Reply to: ‘Illicit drugs and cluster headache: An inevitable discussion’

To the Editor,

Readership should be made aware of a number of errors in Dr Arne May’s editorial (1).

1. Dr May mischaracterizes the significance of BOL-148’s relatively mild side-effects observed (as reported in our 2010 Cephalalgia paper (2) on the open-label, pilot trial of BOL-148 for cluster headache (CH)) and revisits Dr Tfelt-Hansen’s question of hallucinogenic potential that we had already fully addressed in our reply to Dr Tfelt-Hansen’s letter (3). From experiments in nearly 300 human subjects the fact remains that BOL-148 is non-hallucinogenic. It is quite perplexing that Dr May raises concern for what, at worst, were transient (<2 hour) ‘light drunk’ or ‘tipsy’ feelings from BOL-148, which achieved significant CH reduction in pain and attack frequency lasting weeks to months or more. Sumatriptan’s product package insert, for example, warns of possible ‘aggressiveness’, ‘drug abuse’, ‘hallucinations’, ‘personality change’, ‘agitation’, ‘suicide’, ‘disturbance of emotions’ and ‘intoxication’ (see http://www.drugs.com/pro/imitrex.html).

2. Dr May claims that BOL-148 was administered to ‘five patients (one episodic CH) with three patients not having tried any other preventative than Verapamil 240 mg in the past’. In fact, all five subjects were CH patients reporting failure of verapamil and many other standard treatments. Indeed, Table 1 lists several (but not all) of these other drugs including that subject 4 had a trial of verapamil at 320 mg/day and subject 5 had a trial of verapamil at 960 mg/day (2). The three subjects who at time of testing had most recently been on verapamil 240 mg/day failed to tolerate higher doses of the drug and this fact, too, is noted in Table 1 (2). All subjects had reservations (quite common in this patient population) to try medications like lithium because of concern about side-effects and controllability.

3. Dr May claims that there are consequences from the Rossi et al. (4) paper’s data ‘when considering the recent hype promoting the use of illicit drugs in CH’. Rossi et al. write: ‘Web sites devoted to CH actively promote therapeutic use of illicit drugs, and, by doing so, they possibly create or reinforce a specific interest in and demand for these drugs for CH’ (4,5). In fact, there is no evidence that either the referenced 2006 paper (6) or CH websites promote illicit drug use. The 2006 paper (6) merely presents data in a very large case series (by the standards of CH research) on symptom relief from the hallucinogens LSD and psilocybin for CH in ways that current, standard medications fail to achieve. Rather than ‘promote illicit drug use’, it calls attention to significant benefits described from LSD and psilocybin and that such findings warrant further research. Indeed, that is why we next came to evaluate a non-hallucinogenic homolog of LSD, BOL-148, for CH, which appears to be even more effective and has a much better risk profile for bringing to market since it is without the serious side-effects of hallucinogenesis (2).

Moreover, all drugs of abuse are not equivalent in risk for addiction. LSD and psilocybin, for example, do not induce any physical dependence as opposed to other drugs (e.g. opioids, nicotine, alcohol). Even the data of Rossi et al. (4) quite clearly show that there is no increase in hallucinogen use, male or female, in the CH patients surveyed. So why does Dr May still try to link Rossi et al. to the increasing awareness among CH patients that hallucinogens may help them?

4. Two significant reasons as to why Dr May discounts the use of hallucinogens and in the same breath that of BOL-148 may be the following.

Dr May asserts that society’s need to fight against drug abuse can take precedence over the therapeutic application of such drugs as medicines. He writes: ‘Are we allowed to ban or prohibit possible treatments for excruciating pain on the grounds of possible side-effects or the potency of addictive behaviour? Certainly yes, if we have effective alternatives; probably not if there are no other choices’. In fact, in the United States and much of the Western world, there is no such litmus test. Medicines for excruciating pain are not banned based on possible side-effects, diversion potential for abuse or the availability of other effective drugs. Instead, such medicines are placed in more restrictive schedules that control dispensing and/or may require greater education in order to safely prescribe. In the United States, for example, cocaine, methamphetamine and even tincture of opium are all available for prescription as medicines even though all clearly have serious abuse liabilities. Moreover, studies with drugs, controversial or not, are not predicated on research with only the medically intractable as also argued for in Dr May’s editorial (1).

Dr May is the principal investigator of a CH specific ‘observational’ trial (see http://clinicaltrials.gov/ct2/show/NCT01677026) of a sphenopalatine ganglion stimulator manufactured by Autonomic Technologies, Inc. of San Francisco, CA. If the treatment benefits from BOL-148 are proven and brought to market, very expensive and medically risky implantable devices like this one may prove unnecessary. While Dr May disclosed in a 2012 published abstract that: ‘Dr May has received personal compensation for activities with Autonomic Technologies as a consultant’ (6), he nevertheless asserts ‘none declared’ on ‘Conflicts of interest’ in his editorial (1), which downplays the significance of a drug that may trounce in competition a product he has a financial interest in. Here is where the appearance of a conflict of interest would be important for readers to know while considering the merits of Dr May’s editorial position and, as such, we now bring it to light.