Ibogaine…Again

Recent media coverage of the Opioid Crisis has highlighted our historically two-edged relationship with opioids. Drugs like morphine are clearly the most effective agents for dealing with many types of pain. They are essential for most surgical procedures and, when used appropriately, they are our most effective drugs for treating many acute injuries or other causes of pain. On the other hand, opioids are dangerous to use, a high dose will kill you by stopping your breathing, and they are extremely addictive. The results of the unrestricted availability of opioids became clear during the first Opioid Crisis which occurred in China in the 19th century due to the enormous opium burden foisted on the Chinese by western powers, particularly the British. The result was a social catastrophe. The current situation in the USA is another version of the same scenario, although in this case the opioid suppliers were drug companies and doctors rather than aggressive merchants. Because we have always been aware of these potential problems, drug makers have tried to produce novel, problem-free opioid drugs since the 19th century. Indeed, heroin, first marketed in 1898 by the Bayer drug company, was originally sold as a non-addictive alternative to morphine—clearly rather an unfortunate error. Since that time, there have been thousands of attempts to produce non-addictive opioids based on all kinds of strategies ranging from lower agonist efficacy to biased receptor signaling. These attempts inevitably produce high-profile scientific publications in journals like Nature or Science but, unfortunately, have yet to yield any benefit in the human population. Smaller piecemeal approaches such as the use of methadone, suboxone or opioid antagonists have made some differences but a knockout punch is still to be delivered. Strangely, one of the most promising treatments for opioid abuse disorders may have been hiding in plain sight. The name of the drug is ibogaine. As I will discuss, ibogaine itself is unlikely to ever come to market as a treatment for substance abuse. Recently, however, a new company called MindMed announced that it was starting phase II trials on a substance called 18-MC which is closely related to ibogaine and may share a similar mechanism of action. But what is 18-MC and why might it be important?

In many respects it’s an old story because ibogaine has been around for a long time, flitting in and out of our collective consciousness. During the 1960s and 1970s, several classes of psychotropic drugs became illegal following the passage of the Controlled Substances Act and similar laws. This included psychedelic drugs such as LSD, psilocybin and mescaline. Laws that made cannabis illegal had been passed prior to this time, stretching back to the 1930s. Nevertheless, there was a great deal of scientific evidence that both cannabis and the psychedelics might have important medical benefits. Whatever the truth of the matter, after 1970 research into the potential uses of these types of drugs generally ceased. During the past decade however, there have been signs that interest in these substances is reviving and that changes in the laws are making it easier to investigate them once again. Although cannabis is still illegal at the federal level, many states have gone their own way and have legalized its medical or recreational use once again. Recently there have been signs that psychedelic drugs such as psilocybin may be undergoing a similar renaissance. These events have been widely covered in the press and most people will be aware of at least some of the things that are going on.

The stories of all of these drugs have followed a somewhat similar path. Originally discovered by ancient peoples and used for religious purposes, they were “rediscovered” by western societies and were taken up by both the pharmaceutical industry and by many people for recreational use. All of these drugs are related to natural products derived from plants found in Europe, Asia and South and Central America. But what about Africa? The African continent certainly has its fair share of interesting plants and natural products which, as in other parts of the world, originally saw the light of day in the context of religious practice. For example, in western parts of Africa around Gabon and Cameroon there are large numbers of people, particularly among the Fang population, who practice a religion called Bwiti—a syncretic combination of indigenous animist beliefs and Catholicism. An important feature of Bwiti religious practice is the use of Tabernanthe iboga, a hallucinogenic shrub. The bark of the roots of the plant produces powerful psychotropic effects and is used in religious ceremonies. The drug is described as producing visions and a state of lucid dreaming as well as long-lasting introspection. On the other hand, unlike other psychotropic drugs such as LSD, the experience of taking ibogaine is not reported as being a particularly pleasant one—more like hard work, which has limited its use as a recreational drug. According to the Fang themselves, the discovery of the psychoactive properties of the plant goes back to their encounters with the Pygmies, who were very knowledgeable about the properties of plants in the African rainforest. This knowledge was passed on to the Apindji and the Mitsogo peoples as they migrated into west Africa and originated the Bwiti faith. The Bwiti practice was then passed on to the Fang people in the 1890s, and they have established a complex mythology around the use of T. iboga. Consider this quote: “You have heard what the Catholics tell us regarding a fruit that our first parents ate. What kind of fruit did our first parents think they ate, Adom-Obola and Eve-Biome? What type of tree was it? They are lying because they do not want to tell us the truth. For this reason, God left the iboga so that men would see their bodies as God had made them, as He himself has hidden inside them. Therefore brothers, take the iboga plant that God gave to Adam and Eve.”

When Bwiti shamans consume T. iboga, they believe that they gain the ability to heal the sick, communicate with the dead, and experience visions of the future. Perhaps most significantly, the drug is crucial to the initiation rites and coming-of-age rituals of the Bwiti religion.

T. iboga was first introduced to the West in 1864, when samples of the plant were brought back to France from Gabon by French anthropologists who visited the region as part of expanding French colonial influence. The first publication in the literature as to its ritual use appeared in 1885. Although the plant contains a large number of chemically related pharmacologically active substances, the major component, known as ibogaine, was first crystallized from extracts of the shrub’s root bark in 1901. The introspection that results from taking the drug meant that it was subsequently developed for use in psychiatry as an aid to psychotherapy. From 1939 to 1970, ibogaine was marketed in France under the trade name “Lambarene,” a “neuromuscular stimulant” in the form of 8-mg tablets, a fairly low dose, for conditions including fatigue and depression. However, as discussed above, by 1970 the effects of the counter cultural movement had prompted all western governments to make any kind of drug with hallucinogenic properties illegal. This included ibogaine which, in the USA, became a Schedule 1 drug. This meant that along with the likes of heroin, cannabis and LSD, it was supposed to be extremely dangerous and to have no medical utility whatsoever. Nevertheless, this was not to be the drug’s ultimate fate.

The history of ibogaine in the USA makes an interesting story. It is well known that in the 1950s and 60s the CIA had a large “secret” program variously called BLUEBIRD, ARTICHOKE or MK-ULTRA tasked with discovering mind-altering drugs for combating the menace of communism. The CIA experimented with virtually every known psychotropic agent and that included ibogaine. Although most of this work was secret, some of the programs supported by MK-ULTRA involved funding individuals in academia who would carry out drug studies on “volunteers” and pass the information back to the CIA. One such individual was Dr. Harris Isbell, director of the NIMH addiction research center in Lexington, Kentucky. Isbell used ibogaine to treat eight African American men recovering from drug addiction. There was generally some interest at the time about the potential interactions between ibogaine and opioids, and the CIBA drug company had patented its use as a drug that would enhance the analgesic effects of morphine. Isbell’s experiments, which were conducted without patient consent, were looking for substances that could “rewire” the human brain and might positively impact recovery from opioid addiction and also be of use for the CIA’s secret brainwashing program. There can be no doubt as to the powerful psychotropic effects produced by ibogaine, particularly at higher doses, and in November of 1956 Isbell reported to the CIA that ibogaine was useful for treating heroin addiction. Unfortunately, his data never actually appeared in the public scientific literature.

In the 1960s, public experimentation with psychotropic drugs was becoming increasingly popular with young people in the USA and this included experimentation with ibogaine. Around 1962, a resident of New York city named Howard Lotsof , who was a heroin addict, began experimenting with ibogaine and other psychotropic agents which he hoped might be helpful in treating his addiction. Lotsof and 19 of his friends, seven of whom were heroin addicts, took a moderate dose of ibogaine. Most of them reported a reduction in their drug craving and withdrawal symptoms. Indeed, five of the seven reported that they were free from heroin use for up to six months.

Lotsof believed he had found the “cure” for opioid abuse disorders and began to proselytize for ibogaine’s use for the treatment of addiction. But several things stood in his way. First of all, he had no medical research credibility, that is no degree or other training that would help to convince people he could carry out a research program like this. Furthermore, in 1970 when ibogaine became a schedule 1 drug, it made performing research into its properties extremely difficult even for university-trained scientists. Thirdly, pharmaceutical companies weren’t interested in helping to develop ibogaine. Because ibogaine is a natural product, drug companies thought that they wouldn’t be able to get the sort of patent on it that they wanted if they were going to make a big profit. But Lotsof wasn’t easily put off. By the mid-1980s, he had managed to raise some private funding which allowed him to carry out informal trials with the drug in the Netherlands. A large number of informal but promising ibogaine trials treating drug addicts subsequently took place and, eventually, the NIH became interested in it as did an academic lab at the University of Miami. Unfortunately, all of this activity was cut short following the death of a patient in the Netherlands from a heart attack. Although it was never clear that ibogaine was responsible for this death, it naturally made people cautious. Informal testing of the drug continued in several countries around the world with a particularly large cohort of patients being treated in St. Kitts in the Caribbean. Other studies conducted in Brazil, New Zealand, and Mexico all suggested that ibogaine may have a significant beneficial effect when treating drug addiction. While most of these ibogaine studies have been fairly small, they have generally found that the drug seems to reduce cravings and physical withdrawal symptoms for individuals dealing with a variety of addictions, as originally observed by Lotsof.

Lotsof also made progress at the preclinical level. He persuaded Dr. Stanley Glick, a pharmacologist at Albany Medical College in New York to test ibogaine in morphine-dependent rats. The experiments appeared to work, reducing the animals’ desire to take morphine. Moreover, further experiments suggested that ibogaine was also effective in animal models of addiction to cocaine, alcohol and nicotine. The results were promising enough to encourage the Glick team to work with Dr. Martin Kuehne at the University of Vermont in an attempt to synthesize more potent, but hopefully less toxic, ibogaine analogs, leading to the synthesis of 18-methoxycoronaridine (18-MC). Like ibogaine, 18-MC also showed promise in animal studies of drug abuse. In order to promote ibogaine and related substances, Glick cofounded his own drug company, Savant Health and Wellness Partners. Through this organization, Glick was able to obtain an NIH research grant for just over $6.5 million that would take 18-MC through phase 1 human safety trials. Nevertheless, after working on 18-MC for nine years, Savant ran out of money and was not able to move the program to the next phase of clinical trials. In September 2019, MindMed bought 18-MC and also hired the team working on it. According to their publicity, MindMed now plans to run their own safety trials in the second half of 2020 and then hopefully proceed to the next stage of testing the effectiveness of the drug.

While all this is interesting, there are several things to note. The first is that ibogaine used at the doses previously required for treating addictions is not altogether free of side effects. Several people have died from cardiovascular issues over the years and, although it is not clear that ibogaine was responsible for these deaths, it is certainly quite possible. Ibogaine can also produce neurotoxic effects. Secondly, ibogaine produces profound hallucinations which are not really compatible with somebody wanting to take it on a routine basis and have a productive day at work. Which brings us to 18-MC. Because 18-MC produces some of the same beneficial effects as ibogaine in animal studies, if it turns out that 18-MC is also effective in treating human addicts but is non-hallucinogenic and doesn’t produce issues like heart problems, then it might be an excellent alternative to ibogaine itself. There are no published data on the effects of 18-MC in humans so far, although the CEO of MindMed has said that it looks to him as if the drug is free of hallucinogenic properties and is safe to take.

Nevertheless, we are still left with the biggest question of all, which is “how does ibogaine work?” This kind of knowledge is very helpful these days as drug regulatory organizations like to have an indication as to a drug’s mechanism of action if they are going to approve it for general use. Historically it has been thought that the profound psychotropic experience of taking ibogaine, as well as the ensuing drug-induced introspection, was key to helping an addict cope with a drug abuse issue. In other words, this was a transcendental type of cure based on profound introspection and self-analysis enabled by the drug. It was a mystical cure that was related to the original use of the drug by the Bwiti. But if 18-MC is not hallucinogenic—then what? We would have to conclude that the drug can produce effects on the nervous system that were beneficial for treating addiction and that these were not the same as the effects needed to produce hallucinogenic mystical and religious behaviors. Here we have a problem with ibogaine and drugs like 18-MC because really, nobody knows how they work. It’s not that they can’t be shown to produce effects in experiments that scientists carry out. In fact the situation is just the opposite. They produce every kind of effect but don’t produce any one of them very well—they are pharmacological dilettantes.

This is unusual. In the case of other types of hallucinogenic drugs, their mechanism is well established. For example, we know that classical hallucinogenic drugs like LSD, psilocybin, ayahuasca and mescaline all act as agonists at 5-HT2A receptors, a type of receptor for the neurotransmitter serotonin (5-HT). On the other hand, muscimol, the hallucinogenic molecule derived from the mushroom Amanita muscaria acts as an agonist at GABA-A receptors. Scopolamine and atropine, hallucinogenic molecules derived from a variety of plants, act as blockers of muscarinic acetylcholine receptors. However, none of these mechanisms appear to explain the effects of ibogaine. There is, however, another possibility. Some research has demonstrated that ibogaine’s major metabolite, noribogaine, is an agonist at κ-opioid receptors (KORs). Why might this be important? Here we should note the activity of another psychotropic natural product obtained from the plant Salvia divinorum, commonly known as magic mint. S. divinorum is used by the Mazatec Indians in Mexico to produce hallucinogenic effects in their religious ceremonies. The active molecule derived from the plant is called salvinorin A and seems to produce its effects by activating KORs. Indeed, other opioid drugs which activate KORs are also known to produce dysphoric hallucinatory effects. Ibogaine doesn’t activate KORs itself, so we might conclude that the psychotropic effects of ibogaine are mediated by its metabolite noribogaine. This would be a reasonable mechanism because quite a few drugs work this way. Heroin, for example, works through its conversion to morphine in the brain. Moreover, as 18-MC is free of KOR agonist activity, this would also explain why this drug is not hallucinogenic. Nevertheless, these explanations are very speculative.

Salvia divinorum
Salvinorin A

However, if 18-MC is really not hallucinogenic then what explains the effects of ibogaine or 18-MC on substance abuse disorders? There are two types of explanations that have been put forward. The first of these is that, like other psychotropic drugs, there is a specific mechanism of action involved—such as an interaction with a neurotransmitter receptor or uptake system. On the other hand it has also been speculated that the effects of these drugs are genuinely non-specific and are the result of a mixture of low affinity sites of action. If there is a specific site of action, what could it be? One mechanism that has been suggested for the anti-addictive properties of ibogaine concerns its effects on nicotinic acetylcholine receptors in the brain. The important neurotransmitter acetylcholine works by activating two different types of receptors, nicotinic and muscarinic, and it is the former type that concerns us here. Because nicotinic receptors are constructed from five different protein subunits there are a very large number of different types that can be arranged by putting subunits together in different ways. Ibogaine has been shown to be an antagonist at several nicotinic acetylcholine receptor types including the α1β1 and α3β4 subtypes. The α3β4 receptor is expressed within the habenulo-interpeduncular cholinergic pathway of the brain, which seems to be involved in producing some of the rewarding effects of addictive drugs, and so it has been speculated that interaction with these receptors may be a major contributor to ibogaine’s beneficial effects on drug addiction. However, the reported effects of ibogaine on these nicotinic receptors are not all that potent, and those of 18-MC are even weaker, so this mechanism doesn’t seem to be all that convincing. Really, at this point in time, one would have to consider the hypothesis that the anti-addictive effects of ibogaine and 18-MC are produced by a large number of relatively weak effects on different neurotransmitter systems. Scientists don’t like conclusions like this—they like things to be clear cut. There are really very few drugs that are widely used today that don’t have a specific mechanism of action. Nevertheless, there is nothing in principle to suggest that a drug couldn’t produce useful effects in this way. Whatever the truth of the matter, ibogaine remains a scientific mystery and it will probably be necessary to keep returning to the question of its utility as a treatment for drug addiction and its mechanism of action again and again.

SICKLE CELL DISEASE: CRISES AVERTED?

The current opioid epidemic involves hundreds of thousands of individuals who have become addicted to opioids such as extended-release oxycontin. It should be remembered, however, that opioids are not just addictive recreational drugs. They also have an important bona fide use in medicine. Opioids are the most effective drugs we know of for the treatment of many kinds of pain, and normal surgeries—as practiced today in hospitals around the world—would be impossible without their use. Opioids are effective in controlling many types of pain. However, their chronic use almost inevitably leads to addiction. An important goal therefore is to produce drugs that effectively control long-term pain, but are free from the addictive potential of opioids. Since the advent of the opioid crisis, the National Institutes of Health (NIH), which is the main funding source for medical research in the United States, has been offering more research grants for people who are trying to develop “non-addictive”, but highly effective, analgesic drugs. One of the reasons why drugs like morphine are so good at controlling pain, and also why they have so many side effects, is that their receptors, known as μ-opioid receptors, are abundantly expressed at diverse points throughout the nervous system. These receptors are localized in peripheral nerves that transmit pain sensations, in the spinal cord, and in higher brain centers where they effectively control the flow of information along pain-conducting nerve pathways. Whether the receptors for other potential analgesics will be so conveniently placed is not at all clear, and so reproducing the powerful and widespread analgesic effects of opioids using other approaches may be difficult. Cannabis is one possibility, as cannabinoid receptors—like those for opioids—are widely expressed in the nervous system. Other approaches to the problem, such as synthesizing novel opioids that are free of addictive potential, have also proven to be challenging and, in spite of numerous claims in the scientific literature, have never ultimately succeeded. For reasons such as these, the replacement of opioids as generally effective analgesic drugs is a challenging undertaking.

On the other hand, all types of pain have unique triggers. For example, the trigger for osteoarthritic pain, involving movement of a degenerating joint, is different from that of painful diabetic neuropathy, involving dying peripheral neurons, or other causes. It is quite possible, therefore, that rather than discovering a replacement for opioids per se, new drugs for pain will be developed in a disease-specific manner, based on the particular pain-triggering mechanism that is involved in each syndrome. One example of such an approach is a new drug that is targeted to the treatment of sickle cell disease (SCD).

To understand this new therapeutic approach, we should first look at the mechanisms that underlie SCD, which has a particularly interesting origin. One of the greatest scourges known to man is the mosquito. The bite of the mosquito is associated with the transmission of a large number of diseases including dengue, West Nile virus, chikungunya, yellow fever, filariasis and zika, among others. However, by far the most prevalent and devastating of mosquito-associated diseases is malaria, which has tracked the development and migration of human society over millions of years. As described in a recent book (The Mosquito by Timothy C. Winegard), mosquitoes accompanied humans as they left Africa and colonized many other parts of the world. For example, the conquistadors brought malaria with them when they first came to the New World and it was diseases of this type, rather than their prowess as warriors, which were probably mostly responsible for their relatively easy conquest of Central and South America. Mosquitoes tend to breed in warm, marshy areas such as the Pontine Marshes surrounding the city of Rome which, in ancient times, were notorious for being a hot bed of malaria. Here again, it is quite possible that it was these malarial marshlands that protected Rome from many rampaging invading armies over the years.

An Anopheles mosquito takes a blood meal

Prior to mosquitoes being identified as the “vector” that carried the disease, it was thought that malaria was spread by foul air—hence its name mal (bad)-aria (air). In actuality, malaria is spread by the bite of female Anopheles mosquitoes. The reason why female Anopheles mosquitoes bite you is to obtain your blood. Male and female Anopheles mosquitoes actually feed on nectar—blood isn’t what they eat. However, it turns out that there are nutrients in human blood—protein and iron—that are vital for the female Anopheles mosquito to be able to develop her eggs. This is the reason why she will drink about 3 millionths of a liter of human blood when she bites a human victim.

However, in addition to drinking your blood to obtain iron, mosquitoes also take up and inject disease-causing agents which basically go along for the ride. The infectious agent that causes malaria is a protozoan (single-celled eukaryotic organism), and we have a detailed description of its entire life cycle. There are actually several closely related protozoan parasites that can cause the disease. Moreover, there are also different species of mosquitoes that can spread malaria. However, only different types of female Anopheles mosquitoes can transmit human malaria. The organisms involved are 5 species of the protozoan Plasmodium—P. vivax, P. falciparum and P. malariae being the most common forms of the disease in humans. Related protozoa can infect other animals including birds and even fish. When a female mosquito bites somebody, if her victim is infected with a malaria parasite—let us assume it is P. falciparum as an example—then she will also take up male and female protozoan gametocytes (precursors of sperm and eggs) that circulate in the victim’s peripheral blood. Once within the mosquito, these gametocytes will develop further into male and female gametes (the sperm and eggs). The motile male gamete seeks out a female gamete and fertilization results in a motile zygote, also known as an “ookinete,” formed within the lumen of the mosquito’s gut. The ookinete then penetrates the gut wall where it becomes an “oocyst.” This then multiplies, forming infectious “sporozoites” that migrate to the salivary glands of a mosquito and are injected when the mosquito bites to obtain her next blood meal. Once the infectious sporozoites have entered the blood of the victim, they circulate around the body, eventually taking up residence in liver cells where they undergo further multiplication (exoerythrocytic schizogony), producing the next stage of development: the merozoites. Merozoites exit the liver into the blood and they are the species which now infect red blood cells (erythrocytes). Here, they multiply further to produce more merozoites which then destroy the erythrocyte and enter the blood once more and infect further erythrocytes. This process continues ad infinitum, until the host’s blood is used up and the individual dies. During the time when merozoites are multiplying within red blood cells, some of them turn into gametocytes that can be taken up by a mosquito during a blood meal to be transferred to the next victim. And so it goes. Around and around in a horrible dance of death and destruction reminiscent of the most terrifying scenes of the classic horror movie, Alien.

Life cycle of the malaria parasite

The well-known bouts of fever associated with human malaria result from rounds of bursting of red blood cells and release of infectious particles and toxins. The different types of Plasmodium parasites have slightly different properties in this regard generating “tertian” or “quartan” fevers which occur on average every two or three days. P. falciparum is the most deadly form of the disease. Some types of malaria such as P. vivax can also produce forms that lie dormant in the liver (hypnozoites) even when the disease has been cleared, only to awaken again after many weeks to initiate another deadly round of fevers, vomiting, and other symptoms of the disease.

The powerful selection pressures on individuals living with the constant threat of malaria in Sub-Saharan Africa led to the appearance of a genetic trait some 7,300 years ago that afforded some resistance to P. falciparum. This trait was caused by a mutation in the protein hemoglobin, the major protein found in red blood cells whose job is to carry oxygen from the lungs to the rest of the body. The most common mutation is known as sickle hemoglobin (HbS). HbS is a structural variant of normal adult hemoglobin. Adult hemoglobin (HbAA) is made up of two α and two β globin chains. HbS is the result of a single point mutation (Glu → Val) on the sixth codon of the β-globin gene. People who are heterozygous for the HbS allele carry the sickle cell trait (HbAS) but do not have SCD, whereas individuals who are homozygous for the HbS allele have SCD of which sickle cell anemia (SCA) is the most common manifestation. SCA is characterized by chronic hemolytic anemia, unpredictable episodes of pain, and widespread organ damage.

SCD is one of the most common genetic disorders found in the world. An estimated 20–25 million people live with homozygous SCD (HbSS). Approximately 300,000 infants are born annually with HbSS. Areas with a high prevalence of malaria such as Sub-Saharan Africa, the Mediterranean basin, Middle East, and India tend to have higher populations of patients affected with SCD. In the United States, approximately 100,000 people—many of them the descendants of the African slave trade—have SCD, accounting for more than 110,000 sickle cell-related hospitalizations annually. There is a wide variability in the clinical severity of SCA, as well as in the life expectancy. Interestingly, although people who carry the HbAS trait (heterozygotes) are clearly resistant to malaria, the mechanism of this effect isn’t entirely clear. Different kinds of biochemical changes have been detected in red blood cells from HbAS individuals, which must make it harder for P. falciparum to establish an infection but there is no real consensus as to how this occurs. Clearly, SCD is an extremely serious health problem. The fact that it has been maintained in populations such as those in Sub-Saharan Africa where malaria is endemic, speaks to the fact that just about anything is better than having malaria.

Individuals who are homozygous for hemoglobin S (HbSS), having two affected β-chains, develop SCD. The HbS allele has a lower-than-normal affinity for oxygen and also has a tendency to aggregate at low oxygen concentrations. Hence, when red blood cells have delivered their oxygen to the tissues and are returning to the lungs via the venous system in an oxygen-depleted state, the hemoglobin of SCD patients polymerizes, which produces sickle-shaped malfunctioning erythrocytes and reticulocytes (erythrocyte precursors). These cells are sticky and form clumps that occlude blood vessels, particularly small and some large vessels producing what is known as a vaso-occlusive crisis (VOC) which causes ischemic injuries. The sickled red blood cells are also brittle and burst, producing profound hemolytic anemia. During a VOC, the most common complaint is pain, and recurrent episodes may cause irreversible organ damage. One of the most severe forms is the acute chest syndrome which occurs as a result of infarction of the lung parenchyma. This can rapidly result in death. For a patient with SCD, both chronic pain and intense bouts of acute pain are particularly hard to deal with. Traditionally, patients with SCD-associated pain are treated with opioids and around a quarter of patients use opioids chronically throughout life, but of course, this also comes with the well-known risks of chronic opioid use.

In order to produce an alternative to opioid use, we need to know exactly why pain occurs in SCD. Nerves that sense pain innervate blood vessels and can be activated by inflammatory mediators and other processes occurring during a VOC. Drugs that interfere with these processes may be helpful in treating pain occurring in SCD patients in particular. Recently, there has been progress in achieving this aim. The first new therapy to be introduced for treating SCD was hydroxyurea (or hydroxycarbamide), which is the only drug frequently employed in SCD management that is approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Hydroxyurea’s principal mechanism of action is stimulating the production of HbF: a fetal form of Hb. When HbF is produced, it reduces HbS polymerization and so ameliorates pathological processes such as sickling, VOCs, and events downstream of these triggers. The mechanism by which hydroxyurea induces HbF generation is unclear. Since 1998, hydroxyurea has been the only FDA-approved therapy for SCD. By increasing both fetal hemoglobin concentrations in erythrocytes and reticulocytes, hydroxyurea treatment has significantly reduced the rates of VOCs, subsequent hospitalizations, and mortality in a range of patients. Unfortunately, despite these benefits, adherence to a hydroxyurea regimen has been problematic for some patients. Adverse effects of the drug include bone marrow suppression, large inter-patient variability in the effects it produces, and variations in the maximum tolerable dose. Consequently, other therapies have been sought based on a detailed understanding of the molecular and cellular events that produce VOCs.

Disturbances in blood flow produced by phenomena such as red cell sickling can be “sensed” by the endothelial cells that line blood vessels. Circulating sickled blood cells adhere to each other and to the activated endothelium, contributing to and potentially initiating VOCs. Activation of endothelial cells involves a large number of cellular responses that have pro-inflammatory consequences. For example, in postcapillary venules, activated endothelial cells express the proteins P‑selectin and E‑selectin. These are lectin-like molecules that can bind to specific patterns of sugar residues attached to proteins on the surfaces of circulating cells, allowing them to leave blood vessels and enter tissues as part of the inflammatory response. Activated platelets and adhesive sickle erythrocytes can adhere to circulating or endothelium-bound cells like neutrophils and form aggregates. Sickle erythrocytes can also bind directly to the activated endothelium. Endothelial cell activation—which occurs as a consequence of endothelium-derived nitric oxide (NO) depletion by cell-free hemoglobin released during hemolysis—oxidative stress, and constant inflammatory processes all play a key role in the initiation of VOCs. The adhesion of red blood cells and leukocytes to the activated endothelium acts as a trigger for VOCs.

These mechanisms means that P-selectin may well be an important drug target in situations like SCD. Over the past 25 years, selectins—particularly P-selectin—have been shown to contribute to pathological inflammation and thrombosis in many preclinical disease models, including atherosclerosis, ischemia–reperfusion injury, arterial thrombosis, and deep vein thrombosis. Patients with SCA develop injury to many organs that is consistent with repeated episodes of ischemia–reperfusion injury caused by the occlusion of blood vessels in VOC. Models of sickle cell anemia in experimental animals have established that sickled red cells obstructing small vessels trigger pathological inflammation and thrombosis that involves adhesive interactions among red cells, platelets, and the endothelium. P-selectin on the surface of activated platelets and endothelial cells binds directly to ligands on sickled red cells and immune cells like neutrophils. Blockade of P- or E-selectin decreases these adhesive interactions and improves microcirculatory flow in sickle cell mice. Results such as these suggest that agents that interfere with the functions of P-selectin might have value in preventing VOCs in SCD, and such an approach has recently been shown to have considerable promise.

Crizanlizumab is a recently developed humanized monoclonal antibody (a “mab”) that binds to P-selectin on the surface of endothelial cells and platelets and blocks its interaction with other cells. A large international clinical trial investigated the effects of crizanlizumab therapy on the rate of VOCs in a total of 198 participating SCD patients (aged 16–56 years), during 52 weeks of treatment. The intravenous administration of the P-selectin inhibitor was well tolerated, and high-dose crizanlizumab (5 mg/kg) was associated with a significantly lower frequency of VOCs in the treated patients, compared with the placebo group, where the median rate of VOCs per year was 1.63 versus 2.98 with placebo. Additionally, the median time to first crisis was significantly longer with 5 mg/kg crizanlizumab than with placebo (4.07 vs. 1.38 months). With VOCs being the major contributing factor to hospitalizations and reduced patient quality of life, these results were considered to be extremely promising and the United States Food and Drug Administration granted crizanlizumab a “Breakthrough Therapy” designation for the prevention of VOCs in SCD, implying that crizanlizumab demonstrated substantial improvement over existing therapies based on the available preliminary clinical evidence. On November 15, 2019, the FDA approved crizanlizumab-tmca (ADAKVEO, Novartis) for use in the reduction of the frequency of VOCs in adults and pediatric patients aged 16 years and older with sickle cell disease.

The FDA approval of crizanlizumab is hopefully good news for SCD sufferers. It also illustrates the important principle of treating pain on a disease-by-disease basis rather than going for a “home run” knockout drug that will treat more or less everything. This is what happened in the field of cancer. In the end, there was no “cure for cancer.” What we have achieved is a piecemeal approach where different cancers are targeted with different types of therapeutic agents depending on their particular mechanisms. There are plenty of painful diseases that might be helped by such an approach. Consider Ehlers-Danlos syndrome (EDS), for example. Like SCD, EDS is a genetically inherited disease which, in this instance, attacks connective tissue rather than the blood. Like those with SCD, EDS patients are afflicted with chronic pain that is often treated by long term use of opioids. However, judging by the success of crizanlizumab for SCD, we can easily imagine producing a drug for EDS pain that was directly targeted to a specific trigger. Moreover, there are many other painful diseases of this type. It is unlikely that we will ever improve on opioids for some types of pain but, as for many other situations, progress may well be made one step at a time.