addiction indicates that anti-addiction effects of ibogaine are most commonly observed in the acute aftermath of its administration.  The acute anti-addiction effect is likely a byproduct of ibogaine and noribogaine circulating throughout the central nervous system (CNS) and modulating: neurotransmission, signaling cascades, brain activation, gene expression, etc.

It is known that ibogaine and noribogaine can remain in systemic circulation for 22-38.5 hours and 6.42-11.23 days, respectively, after administration.  This considered, one might expect the most potent anti-addiction effects to be observed for up to 11.23 days, or the longest duration noribogaine may remain in systemic circulation.  Perhaps variation among ibogaine users in the durations of acute anti-addiction responses are influenced by the duration over which ibogaine and noribogaine remain in systemic circulation.

Nevertheless, in less than 2 weeks, ibogaine and noribogaine will be fully eliminated from the body and won’t be exerting a physiologic effect.  At this point, most would suspect that, because ibogaine and noribogaine have been eliminated, persons addicted to drugs will relapse.  Though some individuals may relapse once the ibogaine and noribogaine have been eliminated from systemic circulation, others will remain abstinent from addictive substances and report zero cravings.

The ability to maintain abstinence after ibogaine and noribogaine have been eliminated from systemic circulation is likely attributable to sustained physiologic adaptations.  In brief, while circulating throughout your system, ibogaine and noribogaine interacted with a host of neurotransmitter systems and altered numerous signaling cascades.  Though these neurotransmitter systems and signaling cascades are no longer being actively modulated by ibogaine at 2 weeks post-ingestion, their activation will remain altered in comparison to pre-ibogaine administration.

It is the lingering alterations, or protracted ibogaine-mediated physiologic adaptations, that are probably conducive to the maintenance of abstinence.  For those who don’t understand the adaptive response to ibogaine, it may be helpful to think of ibogaine like a tornado and your physiology as a forest.  As the tornado (ibogaine) travels through the forest (your physiology), the entire landscape of the forest remains significantly altered compared to pre-tornado (pre-ibogaine) even though the tornado is long gone (ibogaine has exited the system).

It’s debatable as to how long the protracted ibogaine-mediated physiologic adaptations remain after ibogaine administration.  Some suspect that the protracted physiologic adaptations may persist within physiology for years, whereas others suspect that they are shorter-lived.  That said, it’s likely that for most individuals, endogenous regulators of homeostasis will modulate physiology such that the protracted ibogaine-mediated physiologic adaptations eventually wane.

When these protracted ibogaine-mediated physiologic adaptations wane, individuals may be prone to addiction relapse.  Those who relapse after an extended duration of abstinence post-ibogaine (e.g. months or years) probably reverted back to homeostasis and/or may have also had some synergistic environmental trigger (e.g. seeing an old drug dealer).  However, certain individuals may have developed and maintained such healthy habits post-ibogaine that, even when the protracted ibogaine-mediated physiologic adaptations fade, they are able to maintain abstinence for an indefinite duration (e.g. years) without relapse or need for another ibogaine treatment.

3 Phases of Ibogaine Treatment (Subjective Experience)

Individuals who derive therapeutically-relevant benefit from the administration of ibogaine for the treatment of opiate/opioid addiction and/or withdrawal symptoms usually describe the ibogaine experience as being biphasic or triphasic.  The biphasic or triphasic description stems from the fact that, for relatively similar durations of time following the ingestion of ibogaine, users report transitioning between two or three distinct phases of consciousness.  While the exact subjective experiences of ibogaine users will be individually-nuanced, most report similarities in general experiences during each of the phases.  The three phases of ibogaine treatment are formally categorized as follows: acute, evaluative, and residual.

  • Acute (Visionary): Within the first 1 to 3 hours after ingestion, a user will have entered the acute phase of ibogaine’s physiologic influence. Also referred to as the “visionary” phase, the acute phase can last between 4 to 8 hours.  During the acute phase, most individuals report psychedelic dream-like visuals.  Examples of perceptual changes that may occur during the acute phase include:  color enhancement, color shifting, contact with spiritual entities, dissociation from consciousness, emergence of long-term memories, sensations of floating, hearing voices, visual distortions, and tracers.
  • Evaluative (Introspective): As the acute phase ends, the user enters the evaluative phase of ibogaine’s physiologic impact. The evaluative phase, sometimes referred to as the “introspective” phase, begins approximately 4 to 8 hours after ibogaine administration and can last between 8 and 20 hours.  Upon entering the evaluative phase, psychedelic visuals decrease, and many users report feeling emotionally neutral, balanced, or stable.  Emotional neutrality is accompanied by enhanced introspection whereby individuals calmly reflect upon the acute phase (e.g. psychedelic visuals) and long-term memories that may have emerged.
  • Residual: Between 20 and 24 hours after ibogaine ingestion, the evaluative phase of ibogaine’s physiologic impact will diminish and individuals will enter the residual phase. The residual phase is thought to last between 24 and 72 hours following ibogaine ingestion.  During this phase physiology will undergo more substantial homeostatic reversion, thus exhibiting homeostasis to a greater extent than in the evaluative phase.  As a result, excessive internal focus diminishes, individuals regain awareness of their external surroundings, and cognition normalizes.  In the residual phase, it is common to experience increased physiologic arousal, decreased need for sleep (for days or weeks), and lingering mild psychoactive effects.

Upon transitioning out of the residual phase and back to normative homeostatic physiology (i.e. consciousness), many individuals will testify that the ibogaine experience was psychologically transformative.  In many cases, the desire to utilize addictive substances completely ceases and/or withdrawal symptoms associated with the discontinuation of an addictive substance either diminish or become easier to manage.  The therapeutic effect of ibogaine is often attributed to intense self-reflection, dealing with emotional traumas, spiritual awakenings, or mystical experiences.

Despite the commonly-reported therapeutic benefit derived from ibogaine in the immediate days or weeks after treatment, a subset of ibogaine users will revert back to usage of an addictive substance.  This may be due to the fact that physiology eventually transitions back to homeostasis, which in turn, reignites the high propensity to use addictive substances.  For another subset of individuals, ibogaine will alter physiology enough to help them overcome a substance addiction for an extremely long-term duration, or perhaps permanently.

There are a few potential reasons as to why someone may derive long-term or permanent therapeutic benefit from the usage of ibogaine to treat a substance use disorder.  It’s possible that, for a subset of users, ibogaine permanently alters physiology in such a way as to inhibit substance cravings indefinitely.  However, what’s more likely is that ibogaine treatment leaves a user’s physiology altered post-treatment in such a way as to suppress cravings and decrease withdrawal symptoms for a finite duration.

Although the ibogaine-induced physiologic alterations attributable to craving suppression are not permanent, the acute suppression that occurs post-treatment is sufficient as to disrupt the vicious circle of addiction.  While cravings are suppressed, the individual may feel motivated or empowered to make positive changes such as:  cutting ties with drug dealers and/or friends who use drugs, eradicating drug-associated stimuli, recalibrating one’s social circle, engaging in healthier activities to replace the prior drug use (e.g. working out), and/or changing one’s environment (e.g. relocating).  As these positive changes are implemented post-ibogaine and sobriety is maintained, a person builds momentum.

Each additional day of abstinence post-ibogaine treatment makes it easier for the former substance addict to maintain sobriety.  When sobriety is maintained for a long enough duration, many may never reconsider reinitiating substance use.  Moreover, it’s fair to hypothesize that sobriety may be easiest to maintain for persons who carry genes that are protective against addiction, giving them a substantial genetically-mediated physiologic advantage compared to persons exhibiting an overt genetic predisposition to substance addiction – in the aftermath of ibogaine treatment.  Genetic propensity to a particular addiction probably explains why certain individuals are able to maintain sobriety indefinitely and why others relapse after ibogaine treatment.

Ibogaine for Opiate Addiction and Withdrawal (Research)

As an intervention for the treatment of opiate dependence, ibogaine was first tested in 1955 by Dr. Harris Isbell at the Federal Narcotic Hospital in Lexington, Kentucky.  Isbell reportedly administered ibogaine at dosages up to 250 mg to 8 individuals with a history of morphine dependence.  However, because the 8 participants in Isbell’s trial had been abstinent from opiates for a 6-month period prior to the trial, and the dosage of ibogaine administered was likely subtherapeutic, no benefit was observed following its administration.

In 1962, Howard Lotsof and a group of his friends, each of whom were addicted to heroin, administered ibogaine at dosages from 6 mg/kg to 19 mg/kg.  After the ibogaine experience, Lotsof and his friends reported substantial reductions in heroin cravings and fewer heroin detoxification symptoms.  This experience and further investigation would convince Lotsof that ibogaine was of therapeutic value in the treatment of opiate addiction, leading him to purchase ibogaine tablets for the initiation of clinical trials and patent ibogaine in 1985 for the treatment of opiate withdrawal.

By 1988, other researchers had published results from placebo-controlled experiments in which ibogaine appeared efficacious for the attenuation of opiate withdrawal symptoms in animal models.  Between 1988 to 1993, results of additional preclinical studies provided additional support for the therapeutic efficacy of ibogaine in the management of dependence to morphine, cocaine, and alcohol.  Due to the promising preliminary findings, the National Institute on Drug Abuse (NIDA) introduced an ibogaine project in 1991 with the intent of collecting toxicological data, forming treatment guidelines, and organizing clinical trials.

However, by 1993, the ibogaine project was suspended due to inadequate funding, and in 1995, the project was completely terminated due to lack of funding and recommendations from pharmaceutical representatives.  Nevertheless, from the 1980s throughout the 2000s, independent research of ibogaine for the treatment of addiction continued.  To know whether ibogaine is likely to be safe and effective for the treatment of opiate addiction and/or withdrawal, it is necessary to evaluate relevant data from the scientific literature.  Included below are brief summaries of trials and discussions in which ibogaine was investigated.

2016: The anti-addictive effects of ibogaine: A systematic literature review of human studies.

Dos Santos, Carlos Bouso, and Hallak (2016) acknowledged that there’s mounting preliminary evidence in support of ibogaine’s efficacy for the treatment of substance dependence and withdrawal symptoms.  However, despite this preliminary evidence, no systematic reviews had been conducted to critically examine the quality of existing human studies and their findings.  For this reason, researchers opted to conduct a systematic review of human studies to determine the strength of evidence in support of ibogaine for the treatment of substance dependence and withdrawal symptoms; the results were published in the Journal of Psychedelic Studies.

The systematic review involved conducting a literature search in scientific databases (e.g. PubMed) for human studies published prior to July 2016 in which the anti-addictive effects of ibogaine were assessed.  To be included in the review, studies needed to be either case reports or clinical studies published in peer-reviewed journals OR derived from books in scientific databases.  In their search, researchers identified 259 studies, however, just 8 of these met necessary inclusion criteria for the review.

Of the 8 studies that met inclusion criteria, 7 were classified as open-label case series, and just 1 was a randomized controlled trial.  Results from the 7 case series indicates that ibogaine or noribogaine significantly attenuates symptoms of opiate/opioid withdrawal for a protracted duration [of days] post-ingestion.  Moreover, documentation from the 7 case series suggests that ibogaine can significantly decrease substance cravings and self-administration among persons with a history of substance dependence, and that these reductions may be sustained for days, weeks, or months – depending on the individual and number of treatments.

That said, results from the standalone randomized controlled trial indicated that noribogaine was ineffective for the treatment of opiate/opioid withdrawal symptoms as compared to a placebo.  In this trial, however, researchers speculate that utilization of subtherapeutic noribogaine doses may have been to blame for its inefficacy.  Because data from 7 case studies support the efficacy of ibogaine, there are clearly more data supporting ibogaine as a treatment for substance addiction and withdrawal symptoms – than data that do not support its efficacy.

However, the quality of data from the 7 case studies is relatively low (due to lack of randomization and controlling) compared to the quality of data from the standalone randomized controlled trial.  Predictably, the researchers recommend interpreting preexisting data regarding ibogaine’s efficacy [as a treatment for substance dependence and/or withdrawal symptoms] with caution, emphasizing that further well-designed (randomized controlled trials) are needed to better elucidate its efficacy.

  • Source: http://www.akademiai.com/doi/pdf/10.1556/2054.01.2016.001

2016: Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

The first double-blind, randomized, placebo-controlled clinical trial of noribogaine (ibogaine’s active metabolite) was conducted by Glue, Cape, Tunnicliff, et al. (2016).  The aim of the trial was to evaluate the safety, tolerability, and pharmacokinetics of noribogaine, as well as its ability to treat opioid withdrawal symptoms.  For trial participation, researchers recruited 27 individuals (21 male / 6 female) with a history of opioid dependence that had been receiving methadone maintenance therapy.

Approximately 1-week prior to the trial, it was noted that all 27 participants had been switched from methadone to morphine.  The reason participants were switched from methadone to morphine had to do with the fact that methadone stays in your system for much longer after its discontinuation [as compared to morphine].  By switching participants from methadone to morphine 1-week before the trial, researchers could ensure that a majority of methadone would be eliminated from systemic circulation among participants.

This was a necessary action because, had participants abruptly discontinued methadone prior to receiving ibogaine, many may have reported no withdrawal symptoms due to lingering methadone in systemic circulation, thus confounding the results.  It was noted that a majority of methadone (91%) had been cleared from systemic circulation among participants prior to initiation of the trial.  Initiation of the trial involved assigning 27 participants to receive single noribogaine doses (60 mg, 120 mg, 180 mg) or a placebo control.

To determine the effect of noribogaine on withdrawal symptoms, researchers assessed changes in baseline recordings of pupillometry (pupil diameter), oximetry (blood oxygen / volume), and capnography (respiratory carbon dioxide pressure) to recordings collected at various post-treatment intervals.  In addition, withdrawal symptoms were assessed via post-treatment changes in scores on the Subjective, Objective, and Clinical Opioid Withdrawal Scales (SOWS, OOWS, COWS).  Researchers also documented the amount of time it took for patients to resume methadone maintenance therapy following their last morphine dose.

Results of the trial suggested that noribogaine was ineffective for the attenuation of opioid withdrawal symptoms.  Noribogaine failed to significantly reduce scores on the SOWS, OOWS, and COWS, and did not increase time between final morphine dose and methadone reinitiation.  Still, somewhat intriguing was the finding that recipients of the highest noribogaine dosage (120 mg) exhibited the greatest durations of time between final morphine dose and methadone reinitiation – and also the lowest scores on opiate/opioid withdrawal scales.

Measures of safety and tolerability suggested that noribogaine was well-tolerated and no hallucinations were reported.  The most common adverse reactions to noribogaine included:  sensitivity to bright light, headache, and nausea.  At the highest dose, a safety concern emerged such that recipients of 180 mg exhibited significant QT interval prolongation – increasing risk of cardiac arrhythmia and/or death.

Based on the results of this trial, it’s fair to suspect that noribogaine may be ineffective for the treatment of opioid withdrawal symptoms.  That said, there are numerous limitations associated with this trial including: usage of noribogaine (as opposed to ibogaine); lack of a psychedelic effect (this may be therapeutically valuable); dosage of noribogaine (likely too low); transition from methadone to morphine (could’ve been extended to 2 weeks); small sample size (27 participants); and certain aspects of the study design.  Until these limitations are addressed, the effectiveness of noribogaine for the treatment of opioid withdrawal symptoms will remain unclear.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/27870477

2016: Remission of Severe Opioid Use Disorder with Ibogaine: A Case Report.

Cloutier-Gill, Wood, Millar, et al. (2016) underscored the fact that opioid use disorders (OUD) typically compromise health, social relationships, and finances of those diagnosed.  Furthermore, the authors noted that while opioid agonists (i.e. replacement therapies) can aid in the management of opioid use disorders, many persons with opioid use disorders derive insufficient benefit from these interventions.  For this reason, the authors acknowledge that alternative interventions are warranted, and that one such [potentially-efficacious] alternative is ibogaine.

The team of authors Cloutier-Gill, Wood, Millar, et al. published a case report in which a 4-day ibogaine treatment helped a 37-year-old female with a 19-year history of severe opioid use disorder maintain abstinence from opioids for an 18-month duration.  Prior to this, the patient’s longest duration of abstinence from opioids was a 2-month duration while undergoing methadone maintenance therapy.  Moreover, it was noted that the patient had repeatedly attempted to overcome her addiction with interventions such as:  12-step programs, inpatient detoxification centers, support groups, recovery houses, and opioid replacement therapies – none of which proved effective over a long-term.

It was noted [in the case report] that the patient received ibogaine treatment for her opioid use disorder at a residential ibogaine center in Vancouver.  It was further noted that the patient had ingested hydromorphone (16 mg) within 12 hours of entering the center.  While at the center, the patient received ibogaine hydrochloride (HCl) administered at: test doses (up to 2.5 mg/kg) on Day 1, large doses (up to 20 mg/kg) on Day 2, and “booster” doses (5 mg/kg) on Day 3 and Day 4 – for a cumulative dose of 2300 mg over a 4-day duration.

Authors of the case report mentioned that usage of hydromorphone was permitted at the center to attenuate acute detoxification symptoms, and that hydromorphone was ingested by the patient on Day 1 (32 mg) and Day 2 (45 mg).  Although food and a quiet resting space were provided for the patient at the center, neither psychotherapy nor counselling were offered.  The patient exhibited various side effects from the ibogaine treatment such as: bradycardia, weakness, dizziness, poor concentration, and sweating, however, these eventually subsided.

At a follow-up evaluation with medical professionals, the patient cited an ibogaine-induced “spiritual awakening” the primary reason for her recovery from opioid use disorder.  The awakening was said to have: involved revisiting and reflecting upon important life events, provided insight regarding the severity of her opioid use disorder, and improved her emotional status.  Based on this case report, it’s reasonable to suggest that ibogaine may be a safe, tolerable, and effective treatment for a subset of persons with refractory opioid use disorder.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/27192438

2016: Ibogaine and addiction in the animal model, a systematic review and meta-analysis.

A systematic review and meta-analysis were conducted by Belgers, Leenaars, Homberg, et al. (2016) to determine the safety and efficacy of ibogaine for the treatment of addiction in animal models.  For reference, a systematic review involves compiling and critically analyzing all relevant quality trials – then discussing the overarching findings, and the meta-analysis component involves combining statistical data from those trials.  Within the introductory section of this review, authors noted that usage of ibogaine has been steadily increasing as an alternative intervention for the management of substance use disorders.

Moreover, authors mentioned that, despite a shortage of human trials involving ibogaine, many trials have been conducted to test its efficacy in animal models of addiction – hence the impetus for this systematic review.  In this systematic review, researchers assessed ibogaine’s efficacy in treating substance use disorder, its toxic effects, and its neurobiological effects – among animal models.  The efficacy of ibogaine in the treatment of substance use disorder among animals was determined using paradigms of drug self-administration (SA) and drug-induced conditioned place preference (CPP).

Self-administration paradigms are thought to measure the reinforcing effects of drugs, and sometimes the pattern and/or motivation of drug seeking behavior or administration – whereas conditioned place preference (CPP) paradigms are thought to measure rewarding value of drugs and whether associations are formed between this reward and its context.  The toxicity of ibogaine in animal models was determined via assessment of motor function, cerebellar cell loss, and cardiac function.  Additionally, the neurobiological effects of ibogaine were determined based upon ibogaine-mediated modulation of dopaminergic and/or serotonergic transmission.

Dopaminergic and serotonergic transmission were specifically analyzed because each system is causally implicated in substance use disorders.  For the review, researchers initially conducted a scientific literature search and compiled all relevant animal model studies published up until November 2014.  While hundreds of relevant articles had been published in the scientific literature, only 30 articles [containing 32 studies] met inclusion criteria for the systematic review.

Of the aforementioned 32 studies: 11 were relevant for the analysis of self-administration and conditioned place preference paradigms; 19 were relevant for the analysis of ibogaine toxicity; and 2 were relevant for the analysis of neurobiological effects.  Analysis of self-administration paradigm data indicated that ibogaine decreased self-administration of opioids, cocaine, and alcohol in animals for over 3 days post-ingestion.  Analysis of toxicological data indicated motor impairment [for 24 hours] following ibogaine ingestion and loss of cerebellar neurons [observed months after administration].

Authors of the review concluded that ibogaine appears to facilitate long-lasting decreases in the self-administration of addictive drugs among animal models of substance use disorder.  Although concerns remain regarding adverse potential adverse reactions (e.g. neuronal loss, cardiac irregularities, etc.), findings of the review are consistent with preclinical human reports in which ibogaine administration suppresses drug cravings among persons with a history of addiction.  Nevertheless, further research is needed in animal models and humans to: pinpoint all risks of ibogaine administration, elucidate the neurobiological effects by which ibogaine attenuates addiction, develop optimal dosing parameters, and gauge the reliability and significance of therapeutic benefit.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/27244235

2016: Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents.

Mash, Ameer, Prou, et al. (2016) conducted a series of three experiments to determine the effect of ibogaine’s chief metabolite “noribogaine” on animal models of substance use disorders.  In the first experiment, researchers tested ibogaine in a group of mice that had been subject to chronic morphine administration.  After chronic morphine administration, the mice received oral noribogaine followed by subsequent administration of naloxone [2 hours later] to induce withdrawal.

Results of the first experiment indicated that noribogaine dose-dependently attenuated global opiate withdrawal scores in the mice by up to 88% and that the median effective dose was 13 mg/kg.  In the second experiment, researchers sought to measure noribogaine concentrations in the blood and brains of mice.  Results of the second experiment revealed a brain to blood ratio of approximately 7 for noribogaine, regardless of the dosage, indicating that noribogaine efficiently crosses the blood-brain-barrier.

In the third experiment, the abuse potential of oral noribogaine was evaluated in rats using a conditioned place paradigm (CPP).  After receiving oral noribogaine at dosages up to 100 mg/kg, rats did not exhibit place preference, indicating that noribogaine was not rewarding and therefore unlikely to be a drug of abuse.  Based on results of the aforementioned series of experiments, researchers suggested that the therapeutic efficacy of ibogaine for the treatment of opiate withdrawal symptoms may be mostly attributable to its noribogaine metabolites.

Moreover, researchers concluded that noribogaine appears promising as a non-addictive alternative to conventional opiate replacement medications for the treatment of opiate dependence.  Still, it should be emphasized that the safety and efficacy of standalone noribogaine in animal models may differ from that of humans.  Nevertheless, this trial supports the therapeutic potential of ibogaine for the treatment of opiate withdrawal.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/27044509

2014: Treating drug dependence with the aid of ibogaine: a retrospective study.

Schenberg, de Castro Comis, Chaves, and da Silveira (2014) mention that while ibogaine is hypothesized as efficacious for the treatment of drug addictions, its efficacy has been difficult for researchers to gauge.  Difficulty gauging the efficacy of ibogaine for the treatment of drug addictions is partly attributable to its classification as an illicit substance throughout certain countries – including the United States.  Its illicit status leads individuals with addictions [who wish to use ibogaine] to seek ibogaine treatment in covert settings devoid of professional medical personnel and data collection.

For this reason, there are few published case reports in which patient history, dosing protocol, safety, and efficacy – are discussed.  That said, researchers underscored the fact that ibogaine remains an unregulated substance in various countries, one of which is Brazil.  Throughout Brazil, ibogaine is commonly utilized as part of a multifaceted treatment for drug addiction with concomitant medical supervision and concurrent psychotherapy.

Knowing that ibogaine is legally utilized in Brazil, researchers opted to conduct a retrospective analysis of patients who underwent and completed ibogaine treatment in this country.  A total of 75 patients were included in the retrospective analysis and presented addictions to a variety of substances including:  alcohol, cannabis, cocaine, and crack.  Results of the retrospective analysis indicated that 61% of patients attained abstinence following ibogaine treatment.

It was further noted that patients who received a single ibogaine treatment remained abstinent for over 5 months, whereas persons who received multiple ibogaine treatments remained abstinent for over 8 months.  None of the patients experienced severe adverse reactions or death as a result of the treatment.  Predictably, researchers concluded that the administration of ibogaine [under professional medical supervision] with concomitant psychotherapy appears safe and effective over a long-term for the treatment of substance addiction.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/25271214

2013: Ibogaine in the treatment of substance dependence.

An article by Brown from 2013 discusses ibogaine as an intervention for substance dependence.  Brown highlights the fact that, because ibogaine is classified as a “Schedule I” drug in many countries (including the United States), few controlled trials have investigated its efficacy as a treatment for substance dependence.  Additionally, due to the fact that ibogaine is an illicit substance, persons who wish to use it as an intervention for substance dependence will pursue treatment outside of mainstream medical settings.

For this reason, cases of persons who receive ibogaine-based therapies to treat substance dependence are not formally documented and/or won’t be published in the medical literature.  Also, according to Brown, further research and controlled trials of ibogaine have been largely stymied by safety concerns.  Nonetheless, Brown notes that results of preliminary research of ibogaine [for the treatment of substance dependence] supports anecdotal accounts of individuals who claim that it effectively mitigates cravings and/or withdrawal symptoms – associated with addictive substances.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/23627782

2008: Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review.

Maciulaitis, Kontrimaviciute, Bressolle, and Briedis (2008) conducted a review attempting to pinpoint the pharmacodynamics of ibogaine [and its chief metabolite noribogaine] as they pertain to treating addiction.  In the review it was noted that the psychoactive properties of ibogaine have been understood for decades, yet its pharmacodynamics remained unelucidated.  One reason its pharmacodynamics never received much attention nor investigation may have been due to initial perceptions that ibogaine was devoid of medicinal value.

However, from the 1960s through the 1990s, reports from ibogaine users began surfacing, many of which claimed that ibogaine effectively cured drug addictions.  Thereafter, trials with ibogaine in animal models of substance dependence were conducted, most of which observed anti-addictive effects following its administration.  Within this review, researchers reported that ibogaine interacts with a variety of neurotransmitter systems, and that these interactions may yield reductions in drug cravings and/or withdrawal symptoms.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/18650249

1999: Treatment of acute opioid withdrawal with ibogaine.

Alper, Lotsof, Frenken, et al. (1999) report that ibogaine is allegedly effective for the management of symptoms associated with opioid discontinuation.  The researchers examined 33 cases in which individuals underwent ibogaine treatment [in non-medical settings] to aid in detoxification from opioids.  Across the 33 cases, researchers noted that average heroin dosage prior to detoxification was approximately 0.64 grams per day – (usually) administered via intravenous injection.

In 25 of the 33 cases (~75.8%), symptoms of opioid withdrawal ceased and drug seeking behavior subsided within 24 hours of ibogaine treatment.  Furthermore, in these 25 cases, cessation of opioid withdrawal symptoms and inhibition of drug seeking behavior were maintained throughout a 72-hour post-treatment period in which individuals were monitored.  Of the remaining 8 cases, a variety of outcomes were observed including: drug seeking behavior without withdrawal (4 individuals); reduced withdrawal symptoms without drug seeking behavior (2 individual); drug seeking behavior and withdrawal symptoms (1 individual); and death (1 individual).

Considering these results, it appears as though ibogaine is highly effective for the treatment of opioid withdrawal symptoms and drug addiction.  Additionally, it appears as though the therapeutic effect of ibogaine persists beyond 72-hours [for most individuals].  However, because this was not a double-blinded, randomized, nor controlled trial – it’s possible that responses (or a subset of responses) to ibogaine may have been mediated by a placebo effect.

Moreover, even if ibogaine is legitimately effective for the treatment of opioid withdrawal and addiction, concerns about its safety remain as a result of the death that occurred in one of the cases.  Although researchers suspect that this individual’s death was attributable to covert heroin usage rather than ibogaine, toxicological reports suggest that ibogaine could be toxic to humans (or a subset of humans), and thus, its administration could prove fatal.  The possibility of death is a serious concern and further research in animal models should explore ways to minimize this risk.  That said, this analysis of 33 case reports supports the idea that ibogaine could be effective for persons attempting to overcome opioid addiction.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/10506904

1995: Attenuation of alcohol intake by ibogaine in three strains of alcohol-preferring rats.

Rezvani, Overstreet, and Lee (1995) conducted a series of experiments to determine the effect of ibogaine on alcohol intake in rats.  Several groups of rats were utilized for these experiments including: alcohol-preferring (P), Fawn-Hooded (FH), and alcohol-accepting (AA).  In the first experiment, rats received either:  ibogaine (10 mg/kg, 30 mg/kg, 60 mg/kg) OR a vehicle – intraperitoneally (IP) or subcutaneously (SC).

In the second experiment, Fawn-Hooded (FH) rats received either: Ibogaine (60 mg/kg) or a vehicle – intragastrically (IG) – for a 5-day period.  Results of the first experiment indicated that intraperitoneal (IP) ibogaine administration led to dose-dependent reductions in alcohol intake among rats, however, this was not observed following subcutaneous (SC) administration.  Results of the second experiment indicated that that subchronic administration of intragastric (IG) ibogaine [at a dosage of 60 mg/kg in Fawn-Hooded (FH) rats] yielded significant reductions in alcohol intake of the rats without affecting feeding/drinking habits.

Based on these results, researchers hypothesized that ibogaine modulates neurotransmission in ways that are conducive to reducing alcohol intake.  Although these findings cannot be extrapolated to humans, this study provides preliminary evidence that ibogaine could prove efficacious as an intervention in the management of alcohol dependence.  Moreover, considering the fact that ibogaine treatment could help reduce alcohol intake, it’s reasonable to suspect that it might also help reduce intake of other addictive substances – possibly via modulation of brain regions implicated in craving and/or reward.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/8545483

1993: Inhibitory effects of ibogaine on cocaine self-administration in rats.

Cappendijk and Dzoljic (1993) sought to investigate the anti-addictive properties of ibogaine in animal models of substance addiction.  Experiments were organized in which rat models of cocaine self-administration received ibogaine.  Following a single intraperitoneally-administered ibogaine dose of 40 mg/kg, cocaine intakes among the rats had significantly decreased.

Following the repeated administration of ibogaine for 3 consecutive days (40 mg/kg/day), cocaine intake among the rats had also significantly decreased.  That said, the most significant reduction in cocaine intake was observed following the administration of ibogaine once per week for 3 consecutive weeks (40 mg/kg/week).  Given the findings in these experiments, researchers concluded that ibogaine (and/or its metabolites) appear to attenuate cocaine dependence with protracted therapeutic effect.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/8243561

1991: Effects and aftereffects of ibogaine on morphine self-administration in rats.

In the late 1980s, anecdotes circulated suggesting that ibogaine may be effective for the treatment of drug addiction in humans.  These anecdotes prompted Glick, Rossman, Steindorf, et al. (1991) to organize a preclinical study assessing the effect of ibogaine in animal models of substance addiction.  For this study, researchers utilized rat models of [intravenous] morphine self-administration and administered ibogaine at various dosages (2.5 mg/kg to 80 mg/kg).

Results indicated that a single ibogaine injection significantly reduced morphine self-administration for a 1-hour period.  Furthermore, reductions in morphine self-administration appeared to be contingent upon ibogaine dosing such that larger doses yielded more substantial reductions in morphine intake than smaller doses.  It was noted that reductions in morphine self-administration among the rats were maintained for 1-day after the single ibogaine injection.

That said, reductions in morphine self-administration observed in the day after the single ibogaine injection were less significant than those observed within the first hour of injection.  What’s more, a subset of rats exhibited protracted reductions in morphine self-administration that persisted for durations ranging from several days to weeks – after the single injection.  Other rats required 2 or 3 weekly ibogaine injections to exhibit protracted reductions in morphine self-administration.

It was also noted that, for reasons unknown, a small percentage of rats exhibited no sustained reductions in morphine self-administration after ibogaine injections.  Researchers concluded that ibogaine appears to elicit an effect that may attenuate morphine reinforcement.  While results of this study cannot be extrapolated to humans, they align somewhat with anecdotal reports of humans claiming that ibogaine ingestion led to fewer drug cravings.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/1868880

1988: Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats.

The first study to formally document the therapeutic potential of ibogaine for the treatment of substance withdrawal was conducted by Dzoljic, Kaplan, and Dzoljic (1988).  At the time, researchers utilized morphine-dependent rats and administered ibogaine intracerebroventricularly (injecting into ventricles of the brain) at dosages of 4 mcg to 16 mcg.  Following the intracerebroventricular injections of ibogaine, researchers administered naloxone to the rats.

Naloxone is a drug that functions as a mu-opioid receptor (MOR) antagonist, and when administered to morphine-dependent rats (or humans), it induces withdrawal symptoms.  The aim of researchers was to determine whether ibogaine could attenuate naloxone-precipitated withdrawal.  Results suggested that ibogaine significantly reduced a subset of naloxone-precipitated withdrawal symptoms, particularly those associated with locomotion.  These results supported the idea that ibogaine may be useful for the attenuation of opiate withdrawal symptoms.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/3233054

Limitations associated with the research of Ibogaine for opiate/opioid addiction and withdrawal

There are numerous limitations associated with the research of ibogaine for the treatment of opiate/opioid addiction and/or symptoms of withdrawal.  Perhaps the most substantial limitation is that, as of current, zero randomized controlled trials have been conducted in which the safety and efficacy of ibogaine were evaluated for the treatment of substance use disorders in humans.  In addition to the lack of randomized controlled trials, other striking limitations associated with the research include: dosing protocols, lack of long-term follow-up assessments, and small sample sizes.

  • Dosing protocols: In terms of dosing and/or administration of ibogaine, there are no consistent protocols that have been developed for the treatment of opiate/opioid addiction and withdrawal. Although ibogaine appears useful at dosages between 6 mg/kg and 29 mg/kg (based on body weight) and 500 mg to 800 mg (fixed doses), the optimal safe and therapeutic dosage range for a majority of users remains unknown.  It is also unclear as to whether multi-dose ibogaine protocols are superior to single-dose protocols.  Preliminary evidence suggests that multi-dose protocols may yield longer-term benefit than single-dose protocols.  Moreover, in the only randomized controlled trial testing noribogaine as a treatment for opiate withdrawal symptoms, it is thought that a subtherapeutic dosage of noribogaine was administered.  Assuming the dosage of noribogaine was subtherapeutic, this would explain the insignificant opiate withdrawal symptom reduction among recipients.
  • Follow-up assessments: When investigating the efficacy of ibogaine for the treatment of substance use disorders and/or withdrawal symptoms, it may be important to gauge the average duration over which recipients derive therapeutic benefit. Knowing the average duration of therapeutic benefit may allow patients and/or practitioners to implement safeguards to prevent substance use disorder relapse – upon decline of the therapeutic effect.  Some currently-published trials have conducted follow-up assessments several months after ibogaine administration, however, no studies have conducted follow-up assessments over a year after ibogaine administration.  Because therapeutic benefit is often observed in follow-up assessments conducted several months after ibogaine administration, it’s reasonable to suspect that average duration of therapeutic benefit might exceed several months.  Moreover, a case report in which a follow-up assessment was conducted 18 months after ibogaine treatment suggests that duration of therapeutic benefit may exceed a year for some users.  Conducting longer-term follow-up assessments post-ibogaine treatment are needed in future studies.
  • Human research: While many studies have evaluated the safety and efficacy of ibogaine in animal models of substance use disorders, very little research has been conducted in humans. As of 2017, there are 8 studies in which the effect of ibogaine was evaluated in humans as a treatment for substance dependence and/or withdrawal.  Of these 8 studies, just 1 was a legitimate randomized controlled trial.  Unless more research is conducted in humans, the safety and efficacy of ibogaine for the treatment of opiate/opioid addiction and/or withdrawal shall remain unclear.
  • Ibogaine vs. Noribogaine: While most research involved evaluating the safety and efficacy of ibogaine for the treatment of opiate/opioid addiction and withdrawal, a subset of research utilized noribogaine instead. In fact, the only randomized controlled trial conducted prior to 2017 involved noribogaine as opposed to ibogaine.  Clearly more evidence from human trials supports the usage of ibogaine hydrochloride for the treatment of opiate/opioid addiction than the usage of noribogaine.  A limitation is that the safety and efficacy of ibogaine haven’t been compared to that of noribogaine for the treatment of opiate/opioid addiction.  It may turn out that one substance is unexpectedly safer and/or more effective than the other.
  • Incentive: Another dilemma is that there’s little incentive to continue research of ibogaine as a treatment for opiate/opioid addiction. Because ibogaine cannot be patented and sold for a significant profit, pharmaceutical companies are not financially motivated to investigate its safety and efficacy in large-scale randomized controlled trails.  In addition, researchers would need to allocate significant funds and time to independently evaluate ibogaine.  Many may be unable to afford to conduct a trial of ibogaine for the treatment of opiate/opioid addiction or may perceive a trial of ibogaine an inefficient use of time.  Moreover, there are many novel treatments for opiate/opioid addiction on the horizon with greater financial incentive and/or therapeutic potential as compared to ibogaine.  Ibogaine is also a Schedule I controlled-substance and dangers or risks of adverse reactions may disincentivize its investigation.
  • Recipient demographics: Among case reports in which ibogaine was administered for the treatment of substance dependence and/or discontinuation, there is significant heterogeneity among recipients.  Due to the heterogeneity, it is difficult to determine safety and efficacy of ibogaine specific demographics.  It may turn out that the most effective dose of ibogaine for persons with heroin addiction differs from that of individuals with methadone addiction.  It may also be that ibogaine is only useful in specific demographics.  For this reason, researchers may benefit from conducting studies with more homogenous ibogaine recipient demographics such as: similar addictions (drug / severity) and CYP2D6 function.
  • Sample sizes: Another limitation associated with trials of ibogaine for opiate/opioid addiction and withdrawal is that small sample sizes are utilized. The largest sample size utilized thus far in an open-label trial testing ibogaine for the treatment of opiate/opioid addiction and withdrawal is 33 participants.  The largest sample size utilized thus far in a controlled trial testing ibogaine’s metabolite noribogaine was 27 participants.  Most trials consist of fewer than 10 participants or are case reports with just 1 participant.  Small sample sizes yield underpowered results and increase the likelihood that findings won’t apply to the general population.
  • Trial designs: Most human trials in which ibogaine was administered for the treatment of opiate/opioid addiction and/or discontinuation symptoms – implemented open-label designs devoid of randomization, controlling, and blinding. Without randomization, controlling, and blinding – it is impossible to prove that ibogaine treatment is reducing cravings and/or attenuating withdrawal symptoms.  Lack of randomization, controlling, and blinding means that any reported therapeutic benefit may be attributable to a placebo effect or observer bias.

Is ibogaine safe and effective for the treatment of opiate/opioid dependence and withdrawal symptoms?

Possibly.  Based on currently-available scientific research in which the efficacy of ibogaine and noribogaine were evaluated for the treatment of opiate/opioid addiction and withdrawal symptoms, it appears as though ibogaine may be a safe and effective treatment for a subset of individuals.  In fact, nearly all data from animal model studies and human case reports are unanimous in suggesting that ibogaine is effective and safe for a majority of recipients.  However, it is important to emphasize that just because ibogaine appears safe and effective in animal models of addiction does not mean that its safety and efficacy can be extrapolated to humans.

Moreover, the observation that ibogaine appears safe and effective in human case reports yields insufficient evidence as to endorse its utility in clinical settings.  Because outcomes in case reports could’ve been influenced by placebo effects or observer biases, we should not automatically assume that ibogaine is safe and effective in the treatment of opiate/opioid addiction and/or withdrawal.  Finally, it should be noted that there was a standalone randomized controlled trial in which the effect of noribogaine was assessed among persons subject to opioid withdrawal.

In the aforementioned randomized controlled trial, noribogaine was reportedly ineffective for the treatment of withdrawal symptoms.  Although there were some notable flaws associated with this randomized controlled trial, the fact that it implemented a randomized controlled design strengthens the quality of its finding.  Because the finding of this randomized controlled trial contradicts results of case reports, it’s presently impossible to definitively know whether ibogaine and noribogaine are likely to be safe and effective for the treatment of opiate/opioid addiction and/or withdrawal symptoms.

Nevertheless, some believe that the randomized controlled trial utilized a subtherapeutic dosage of noribogaine which would explain its lack of efficacy.  Considering the animal model data, case reports in peer-reviewed journals, and numerous anecdotes suggesting that ibogaine is safe and effective for the treatment of opiate/opioid addiction and/or withdrawal symptoms – as well as the fact that it makes logical sense that specific mechanisms of ibogaine’s action would treat addiction – it’s reasonable to suspect that a subset of persons with opiate/opioid addiction and/or withdrawal symptoms will derive benefit from ibogaine.  That said, further research is warranted to confirm ibogaine’s hypothesized benefit.

Frequently Asked Questions (FAQs): Ibogaine for Opiate/Opioid Addiction and Withdrawal

Below are some frequently asked questions associated with using ibogaine for the treatment of opiate/opioid addiction and withdrawal.  Understand that the answers to these questions may be incomplete and should not be considered professional medical advice.  If you are considering ibogaine as an intervention for a particular medical condition and/or have questions, contact a medical professional – preferably one with knowledge of ibogaine.

Who are the ideal candidates to receive ibogaine treatment?

It is understood that certain individuals are better suited to receive ibogaine treatment for addiction and/or withdrawal symptoms than others.  Individuals who are devoid of serious health problems should be at lowest risk of experiencing adverse reactions to ibogaine and thus should be best suited to receive it for treatment.  Specifically, persons: with low risk of cardiac abnormalities and/or neuropsychiatric complications; who don’t use medications and/or supplements with which ibogaine may interact; and with normative CYP2D6 expression – are less likely to experience adverse reactions, and thus would be ideal candidates for ibogaine treatment.  Moreover, persons who’ve used ibogaine in the past and derived benefit without serious side effects might also be ideal candidates for treatment.

  • Adults: Middle-aged adults are likely best suited for receiving ibogaine compared to pediatrics, younger adults, and/or elderly persons. Because middle-aged adults generally exhibit fully developed brains and nervous systems, ibogaine will not alter the trajectory of CNS development.  If administered to pediatrics or younger adults, there’s a chance that ibogaine administration may yield permanent and/or long-lasting deleterious in CNS development.  Moreover, elderly adults tend to: have a greater number of health problems, use more medications (some of which may interact with ibogaine), exhibit impaired organ function, and physiologic degeneration – each of which could complicate ibogaine treatment compared to middle-aged adults.
  • Low risk of psychosis: Another characteristic of an ideal candidate to receive ibogaine for the treatment of substance addiction and/or withdrawal is low psychosis risk.  Risk of psychosis can be determined based upon a prospective ibogaine user’s current neuropsychiatric status, neuropsychiatric history, and prevalence of mental illness in first-degree relatives.  Ideally, the prospective ibogaine user would be devoid of neuropsychiatric disorders and have no first-degree relatives with neuropsychiatric disorders.  This would minimize likelihood that ibogaine would exacerbate preexisting neuropsychiatric symptoms or induce long-lasting neuropsychiatric complications.
  • Normative CYP2D6 expression: Ibogaine undergoes biotransformation primarily via CYP2D6 enzymes.  Because the function of CYP2D6 is variable within the population (based on genetics), certain individuals will metabolize ibogaine less efficiently than others.  Research suggests that poor CYP2D6 metabolizers exhibit nearly double the systemic concentrations of ibogaine [and noribogaine metabolites] after ibogaine ingestion.  Doubling the systemic concentration of ibogaine yields a more substantial physiologic effect in users, thereby increasing risk of adverse reactions.  Considering that atypical CYP2D6 expression can increase risk of adverse reactions to ibogaine, extensive CYP2D6 metabolizers (i.e. persons with typical CYP2D6 expression) may be best suited for ibogaine treatment.
  • No medication or supplement usage: Persons who aren’t using any other substances such as dietary supplements, pharmaceutical medications, and illicit drugs – will be better suited to receive ibogaine than others. Many substances may provoke an adverse reaction if administered on the same day as ibogaine, or if they remain in systemic circulation when ibogaine is administered.  This is because many substances are known to interact with CYP2D6 enzymes, which would affect the pharmacokinetics of ibogaine and systemic concentrations.  For example, an inhibitor of CYP2D6 like paroxetine (a generic antidepressant) will increase concentrations of ibogaine by nearly 2-fold, thereby bolstering physiologic effect and increasing risk of adverse reactions.  Paroxetine may also increase risk of pharmacodynamic-related interactions such as “serotonin syndrome” if ingested on the same day as ibogaine.
  • No serious medical conditions: Individuals with preexisting severe medical conditions will be at increased risk of experiencing adverse reactions from ibogaine treatment.  Ibogaine might interact with medications that are used to treat preexisting medical conditions or dramatically amplify symptoms of particular conditions.  For this reason, persons devoid of serious medical conditions will be better suited to receive ibogaine than persons with a history of serious medical conditions.  Ideally, individuals who receive ibogaine would be devoid of all medical conditions other than substance use disorder.
  • Normative cardiac function: There are serious concerns of cardiotoxicity and/or cardiac complications occurring as adverse reactions to ibogaine, especially if administered at high doses. For example, at high doses, noribogaine has been shown to induce significant QT interval prolongation.  Knowing that ibogaine may provoke adverse cardiac reactions, persons exhibiting normative cardiac function without histories of cardiac events – lacking first-degree relatives with cardiac problems – will be better suited to receive ibogaine than persons with cardiac irregularities.
  • Recent medical evaluation: Ideally, all prospective ibogaine users will have undergone a recent medical evaluation to rule out an undetected medical condition and/or abnormalities that may put them at increased risk of incurring an adverse reaction from ibogaine. Persons who haven’t recently undergone a medical evaluation may exhibit a medical condition that they’re unaware of, which could result in serious adverse reactions and/or complications post-ibogaine administration.  Therefore, anyone considering ibogaine should have recent documentation from a medical professional indicating that they are healthy and devoid of serious medical conditions.
  • Prior successful ibogaine use: In terms of responses to a particular treatment, the past is usually a reliable predictor of the future.  Someone who successfully used ibogaine in the past (without adverse reactions) for the treatment of substance addiction and/or withdrawal symptoms – would be expected to respond similarly in the future.  It’s impossible to predict whether ibogaine will be safe and effective in persons who’ve never used it before.  For this reason, persons with at least one previous safe and successful treatment may be ideal candidates for [subsequent] ibogaine treatment – especially if the same treatment parameters are employed (e.g. dose, setting, etc.).

Does the setting in which ibogaine is received matter?  If so, what’s the ideal setting?

As of current, there’s no research that’s been conducted to determine whether the setting in which ibogaine is administered may influence treatment outcomes among recipients.  However, ibogaine is a psychedelic drug, and researchers of psychedelic substances routinely emphasize that the setting in which psychedelics are ingested can significantly affect responses and/or treatment outcomes.  This considered, it’s logical to suspect that the setting in which ibogaine is administered may impact its effectiveness in treating opiate/opioid addiction and/or attenuating withdrawal symptoms – as well as the side effects and/or adverse reactions that emerge.

Most speculate that receiving ibogaine in a peaceful, controlled setting with concurrent medical supervision and psychotherapeutic support is preferable to receiving ibogaine in a chaotic, uncontrolled setting devoid of professional medical supervision and psychological support.  Using ibogaine in a controlled setting without environmental stressors will decrease likelihood of environmentally-mediated adverse reactions.  Moreover, medical supervision can help prevent and/or treat adverse physiologic reactions to ibogaine, and psychological support can help a person cope with psychological reactions to ibogaine such as emotional upheavals – or the sudden emergence of extreme [often unpleasant] emotion.

If ibogaine is administered in an uncontrolled setting with environmental stressors, likelihood of environmentally-mediated adverse reactions will increase.  Exposure to environmental stressors while under the influence of ibogaine may alter neurochemistry in ways that yield an unpleasant psychedelic experience (i.e. “bad trip”).  In the event that a “bad trip” occurs, there’s a chance that this could compromise the efficacy of ibogaine in treating opiate/opioid addiction or discontinuation symptoms.

Additionally, those who administer ibogaine in an uncontrolled setting may experience adverse physiologic reactions that could’ve been prevented or treated with professional medical supervision, and/or psychological reactions that could’ve been managed with psychotherapeutic support.  For this reason, all persons considering ibogaine for the treatment of opiate/opioid addiction and withdrawal should ensure that the setting is ideal.  An ideal setting might consist of: peaceful vibes (no bright lights or loud sounds), physical comfort, no potential environmental stressors, professional medical supervision, and professional psychological support.

What dosage of ibogaine should be used to treat opiate/opioid addiction or withdrawal?

Since ibogaine is not approved by the FDA for the treatment of opiate/opioid addiction or withdrawal, no formal ibogaine dosage guidelines have been established.  Furthermore, there are no data from robustly-designed randomized controlled trials (RCTs) supporting its efficacy for the treatment of opiate/opioid addiction and withdrawal in humans – making it extremely challenging to estimate a dosage range at which ibogaine might be safe and effective for the treatment of opiate/opioid addiction and withdrawal.  If someone were to estimate a dosage range at which ibogaine might be safe and effective (in a majority of users) for the treatment of opiate/opioid addiction and withdrawal, it may be smart to examine dosages used in case studies in which ibogaine was reportedly safe and effective.

Potentially safe and effective ibogaine dosages and/or administration protocols

Listed below are all dosages and/or administration protocols in which ibogaine was documented as safe and effective in preclinical studies for the treatment of opiate/opioid addiction and discontinuation symptoms.  Understand that the dosages and administration protocols cannot be verified for safety and efficacy.  If you have a question about safe and/or effective ibogaine dosages, ask a qualified medical professional.

  • Single-dose (1962): The first [anecdotally reported] dosage range of ibogaine to be used safely and successfully for the treatment of opiate addiction and detoxification symptoms was between 9 mg/kg and 16 mg/kg.
  • Single-dose (1994): In 7 opiate-dependent individuals, the administration of ibogaine at single oral doses between 700 mg (11.7 mg/kg) and 1800 mg (25 mg/kg) – safely and effectively treated opiate withdrawal symptoms and decreased cravings. It was noted that all 7 individuals received initial test doses of 100 to 200 mg to ensure tolerability, followed by the remainder of the dose 1-2 hours later.  In this particular trial, no serious side effects were observed among ibogaine recipients.
  • Single-dose (1998): In a sample of 3 individuals (one of whom was addicted to heroin), ibogaine administered at dosages between 20 mg/kg and 25 mg/kg effectively treated substance dependence without serious side effects or adverse reactions.
  • Single-dose (1999): In a sample of 33 individuals, the administration of ibogaine HCl at doses between 6 mg/kg and 29 mg/kg completely resolved opiate withdrawal symptoms and drug-seeking behavior in ~76% of recipients.
  • Single-dose (2000): In a sample of 150 drug dependent patients, 27 opiate/opioid-dependent individuals received single fixed doses of ibogaine HCl at 500 mg, 600 mg, or 800 mg – all of which led to significant reductions in cravings. Another 32 opiate/opioid-dependent patients received single doses of 800 mg which significantly decreased withdrawal symptoms and cravings.  A few transient side effects were reported, but no serious adverse reactions.
  • Single or multi dose (2014): Ibogaine HCl was administered at oral doses between 17 mg/kg and 20 mg/kg to 75 drug-dependent patients – just one of the 75 exhibited opiate-dependence. Before receiving ibogaine, it was noted that all patients remained abstinent from substance use for 30-to-60 days.  Approximately 20 minutes prior to the administration of ibogaine, patients received domperidone (a D2/D3 receptor antagonist) to prevent nausea.  Patients with poor responses to the initial 17 mg/kg to 20 mg/kg dose received an additional ibogaine dose of 100-200 mg.  Those who received the single dose maintained an average abstinence duration of 5 months, whereas those who received the multi-dose maintained an average abstinence duration of 8 months.
  • Multi-dose (2016): A patient with a long-term, refractory case of opiate/opioid addiction derived significant long-term benefit from a 4-day ibogaine treatment. Dosages of ibogaine throughout the 4-day period were as follows: Day 1 = test doses of up to 2.5 mg/kg (to ensure tolerability), Day 2 = large dose of up to 20 mg/kg, Day 3 = booster dose of 5 mg/kg, and Day 4 = booster dose of 5 mg/kg.  Cumulative ibogaine dosage ingested over the 4-day duration was 2300 mg.

Reflecting upon all dosages at which ibogaine safely and successfully treated opiate/opioid addiction and/or discontinuation symptoms, it seems as though effective oral dosages of ibogaine ranged from 6 mg/kg to 29 mg/kg (if contingent upon body weight) and 500 mg to 800 mg (if fixed).  Due to the fact that there are only a couple protocols in which multiple dosages of ibogaine were administered for the treatment of opiate/opioid addiction or withdrawal, it’s unclear as to whether multi-dose protocols are more effective than single-dose protocols.  That said, of the available research, it seems as though multi-dose protocols may yield substantially longer-term therapeutic effects than single-dose protocols.

It’s important to realize that, at the low end of the hypothetically safe and effective dosing range for the treatment of opiate/opioid addiction or withdrawal, physiologic effects of ibogaine will be less substantial.  As a result, lower doses may prove subtherapeutic for certain individuals and/or may yield shorter-term therapeutic benefit.  That said, lower doses of ibogaine should also induce fewer and/or less severe side effects than higher doses.

On the other hand, at the high end of the hypothetically safe and effective dosing range for the treatment of opiate/opioid addiction or withdrawal, physiologic effects of ibogaine will be more substantial.  As a result, higher doses may yield longer-term therapeutic benefit, but also will increase likelihood of serious adverse reactions.  The goal of anyone using ibogaine should be to work with a medical professional who can estimate a minimal effective dose – or the lowest quantity needed to derive substantial therapeutic benefit.

Also keep in mind that safe and effective dosages of ibogaine for the treatment of opiate/opioid addiction or withdrawal should be determined based upon user-specific factors such as:  age, CYP2D6 function, medical status, physical attributes (body size and composition), and treatment goals.  For example, someone with poor CYP2D6 function will exhibit nearly double the systemic concentrations of ibogaine and its metabolites – as compared to persons with normative CYP2D6 function.  For this reason, the literature recommends that poor CYP2D6 metabolizers use half the standard dose of ibogaine to decrease likelihood of adverse reactions.

Will ibogaine work for everyone?

No. It is important to emphasize that, like any drug, ibogaine is not universally safe and effective for the treatment of opiate/opioid addiction and withdrawal symptoms.  Research in both humans and animal models [of substance use disorder] suggests that while ibogaine appears safe and effective in the majority, a subset of recipients derive zero or insignificant benefit from its administration.  Variables that may determine the extent to which ibogaine is effective include: ibogaine dosage, single vs. multi-dose protocol, and user-specific factors (addiction severity, genetics, neurochemistry, etc.).

How long will the therapeutic effect of ibogaine last?

It depends. The duration of therapeutic effect following ibogaine administration will be subject to significant variation in accordance with: ibogaine dosing (dosage, number of doses, etc.) and user-specific factors such as: addiction severity, genetics, and neurochemistry.  Assuming therapeutic effect is derived from ibogaine, research suggests that this may persist for hours, days, weeks, or even months after a single ibogaine administration.  In the literature, the longest-term of therapeutic benefit derived from ibogaine was 18 months – documented in a case report.

Anecdotal claims circulating throughout the internet claim that a single ibogaine treatment resulted in opiate/opioid abstinence for over 8 years after a longstanding addiction.  While many human studies conduct follow-up assessments several months after ibogaine administration, most do not conduct subsequent assessments a year or more after its administration.  This makes it difficult to estimate the average duration over which therapeutic benefit is sustained (e.g. craving reduction and/or withdrawal symptom attenuation).

What is the legal status of ibogaine? (Ibogaine Laws by Country)

It depends where you live.  In the United States, ibogaine is classified as a “Schedule I” controlled substance, meaning that ibogaine is illegal to: buy, possess, distribute, and/or ingest.  However, in a majority of countries, ibogaine remains unregulated such that its purchase, possession, distribution, and ingestion – fall within a legal gray area.  Taking advantage of this legal gray area, many entrepreneurs and companies have opened ibogaine clinics throughout Canada, Mexico, and the Netherlands – charging several thousand dollars for supervised treatment.

In other countries such as Brazil, Gabon, and South Africa, ibogaine can be legally prescribed and administered by professionals. Included below is a list of countries and brief discussion of ibogaine’s legal status in each.  Because the information below may be subject to inaccuracies and/or may require updating, it is recommended to contact a legal professional (i.e. lawyer) if you have questions about ibogaine law in a particular country.

  • Australia: As of 2010, ibogaine was listed as a Schedule 4 substance on Australia’s Poison Standard, meaning it is a prescription-only (Rx-only) medicine. Legal usage of ibogaine in Australia is limited to persons who’ve attained approval and received an ibogaine prescription from a medical professional.  There are also various underground ibogaine clinics throughout Australia without government licensing – typically charging $2800 to $3500 for treatment.
  • Belgium: Ibogaine is documented within the Royal Decree of 1998 on psychotropic substances. This makes it illegal to import, export, manufacture, possess, offer for sale, deliver, or acquire – throughout Belgium.  The only way to legally attain and/or administer ibogaine in Belgium is with express permission from the Minister of Public Health.
  • Brazil: As of 2016, the President of the National Association of the Study of Drug Policy in Sao Paolo issued a declaration calling for the scientific study of psychoactive substances. As a result, ibogaine was approved for legal usage in medically-supervised “hospital environments” throughout Sao Paolo.  Within months of initiation, this law is expected to extend throughout the rest of the country.  For a 4-to-5-day treatment with ibogaine in Brazil, it costs approximately $3,000.
  • Canada: Because ibogaine is classified as an isolate of plant material, it is considered a “natural healthcare product” under Canada’s Natural and Non-Prescription Health Products Directorate. Most consider ibogaine to be an unregulated substance in Canada and there are numerous ibogaine clinics open throughout the country.  Furthermore, ibogaine rumored to be sold at head-shops (stores that sell drug-related paraphernalia) throughout Canada.  That said, Health Canada has expressed concern regarding certain ibogaine suppliers and implied that some may be subject to legal penalization.
  • Costa Rica: Ibogaine is presently unregulated throughout Costa Rica. There are various ibogaine treatment centers in Costa Rica aimed at attracting medical tourists or spiritual seekers.  Certain treatment centers in Costa Rica are conducted by a Bwiti shaman and under professional medical supervision.
  • Denmark: List B of Denmark’s Executive Order 698 of 1933 on Euphoric Substances specifically cites ibogaine and its salts. Specifically, ibogaine is documented under “substances used for medical and scientific purposes with substantial controls.”  Most interpret this law as meaning that ibogaine can be administered by medical professionals if they attain permission from the Ministry of Health.
  • Finland: In 2014 Finland modified its Narcotics Act to cover all “psychoactive substances banned from the consumer market.” This suggests that ibogaine is illegal to possess, sell, and ingest without medical approval.
  • France: In France, ibogaine-containing products were sold “over-the-counter” until 1966. The French Ministry of Health has since made it clear that all ibogaine-containing products are illegal to possess and distribute.
  • Gabon: Gabon is universally recognized as being the first country in which ibogaine was deliberately ingested by humans.  Historians report that ibogaine-containing plants (iboga) were commonly administered in Gabon throughout the 19th century by African tribes as a part of spiritual and/or healing ceremonies.  As of present, ibogaine remains legal throughout Gabon, however, there are no formal ibogaine treatment facilities.  Medical tourists who pursue ibogaine treatment in Gabon generally partake in ceremonies conducted by healers (“N’ganga”) of the Bwiti spiritual discipline.
  • Germany: Ibogaine is presently unregulated throughout Germany. There are various ibogaine clinics and practitioners that will administer treatment without government licensing.  Though ibogaine practitioners could be subject to penalization, most are relatively covert and don’t attract much government attention.
  • Hungary: The New Psychotropic Substances of Government Regulation lists ibogaine under Section C, making it illegal to manufacture, import, export, transfer, purchase, distribute, store, research, analyze, and/or prepare – without proper licensing.
  • Ireland: Although not specifically mentioned in Irish legislation, ibogaine falls under provisions of the Criminal Justice (Psychoactive Substances) Act of 2010.  This law essentially renders all psychoactive substances illegal.  However, under special circumstances, psychoactive substances are permitted for usage by medical professionals.
  • Israel: Legality of drugs in Israel is based upon the Dangerous Drugs Ordinance (1973) and the Fight Against the Phenomenon of the Use of Dangerous Substances Law (2015). With respect to the legislation, most consider ibogaine as illegal to distribute within Israel.
  • Italy: As of 2016, the Italian Ministry of Health classified ibogaine as a Schedule 1 due to its effects within the CNS and hallucinogenic properties. Possession and distribution of ibogaine can result in penalization ranging from 2 to 12 months in prison.
  • Mexico: As of 2009, ibogaine remains unregulated throughout Mexico. Many ibogaine treatment centers have opened throughout Mexico with the intention of profiting from medical tourists.  Mexico remains a popular destination for persons in the United States to pursue ibogaine treatment for an opiate/opioid addiction.
  • Netherlands: Ibogaine remains unregulated in the Netherlands as of 2016. There are a few ibogaine clinics [devoid of government licensing] that will administer treatment.
  • New Zealand: In New Zealand, ibogaine is listed as a “non-approved” prescription medicine, meaning that it can be prescribed by a licensed medical doctor and administered under therapeutic supervision.
  • South Africa: Ibogaine was formerly an unscheduled substance in South Africa, but in 2016 the South African Medicine Control Council (MCC) published a statement classifying ibogaine as a Schedule 6 substance under the Medicines and Related Substances Control act 101 of 1965. Under this legislation, ibogaine can be prescribed by a medical professional and all producers/suppliers are required to attain a permit from the Director General.
  • Sweden: Throughout Sweden, ibogaine is classified as a “Schedule 1” substance and is listed by Drug Administration regulations as having no medicinal value. For this reason, ibogaine is illegal to possess and distribute.
  • Switzerland: The Federal Law on Narcotic Drugs and Psychotropic Substances makes ibogaine illegal to possess, grow, import, manufacture, and distribute – within Switzerland.
  • United Kingdom: The United Kingdom’s “Misuse of Drugs Act” (1971) does not identify ibogaine as an illicit substance.  However, the Psychoactive Substances Act (2016) makes it illegal to import, export, produce, or supply any substance that’s “capable of producing a psychoactive effect in a person who consumes it.”  This act also makes it illegal to possess psychoactive substances in prison or custodial institutions.  That said, possession of psychoactive substances outside of the aforementioned institutions is not mentioned.  As a result, ibogaine is currently considered legal to possess (outside of select institutions), but not to distribute.
  • United States: Ibogaine is listed as a “Schedule I” controlled substance in the United States since the 1970s, implying that it has a high potential for abuse, no accepted medical value, and lacks safety. Due to its illegal status, most Americans who wish to use ibogaine for the treatment of an addiction will visit another country.  Moreover, while there are secretive ibogaine clinics within the United States, the DEA makes an effort to find them, shut them down, and penalize the operators.

Note: In countries other than those listed above, ibogaine is an unscheduled and unregulated substance.

Have you used Ibogaine for opiate/opioid addiction or withdrawal?

If you’ve used ibogaine for the treatment of opiate/opioid addiction and/or withdrawal symptoms, be sure to describe your experience in the comments section below.  Assuming you were asked to rate the therapeutic efficacy of ibogaine on a scale from 1 to 10 (with 1 being ineffective and 10 being highly effective), what numeric rating would you assign it [for the treatment of substance dependence and/or withdrawal symptoms]?  To help others get a better understanding of your ibogaine experience provide details such as: location and setting of administration (e.g. hospital in Brazil); dosage(s) ingested (e.g. 20 mg/kg); cumulative duration of treatment (e.g. 5 days); and whether you received medical supervision and/or psychological support.

Also note some personal information such as: your specific addiction (e.g. heroin); the severity of your addiction (e.g. extremely severe); the duration of your addiction (e.g. 10 years); CYP2D6 metabolism (e.g. extensive CYP2D6 metabolizer); health conditions; and whether you used drugs or supplements that may have interacted with ibogaine.  In the event that you responded well to ibogaine, how long did the therapeutic effect persist after your treatment?  If the therapeutic effect eventually subsided after treatment, were you able to maintain sobriety? Or did you reinstate usage of opiates/opioids?

Did you consider the psychedelic effect induced by ibogaine to be personally meaningful to extent that it led to abstinence? (If so, please explain the specific ways in which it was meaningful).  Regardless of whether you found ibogaine to be effective, were there any unwanted or serious side effects that you experienced while under its influence?  Before using ibogaine, had you tried conventional interventions for opiate/opioid addiction and/or withdrawal such as: opioid replacement therapies (e.g. buprenorphine, methadone, etc.) and cognitive behavioral therapy (CBT)?

Based on your experience, would you recommend ibogaine to others?  (Why or why not?).  Everything considered, realize that the safety and efficacy of ibogaine for the treatment of opiate/opioid addiction warrant further investigation in randomized controlled trials.  Until ibogaine is proven safe and effective in large-scale randomized controlled trials, it should be perceived as a [potentially-safe and potentially-effective] last-resort intervention for persons exhibiting refractory cases of substance dependence who derive inadequate benefit from all conventional, evidenced-based options.

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{ 1 comment… add one }
  • ibogaine works! August 22, 2017, 5:09 am

    Awesome information here. Thank you.

    2 Things:

    1) The replacement drugs given to opiate addicts (methadone and suboxone) are much more addictive than the drugs they were using before, like heroin and oxycodone. instead of the 1-2 week withdrawal you get from heroin, you suffer withdrawals for 3-6 months after the replacement drugs, depending on dosage and amount time you took it.

    2) When you mention the group of addicts who will go back to using soon after taking ibogaine, you should be aware that they relapse because they put themselves in the position to do so. They do not change their lifestyles or friends and end up back in the same place. While the noribogaine does help, it cannot do the job alone; the person needs to be ready. Ibogaine is not a cure, but rather the best form of treatment available to opiate addicts. However, if you don’t change your ways, it will be pointless to take it. It isn’t a small thing and requires, at the very least, a week where you have nothing going on. You will probably not be at full strength and might need some time to hangout.

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