Health Risks Associated with Mephedrone Use: What We Know So Far

When mephedrone first hit the UK drug scene in 2009, there was hysteria in the media. It was a hardly-known, seemingly untested drug with potentially serious long-term health consequences. Despite being prohibited in the country in 2010, it has remained popular among certain groups – including the chemsex population – in the UK and other European countries.

So almost 10 years on from the ban, are we any clearer as to the risks? In this report for TalkingDrugs, Sam Iravani has combed through the data and spoken to the researchers…

 

Cardiovascular effects

 

Both cocaine and methamphetamine directly interact with the heart's electrical system, which - in the simplest terms - regulates the heart's pumping action; however they react with different channels. These reactions have been associated with abnormal heart rhythms called arrhythmias, which is the main cause of sudden cardiac deaths.

Sudden death has sometimes occurred with mephedrone use, which suggested that mephedrone could trigger arrhythmias. However, when researchers investigated mephedrone's effects on these cardiac channels, they found little to no effect, despite the fact that they used drug concentrations that have been present in the blood of deceased persons.[1]

Mephedrone also had no significant effect on action potentials (which are used by the heart to synchronise contraction), regardless of the concentration tested. This is in contrast to amphetamine and MDMA that have been shown to disrupt these bursts of electrical activity, the result of which may also produce arrhythmias.[2] [3]

In addition, electrocardiograms have been taken on some patients who visited a Scottish emergency department after binging on mephedrone for an average of 2.8 days. None of the electrocardiogram parameters collected during these recordings were reported as being abnormal and no arrhythmias, other than an elevated heart rate, have been detected in any of these patients.[4]

However while mephedrone is not directly proarrhythmic, a recent study shows that it causes mitochondrial dysfunction in the heart of a rat, which could still increase the likelihood for arrhythmias. Mitochondrial dysfunction is also considered to be a key contributor to the development of heart failure.

In reality, many of the studies' findings may not be as alarming as they first appear. For instance, any drug which causes the release of large amounts of catecholamines (amphetamine, MDMA etc) can cause mitochondrial swelling just like mephedrone has done here.[5] Nevertheless, mephedrone was shown to cause a very high reduction in ATP levels in rat heart mitochondria, even at the lower concentrations tested.[6] ATP provides energy to drive many processes in living cells, the lack of which can lead to a breakdown in the heart's continuous mechanical work (although to what extent this alone can actually drive heart failure is not clear).

Overall, the study suggests that prolonged mephedrone use could lead to heart problems, which shouldn't be surprising given that it's a powerful stimulant. The epidemiology from the UK doesn't really support a direct link (more on this later), so damage is likely to occur over many years rather than months.

There is also a possibility that long-term mephedrone use could be associated with valvular heart disease (whereby the valve becomes inefficient and blood leaks back into the heart) due to its affinity for the 5HT2b receptor. This is a property shared by MDMA, and mephedrone's affinity for the 5HT2B receptor is around the same as that of MDMA, albeit slightly weaker.[7]

The hearts of people who regularly use MDMA showed abnormalities including aortic regurgitation in one retrospective study.[8] However, these subjects had extremely high MDMA use (an average use of 3.6 "tablets" per week for 6 years), so it may not be at all relevant to people who space their MDMA and mephedrone sessions.

In terms of short-term effects, mephedrone produces a significant increase in heart rate and blood pressure; however, the exact extent in humans is not known. The only human study that looked at mephedrone's effect on blood pressure used a single oral dose of 200mg, which is a relatively low dose compared to what most people who regularly use the drug would take in an average session.[9]

Also, the data from people attending hospital emergency departments for mephedrone use are likely to show levels that have dropped significantly by the time they arrive at the hospital, due to mephedrone's short half-life. However, the Scottish study of patients who visited an emergency department after binging on mephedrone for an average of 2.8 days found that the blood pressure and heart rate of the patients was elevated, but not high enough to be considered dangerous in otherwise healthy people.[10]

As far as stimulants go, mephedrone appears to be relatively benign on the heart. This may explain why 2009 – the year when mephedrone was at its most popular in the UK – was also the year when cocaine deaths fell by 30 per cent[11]. However, being closely chemically related to amphetamine, mephedrone clearly has the potential to cause damage.

“I would suspect that mephedrone would ultimately act like amphetamine on the cardiovascular system, albeit a somewhat weaker effect, perhaps,” said David Rampe, a researcher who was involved in the study that did not find direct evidence of cardiac toxicity caused by mephedrone.

In theory, this means that long-term mephedrone use could cause many of the same problems as other amphetamines such as premature ageing of the heart. However, such studies may not be possible in rodents and would likely require a long-term administration in humans to see any potential changes. So it may be some time before we have the answers.

“I watch PubMed regularly for new research on mephedrone,” Rampe said. “It seems that a fair amount is being done. Mostly regarding central nervous system effects but not much on cardiovascular effects.”

 

Effect on brain chemicals

More peak dopamine release than amphetamine, more serotonin release than MDMA, and a pattern of brain activation similar to that of methamphetamine. Mephedrone is a powerful drug.

It would be unsurprising to find that heavy mephedrone use causes long-term undesirable alterations in neurotransmitter systems, with possible lasting psychiatric consequences (clinical depression and anxiety disorders, most likely). However, the evidence is so far inconclusive.

Despite its similarities to MDMA and methamphetamine, studies have shown that mephedrone produces its rush of dopamine and serotonin in a manner quite different to those two drugs. One study showed that mephedrone and MDMA had a different interaction with the human brain vesicular monoamine uptake; with mephedrone displaying a 10 times lower transport inhibitory potency compared to MDMA.[12]

So, what does this actually mean?

“Some of the long-term effects of amphetamine-related stimulants (and mephedrone is one of them) such as long-term loss of dopamine and serotonin tissue levels and finally loss of dopaminergic and/or serotoninergic nerve endings, are hypothesized to be due to interference with the vesicular storage of these monoamine neurotransmitters,” explained lead researcher Christian Pifl.

“On these lines, mephedrone might be safer than MDMA.”

Another study suggested that mephedrone increases dopamine and serotonin levels in a “safer” way that has less a sustained effect on these brain chemicals, compared to methamphetamine which could cause increases beyond the actual presence of the drug (and thus might be more dangerous).[13]

Additionally, there are some studies on rodents showing less long-term effects by mephedrone than by methamphetamine and MDMA.

One study gave mice a fairly hefty binge-style treatment with mephedrone before examining their striatums (a part of the brain that is related to both movement and addiction, and is very strongly activated by mephedrone) for signs of dopamine neurotoxicity. They found no significant differences between the brains of their drug-treated and control animals.[14] This is in contrast to methamphetamine, amphetamine and MDMA.[15]

A follow-up study found that a binge-style treatment with mephedrone did not cause serotonin neurotoxicity in the hippocampus (a part of the brain that is associated with emotions and motivation).[16] It is worth nothing that female mice were used in both of these studies because they are known to be very sensitive to neuronal damage by amphetamines.

Four rodent studies found no lasting effect of mephedrone on neurotransmitter levels. [17] [18] [19] [20] This is despite the fact that the researchers gave doses that would have been more than sufficient to cause toxicity if it had been MDMA.[21] Converted into human equivalent doses, these doses ranged from around three daily doses of 330mg to around 1 gram twice daily for 4 consecutive days. Additionally, one of the studies gave the rats behavioural tests to see if the mephedrone had done any damage, and all of the anxiety and social tests came back negative.

However, three studies do give some cause for concern.

A team from the University of Barcelona gave mice four doses of mephedrone (equivalent to around a 1.5g session in humans) as well as doses that mimic the typical weekend consumption pattern in humans (around three daily doses of 200mg for 2 consecutive days). When they examined their brains 7 days later, they found severe deficiencies of dopamine and serotonin in the frontal cortex (a part of the brain that controls cognitive skills such as problem solving and memory) as well as the hippocampus and striatum of the mice.[22]

A follow-up study in rats also found similar deficiencies of dopamine and serotonin that persisted 7 days after a binge-style treatment.[23]

Paradoxically, a rodent study from the University of Utah found persistent serotonin deficiencies, but not dopamine deficiencies, at 7 days following a binge-style treatment.[24] This is surprising because mephedrone has a greater affinity for dopamine than serotonin.[25]

It must be noted that in all of the studies that found persistent brain changes, the researchers used high ambient temperatures to simulate the conditions found in dance clubs where the drug is often taken, a condition that wasn't considered in previously published papers. When taken in crowded dance clubs, the elevated temperature associated with mephedrone use can cause hyperthermia (severe overheating) which in turn can cause brain damage.

“In our experiments, hyperthermia only appeared after a binge exposure to mephedrone,” said Elena Escubedo, a researcher who was involved in both of the studies from the University of Barcelona. “This is a critical point, since the raise in body temperature seems to be the result of redosing at both normal or high ambient temperature (more risky). However, this hyperthermia is lower than that induced by MDMA or methamphetamine.”

Although there were results suggestive of possible brain damage in her team's experiments, mephedrone (like many other stimulants) exacerbates hyperthermia in such conditions, meaning it is possible that it was caused by the hyperthermia rather than by the drug directly.

“Probably, and as with MDMA, if hyperthermia is avoided, the neurotoxic injury would be reduced,” said Escubedo. “In this way would it be completely reversed? I don’t think so, but I couldn't tell.”

Her team also produced some evidence that mephedrone-induced brain damage may be avoidable in these hot “nightclub” conditions. When they gave four doses (equivalent to around 750mg in humans) to the mice over the course of one day as opposed to two consecutive days, they found no persistent changes in brain structure, which the researchers think is due to the possibility of recovery.

 

Memory

A team from the University of Sydney followed-up a study which suggested that people who regularly use mephedrone performed much worse on various memory tests as opposed to people who never used, even on the weekends that they didn’t use the drug.[26]

The team tested this out in the lab on rats, and found that the rats showed a substantial memory impairment 5 weeks after being given mephedrone.[27]

This finding was alarming for two reasons: firstly, the dose that caused the impairment was not excessive (around 300mg in humans for 10 consecutive days). Secondly, a month and a half is quite a long time for a rat, so any changes hanging around for that long are quite possibly permanent.

Surprisingly, when the team looked at the brains of the memory-impaired rats, they didn’t find any long-term changes in their neurochemistry: so, whatever was driving the memory impairment was not something as simple and as obvious as too much serotonin, for example.

However, a recent study has shown that enzymes like matrix metalloproteases (MMPs) are a key factor in the cause of this memory impairment. Although elevated activities of MMPs are likely to decrease over time, assuming that mephedrone use is stopped, they can remain elevated even after a long period of abstinence. Moreover, further studies are required to find out if elevated activities of MMPs contribute to brain damage or recovery from brain damage caused directly by mephedrone.[28]

 

Liver/kidney effects

A recent study showed that both high and lower (single) doses of mephedrone significantly reduced antioxidant defences in the liver and kidneys of mice, but not the spleen (which plays a crucial role in proper functioning of the immune system).[29]

This doesn't necessarily mean that there was any injury being done to the mice, but it does suggest that they'd be more vulnerable to oxidative injury than mice with higher antioxidant defences (and therefore become more prone to develop dysfunction and/or disease).

In contrast, blood tests were performed on 30 patients who visited a Scottish emergency department after binging on mephedrone for an average of 2.8 days. None of the liver function tests returned abnormal findings[30]. A blood test was also performed on a man who landed in the emergency room after injecting mephedrone almost every weekend for 4 months (consuming about 3-4g per weekend) and no irregularities were found at all.[31]

None of this refutes the rodent study, but it does suggest that liver/kidney damage would occur only after long-term and heavy mephedrone use.

Also, TOXBASE reports from 2009-2010 noted no clinical cases with abnormal liver function tests. However, there were 2 telephone enquiries from health professionals relating to cases with abnormal liver function tests from exposure to mephedrone alone or in combination with alcohol. Unfortunately, more detailed information wasn't available or wasn't provided.[32]

 

Drug interactions

Very few studies have investigated possible interactions of mephedrone with other drugs. One study found that mephedrone increased the dopamine toxicity of methamphetamine, amphetamine and MDMA, suggesting that a potentially dangerous interaction might occur if mephedrone is taken with other illicit amphetamines[33].

A case report describes a young man who developed acute kidney injury after taking large amounts of mephedrone.[34] The young man had no other relevant medical background or family history of kidney disease. However, he admitted to consuming methamphetamine, diazepam and snorting cocaine over the previous 3 days in addition to mephedrone, so it’s likely to be the combination of mephedrone and the other drugs he took that caused the kidney injury.

In addition, there are two cases in the literature of acute kidney injury following the use of ‘bath salts’ (combination of mephedrone and MDPV), suggesting that a dangerous interaction might occur if mephedrone is taken with other cathinones.[35] [36]

There is some evidence to suggest that mephedrone may interact in a dangerous way with SSRI antidepressants. One case report of serotonin syndrome (a potentially fatal drug reaction caused by serotonergic drugs) occurred in a person taking both mephedrone and fluoxetine, so it's likely that it’s the combination that was responsible.[37]

Although the interaction between mephedrone and alcohol is not well understood, it has the potential to negatively affect how both substances are metabolized and can be very dangerous. For example, a study showed that mixing alcohol and mephedrone significantly increased the serotonin release compared with the rats receiving mephedrone alone, which could make the effects of the drug much stronger while bringing toxicity levels right up with it.[38] Additionally, many of the initial medical case reports on mephedrone suggest that it can cause problems with breathing and the circulatory system, particularly when combined with alcohol.[39]

 

Precaution information

A case report describes an 18-year-old man with type 1 diabetes who developed ketoacidosis following self-reported mephedrone use. Mephedrone and cathinone compounds may therefore directly increase the risk of diabetic ketoacidosis by stimulating the central nervous system.[40]

Mephedrone appears to be particularly dangerous for people who inject it. Mephedrone solutions are somewhat acidic, and users routinely report that snorting or injecting mephedrone is intensely painful. A study of Irish mephedrone injectors found truly gruesome consequences were common amongst their participants.[41]

From the abstract of that paper:

“Although participants were aware of risks and safe injecting practises, compulsive re injecting with excessive binge use over long periods of time was common. Nasal to injection route transitions, intense paranoia, violent behaviour and aggression, emergence of Parkinson type symptomatologies (in the form of spasms and ‘wobbling’), and permanent numbness in lower extremities were reported. Multi and serial drug injecting with heroin was used in efforts to manage the intense rush and avoid unpleasant comedown. Participants reported limb abscesses, vein clotting, damage and recession resulting from product toxicity, crystallisation of the products when diluted and flushing practises. Seven participants were homeless, with groin and street injecting common.”

From the body of the paper:

“All participants reported an intense burning sensation on injection. Continued attempts to inject resulted in vein blockages, with development of skin erosion, localised infections, blisters, spots, cold sores, abscesses, scabs, lumps, gangrenous tissue, blood clots and large holes at overused injecting sites.”

From one of their participants:

“It clots up your veins twice as fast as anything else...that’s one thing I did learn fast from it, say you used one vein on it and got two hits out of it, you wouldn’t get the vein again, you’d have to move onto a different vein to get another hit out of it, that’s why everyone started using their groin.”

 

Fatalities and intoxications

The typical pattern of mephedrone Emergency Room presentations appears to be a patient with amphetamine-like symptoms (i.e. racing heart, chest pains, anxiety, paranoia) which is then resolved through simple bedrest, observation and sometimes the use of tranquilisers. In almost all reports, such treatment allows patients to be discharged in a fairly short time (typically within hours) without obvious lasting ill effects.[42]

In the literature, only 16 fatal cases have been identified in which mephedrone was confirmed in biological samples of the deceased (this excludes cases in which mephedrone was not directly implicated in the cause of death). The death was attributed solely to mephedrone in 6 cases; 3 cases had mephedrone concentrations of around 2000 ng/ml, while the other 3 had mephedrone concentrations of 3300, 5500 and 22000 ng/ml.[43] [44]

So, how much mephedrone did they take?

“It's actually not possible to determine the dose of a drug from post-mortem drug concentrations,” explained Peter Maskell, one of the first researchers to report on mephedrone-related deaths. “There are various factors that we don't know between taking the dose and the blood concentration. This is especially problematic with new psychoactive substances such as mephedrone where we don't have basic clinical pharmacokinetic data that would available for drug that have been through the clinical licencing process.”

However, Maskell notes that there have been at least 2 studies where controlled doses (150mg/200mg) of mephedrone were given to people. This gives a “guess” at what concentrations of mephedrone are “normal.”

“This doesn't take into account the amount people would be taking for [misuse] purposes (which is likely to be higher) or tolerance,” he said. “These 2 studies give peak concentration of around 150 ng/ml. So, compared to those studies a concentration greater than 2000 ng/ml would be high.”

Indeed, the limited data available on mephedrone suggests that fatal cases involve doses that are much higher than what the typical person would take. The most extreme case of non-fatal mephedrone intoxication is of a man who injected 3.8g into his thighs after ingesting 200mg orally. Shortly after the injection, he developed palpitations, “blurred tunnel vision,” chest pressure, and sweating; however, his symptoms were settled after a single dose of lorazepam.[45]

Similarly, there are sub-groups of people who use heavier quantities, who report consuming up to 16g over the course of a session (typically 8-12 hours in length). However, it's impossible to give a suggested safe dose as similar doses may have dramatically different consequences in different individuals.[46]

In the other fatal cases, mephedrone was identified in combination with other drugs, hence it is difficult to describe the exact role that mephedrone played in the reported fatalities. In 2 cases the deceased had heart problems which was a contributing factor, and 2 other cases appear more likely to be overdose from combining multiple opiates and depressants.

However, lower concentrations of mephedrone were found in cases where other substances were consumed compared to cases of solely mephedrone consumption. This suggests that lower dosages of mephedrone can potentially cause serious and fatal consequences when taken in combination with other substances such as alcohol, GHB, benzodiazepines, piperazines, cocaine, opiates/opioids, amphetamine and ecstasy. 

Similarly, from 2009-2011 (when mephedrone use was at its peak), the UK National Programme on Substance Abuse Deaths identified 90 fatal cases where mephedrone was identified in biological samples of the deceased. However, only in 26 cases was the cause of death listed as poisoning by drugs and only in 8 cases was mephedrone identified as the only drug of misuse[47].

More recent data from the Office of National Statistics shows similar low figures. From 2012-2017, there were on average 18 deaths per year relating to mephedrone in England and Wales. The lowest recorded number was just 1 death in 2017. The highest number was 44 deaths in 2015, which could be reflective of an ageing group of people who formerly used heroin starting to inject mephedrone because of its cheap price.[48]

Mephedrone is not a perfectly safe drug; if you are unprepared, unwise, or unlucky, it can kill you. But given the large-scale use of mephedrone in the UK and Europe over the past decade, the rates of acute fatality from mephedrone have been remarkably low.

 

Conclusion

Mephedrone and other cathinones are less toxic than their amphetamine counterparts, agrees Michael Baumann of the Designer Drug Research Unit (DDRU). “It seems that the pharmaceutical industry was already aware of this, i.e., development of bupropion, a tert-butyl cathinone derivative, as an antidepressant and smoking cessation aid many years ago,” he said.

However, while mephedrone might be safer than MDMA, at least from the point of view of acute toxicity, there exists a body of literature that suggests that mephedrone is more addictive than MDMA. This means that limited and reasonable use of mephedrone is something that is hard to do, and many people who use it regularly end up taking massive doses of the drug over short time spans which could cause long-term damage.

Based on the research so far, people using mephedrone wishing to minimise their risk can take the following steps.

  1. Most important is to avoid overheating and dehydration, especially when dancing in hot clubs for long periods. Drink water regularly and take breaks to cool down; but do not drink water in excess as this may cause fatal water intoxication. Gradually drinking a pint of water each hour is recommended.[49]
  2. Avoid using mephedrone with alcohol or any other drugs.
  3. Avoid injecting.
  4. Avoid taking mephedrone for more than one day at a time, and give yourself appropriate breaks.

 

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