Obscure and Unknown: Mefloquine

*WARNING* I'm forgoing the usual disclaimer for this substance, as its effects on humans have by now been well documented. My justification for inclusion in this series is in the body of the text. Under NO circumstances should you attempt to take this drug to intentionally induce hallucinations. The "experience" is literal clinical psychosis with vivid and distressing hallucinations, and worse yet, the effects may in some cases be PERMANENT. 

For today's installment, I bring you a paradoxical substance that is both lifesaving yet in some cases a life-ruining nightmarish burden. As it says in the disclaimer, this should not be taken intentionally for its hallucinogenic effects under ANY circumstances. This includes you, intrepid teenager trying to find out how to get high from the medicine cabinet. This isn't worth it. It can permanently damage your brain. This writing is in no way to encourage the use of this substance, but simply to explore lesser known ways in which substances can powerfully alter perceptions. In fact this write up is a cautionary tale of what happens when medicines aren't sufficiently tested before being approved for mass consumption. So which accursed drug is this? The friendly neighborhood antimalarial, Mefloquine, sold under the brand name Lariam.

uh oh

Yes, I'm aware you might have heard of Mefloquine already. Mefloquine is not obscure by any means in standard medical lexicon. It's standing among psychonauts however, is minimal (And for good reason!). 

It is a typical antimalarial drug of the Quinoline class- other members of this class include well known substances like Quinine, the original antimalarial, a natural extract from the bark of trees in the genus Cinchona and the bittering agent in tonic water. Other related compounds that have been in a news a great deal lately are Chloroquine and Hydroxychloroquine, which have been touted as treatments for COVID-19 despite being, as of this writing, unproven in their efficacy. (And as is to be a theme in this article, still not fully understood in their side effects as an antiviral treatment). 

But those aside, Mefloquine. Mefloquine has been in use as a prescription antimalarial for almost 40 years. It is indicated both as prophylaxis (prevention) for travelers to areas where malaria is known to be resistant to other medications. It is also taken at higher doses to treat already incident cases of malaria. As a preventative, 250 mg are to be taken weekly1. In the case of treating malaria, a single dose of 1250 mg is indicated1. Mefloquine is listed on the WHO's list of essential medicines.

It's an essential medicine! So what is it doing on my degenerate blog? Hallucinations of course. Now other antimalarials like the now-famous hydroxychloroquine are known for their rare hallucinatory side effects2. What makes Mefloquine special is the scale, duration, and severity of these hallucinations. 

Mefloquine's genesis was the result of a historically massive drug-discovery effort funded by the U.S. government, in which 250,000 potential compounds were screened3. This was motivated by the massive casualties inflicted on American troops by malaria during the invasion of Vietnam3. It showed great promise as a preventative for drug-resistant malaria, and due to shady political circumstances, development was rushed and no randomized phase III trials were performed3. It was approved and marketed in 1989. In a short time, reports began to trickle in of alarming psychiatric effects. 

Because so much money and deep pockets (mostly from the U.S. federal government no less) were involved in the invention and marketing of this drug, there was initially pushback against the claims that it may be harmful4. Symptoms were initially attributed to other causes, like travel stress or use of other drugs. The devastating evidence mounted however, and finally, 12 years after its initial approval, proper blinded tests performed, the type that should've been done before the drug had ever hit the market4. But the damage had already been done.

What were these effects? The generalized syndrome begins with a prelude of a shift in personality, unease, and indistinct fear and anxiety. These will then sometimes give way to a full blown psychotic state replete with paranoia, delusions, and hallucinations. The hallucinations are considered "true" hallucinations- in that they seem completely real, and are not regarded by the patient as hallucinations. They often have morbid or religious themes, with auditory hallucinations of incoherent and mumbling voices. Some patients reported feeling a presence nearby. Many patients also described vivid traumatic nightmares that had "technicolor clarity" and were marked in their memories for days4. The psychosis often presented with a fixation on self harm, dangerous objects, and a loss of a sense of self preservation4. These experiences were of course profoundly disruptive to the lives of patients, in some cases leading to suicide. One specific case cites a man who jumped from a window due to a hallucination that his hotel room was on fire. 

Mefloquine induced psychosis is distinguished from schizophrenia due to its dissociative nature. Ritche et al. in their literature review of Mefloquine psychosis describe it as thus:

"Mefloquine psychosis may be distinguished from schizophrenia and certain other forms of psychiatric illness in that it may feature prominent characteristics of dissociation. Symptoms of derealization and depersonalization, compulsions toward dangerous objects, and morbid curiosity about death may accordingly underlie reports of seemingly spectacular and impulsive suicide, suicide attempt, and parasuicidal behavior associated with the use of Mefloquine."

It is also distinguished from endogenous psychosis in its amnesiac nature, causing substantial memory wipes of patients at the peak of their symptoms. This is similar to the experience induced by anticholinergic deliriants like DPH. 

In one particular case study, the patient observed:

"...the impression of focusing on two different planes,of perceiving the surrounding people as very far from him, of perceiving his arms stretching for 5 meters. He also complained that he felt like he was stuck to the ceiling, watching the actual scene from above5"

These are described in the literature as "illusions" as opposed to the "true hallucinations" other patients suffered from. These specific effects are highly reminiscent of dissociatives. This effect came randomly in episodes of a few seconds to an hour in duration and was accompanied with an acute sense of panic. What is noteworthy about this case is these attacks continued for 8 months after the patient stopped taking his prophylactic doses of Mefloquine (which was only 3 250 mg doses over a course of 3 weeks). 

Indeed, the psychotic effects of Mefloquine can last a lifetime. There are several reports of the effects persisting for up to a year or longer, and in some cases, they simply never resolved and have been presumed permanent6. In almost all of these cases, the drug was taken at the exact dosage and regimen indicated. People being stricken with permanent hallucinatory psychosis with no underlying causes from taking a drug meant to prevent Malaria is a travesty, especially when it was due to politically motivated neglect during clinical trials.

One of the worst parts of this entire fiasco is how little is still known about Mefloquine. The hallucinatory effects seem to appear at random, presenting at recommended doses or not appearing in what would otherwise be overdoses (If for some twisted reason you are still considering taking this to hallucinate, this is another reason not to- it is literally impossible to predict the dosage, or if it will induce hallucinations at all, and if it does work-it could be life-ruining. I know this blog is about recreational drug use. Just DO NOT this one time). It is at least known that continuing to take the drug after psychiatric symptoms present will make them worse, and that higher doses have a higher chance of inducing symptoms, though symptoms may still appear from a single recommended dose.The exact mechanisms by which it causes its psychosis are also poorly understood and likely lie outside the Dissociative-Psychedelic-Deliriant trifecta of hallucinogens (though it has qualitative similarities to the nACHr antagonists (deliriants) and NMDA antagonists (dissociatives)). One possible explanation is similar to a hypothesized model for schizophrenia, in which regulation of dopamine is disinhibited, leading to excess dopamine transmission between neurons within the limbic system, supposedly producing or at least being somehow related to psychosis (this is also seen to some degree in "psychotomimetics" such as PCP or MK-801)4. However, this doesn't offer a full explanation- the limbic system only encompasses things such as emotion, memory, and behavior. The existence of vivid visual and auditory hallucinations suggests other parts of the brain are being affected. Perhaps most alarming is that microscopic lesions were observed in the brainstems of rats, which suggests that literal physical brain damage may be involved7.

The risk factors that result in Mefloquine psychosis are poorly understood. One study hypothesized that the presence of certain genes could perhaps indicate vulnerability to psychiatric side effects8. Other researchers have observed that the effects are often comorbid with the consumption of alcohol or other drugs, though alcohol consumption is so widespread that this observation sheds little light on things4. Epilepsy also appears to be a risk factor. Notably, it is not recommended in people with serious mental illness, as they may have trouble distinguishing the effects of Mefloquine from their preexisting symptoms and they may exacerbate and prolong more acute psychosis by continuing dosages.

So little is known about such a widely used drug, so many things where the knowledge should have been a prerequisite to the drug's mass market release. Mefloquine is a cautionary tale that should serve as a stark reminder of why the process of drug development is so long and tedious, something that is particularly relevant in the era of Coronavirus. There is no such thing as a quick cure, and anything developed in a hurry is a certain gamble on the life of the patients who take it. If proper clinical trials are not carried out, unexpected irreparable harm can be done to the people the drug is supposed to help. 

Because of the severe effects and subsequent bad press, the manufacturer, Roche, stopped marketing the drug and it was swept under the rug. With this blow struck, studies on it also quieted.  It is still prescribed in cases where other antimalarials are unsuitable, albeit with a booklet making the possible complications clear. Mefloquine COULD be a useful antimalarial that could be safely applied if it were studied thoroughly enough to determine what the exact risk factors were. But it's too late for that, and its name is already well besmirched. 

Mefloquine was notably widely distributed to armed forces deployed in malaria prone places. In 1993, members of the Canadian Airborne Regiment were in Somalia for what was ostensibly a "humanitarian mission". This culminated in a number of horrendous atrocities including shooting and killing unarmed civilians and the torturing and beating to death of a teenager, Shidane Arone. This became coldly known as the "Somalia Affair". Conservative MPs were quick to point their finger at the new antimalarial drug the soldiers were being given, Mefloquine. While these murders are largely attributable to the epidemic of thuggish racism among western militaries, witnesses claimed that the Arone's murderer, Clayton Matchee had been experiencing vivid hallucinations and paranoia as a result of his Mefloquine treatment. Matchee was declared unfit to stand trial as he was left brain damaged from a suicide attempt 3 days after the trial. Regardless of the true responsibility for these terrible acts, the fact that these allegations were even made raises questions of just how much the atrocities committed by western soldiers deployed in tropical zones was exacerbated by this paranoia and hallucination inducing drug before its effects were fully documented. The disastrous effects of poor testing can be far flung and take many forms and cause many people to suffer, both directly and indirectly.

Sources and further reading:

1-https://www.rxlist.com/lariam-drug.htm#dosage

2- Ferraro V, Mantoux F, Denis K, Lay-Macagno MA, Ortonne JP, Lacour JP (2004) Hallucinations during treatment with hydrochloroquine. Ann Dermatol Venereol 131(5):471-3 (In French)

3-Croft AM (2007) A lesson learnt: the rise and fall of Lariam and Halfan. J R Soc Med. 100(4): 170–174.

4- Ritchie EC, Block J, Nevin RL (2013) Psychiatric Side Effects of Mefloquine: Applications to Forensic Psychiatry. Journal of the American Academy of Psychiatry and the Law Online 41 (2) 224-235

5-Borruat FX, Nater B, Robyn L, Genton B (2001) Prolonged Visual Illusions Induced by Mefloquine (Lariam®): A Case Report. Journal of Travel Medicine 8;3:148–149

6-European Medicines Agency (2014). Updated PRAC rapporteur assessment report on the signal of permanent neurologic (vestibular) disorders with mefloquine. EMA/63963/2014. January 31, 2014.

7-Nevin RL (2012) Limbic encephalopathy and central vestibulopathy caused by mefloquine: a case report. Travel Med Infect Dis 10: 144 –51

8-Aarnoudse AL, van Schaik RH, Dieleman J, Molokhia M, van Riemsdijk MM, Ligthelm RJ, Overbosch D, van der Heiden IP, Stricker BH 2006 MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of Mefloquine. Clin Pharmacol Ther. 80(4):367-74.

9-https://www.thecanadianencyclopedia.ca/en/article/somalia-affair

10-https://nationalpost.com/news/canada/veterans-urge-another-look-at-clayton-matchee-case-in-light-of-malaria-drugs-side-effects

11-https://www.theguardian.com/lifeandstyle/2015/apr/10/experience-anti-malaria-drugs-made-me-psychotic

*It's probably worthwhile to examine my use of the term "hallucinogen". From hereforth, "Hallucinogen" with a capital H, will be used to refer to substances within the trifecta of Psychedelic-Dissociative-Deliriant, or if you want a formal definition, 5-HT2A agonists, NMDA antagonists, and mACHr antagonists respectively. "Hallucinogen" (big H) refers to substances that act primarily on these receptors in a way that causes hallucinatory effects a majority of the time they are administered above a threshold dose. A more general usage, hallucinogen, with a lowercase H, refers to substances that are capable of incidentally inducing hallucinations, though this isn't their primary action and often extremely high doses, heavy repeated use, comorbid factors, or preexisting conditions are required for hallucinations to present. This can include things like cannabinoids or alcohol, or our trouble child Mefloquine here. For this series I will be using "hallucinogen" with the lowercase h.