What can ecstasy (the common party drug) tell us about hydration physiology and metabolic health?

 
The role of drinking water and keeping well hydrated to improve our health is a hotly cited media favourite. However, while we have ample knowledge on the extreme effects of hyperhydration (‘over-hydration’) and hypohydration (the state of lower total body water, commonly called ‘dehydration’), we know surprisingly little about how daily fluctuations in body water balance impact our health (Perrier, 2017).

There are several processes in the body which are designed to maintain our body water; in a life or death situation with very low fluid intake, these processes will save or at least prolong our lives, though in daily life in affluent countries such situations rarely occur. Instead we find that some people naturally drink more than others (Perrier et al., 2013). When people are low fluid drinkers, the lifesaving processes still occur, so we are trying to understand whether these have negative health consequences.

One hormone, arginine vasopressin (AVP, or anti-diuretic hormone), has been of interest. During times of low fluid intake or high solute (e.g. salt) intake, AVP increases and tells the kidneys to stop excreting as much water in urine, so water stays in the body instead. This means total body water remains roughly stable.

So why might AVP be bad for health? Firstly, we need to define health. Research has been focused on blood sugar regulation (or ‘gluco-regulation’) (Carroll & James, 2019). This is a good marker of overall metabolic health, with poor blood sugar regulation being implicated in diseases such as type 2 diabetes. This article focuses solely on gluco-regulation and does not consider other health factors (e.g. kidney function, cognition, cancer). By understanding whether and how hydration or AVP impacts blood sugar, we can hopefully help develop recommendations to reduce people’s risk of diseases like type 2 diabetes.

Secondly, we need to delve into some theory. There are many ideas related to hydration, but a key theory relates to the stress (fight or flight) response. More formally, this is the hypothalamic-pituitary-adrenal (HPA) axis. In brief, in a stressful situation, your body secretes several hormones including cortisol. Cortisol tells the liver to put more sugar into the blood so can disrupt blood sugar regulation. AVP is part of this HPA axis and can modify how much certain stress hormones are secreted (Herman et al., 2016), so in theory, high AVP caused by not drinking very much, could result in higher cortisol which disrupts blood sugar levels and increases the risk of metabolic diseases.

Considering this, it is perhaps no surprise that an early study that infused AVP directly into volunteer’s blood found an increase in blood sugar levels (Spruce et al., 1985). Similar results have been seen in studies that infuse salty water (hypertonic saline) (Keller et al., 2003; Jansen et al., 2019). Hypertonic saline increases the amount of solutes in blood, and this high solute concentration triggers AVP secretion, so it can also be reasoned from these studies that high AVP results in poor blood sugar regulation.

Such findings have seemingly been supported by many other types of evidence, including research in rodents manipulating AVP genes and fluid intake (Tanoue, 2009; Taveau et al., 2015); epidemiological associations between water intake or plasma AVP concentrations and gluco-regulatory health (Carroll et al., 2015, 2016; Enhorning et al., 2010; Pan et al., 2012; Roussel et al., 2011; Zerbe et al., 1979); and dehydration studies in people with type 1 and type 2 diabetes (Burge et al., 2001; Johnson et al., 2017). The consistency in findings suggest that the physiological effect of hypohydration is detrimental to blood sugar regulation, and is at least partly driven by AVP.

However, these studies all assessed different aspects of hydration physiology (rather than hypohydration overall) or have confounding factors that convincingly provide an alternative explanation for the findings. E.g., the dehydration studies in volunteers with diabetes withdrew medication; as such there was evidence that when participants were well hydrated, they were excreting more sugar in their urine (a common symptom of uncontrolled diabetes) (Burge et al., 2001). Therefore, it may not have been AVP which led to the higher blood sugar levels when participants were hypohydrated, but there was just less of an opportunity for blood sugar to be excreted in urine.

Our recent research further cast doubt on the certainty of the conclusions of previous studies. In this work we dehydrated people to lose ~2 % body mass and compared their blood sugar response to when they were well-hydrated. AVP increased by about five-fold (similar levels to those with metabolic diseases) but we did not find a difference in blood sugar, nor did we find differences in stress hormones (Carroll et al., 2019). In support of our findings, another group gave volunteers 1.5 L per day extra water and also found no differences in blood sugar despite reducing AVP (Enhorning et al., 2019).

While we await further data, we have the challenge of forming new hypotheses to explain these findings, and novel ways to test existing and new theories. This is where ecstasy, or more specifically, the psychoactive ingredient in ecstasy, 3,4‑Methylenedioxymethamphetamine (MDMA), comes in. From a hydration physiology perspective, MDMA is possibly the most fascinating drug as it gives all the symptoms of dehydration (thirst, dry mouth, reduced urination, etc), but on a cellular level, it causes over-hydration.

How does it do this? MDMA causes a large increase in AVP (Henry et al., 1998; Simmler et al., 2011). This in turn causes insatiable thirst resulting in increased fluid intake while simultaneously preventing the kidneys from excreting water in urine. The water that would be urinated then stays in the body and causes cells to swell. This effect is so potent that over-hydration is the biggest cause of injury and death in ecstasy users.

Therefore, MDMA poses an interesting and useful model to understand hydration physiology and its impacts on health; typically, when we manipulate hydration status, changes in total body water cause physiological changes (e.g. AVP secretion) to try to maintain body water. In other words, when total body water decreases, AVP increases and vice versa. By using MDMA as a model, we can have both high total body water, along with high AVP, thus separating total body water from the physiological effects of body water changes. So if AVP causes high blood sugar, we would expect to see high blood sugar after MDMA administration, and this effect would be independent of changes in actual hydration status (Carroll & James, 2019).

Unsurprisingly, very little research has been conducted on this. Rats given MDMA seem to get low blood sugar (Soto-Montenegro et al., 2007), contrary to current theories. The few studies looking at MDMA in humans have been too noisy to draw firm conclusions because, for example, participants were allowed to eat freely which directly affects blood sugar. Nonetheless, the overall trend seems to suggest that MDMA (and therefore AVP) has little to no effect on blood sugar (Carroll & James, 2019). This could mean that increasing fluid intake to reduce AVP might not be an effective strategy to impact gluco-regulatory health, though more controlled experimentation certainly needs to be done.

Overall, I am unconvinced that hydration status and/or AVP are meaningfully implicated in blood sugar regulation, especially in healthy adults during everyday fluctuations in total body water. Perhaps at extremely high levels of AVP/dehydration (i.e. > 5 % body mass loss), there might be an effect, but if someone is at that level of hypohydration, blood sugar regulation is probably the least of their worries. However, there is much debate in the hydration community about whether hydration and AVP can influence gluco-regulation so not everyone agrees with my conclusion probably due to the overall lack of data. Additionally, we need longer studies to test whether there is an effect of mild hypohydration over time. Hopefully as more data are collected, a clearer picture will emerge. Until then, considering water has no calories, and there’s some evidence it might be good for health (particularly kidney health which was not discussed or considered here), there is certainly no harm to drinking a bit extra until we have a more complete understanding of its health implications in day-to-day life.