Why are weightlifters so happy?

I have a unique observation: bodybuilders are generally happier people. There is no evidence to support this, but I needed a catchy headline. Yes, there is evidence that moderate continuous exercise can help alleviate symptoms of depression.1 But I, as always, have another theory. Perhaps it is the use of athletic enhancing supplements that could lead to improved mood. This might be a stretch but it seemed like an interesting idea for an article: Could ingredients in pre-workout supplements possess the ability to improve mood? The use of supplements in high-caliber athletes is thought to range from 85% in elite track and field2 to 82% in Crossfit althetes.3 The supplement we shall learn about is called the “pre-workout.” The pre-workout is a drink that contains multiple supplements that are thought to aid in improving athletic performance. The ingredients of note are caffeine, citrulline, beta-alanine and creatine. Usually you consume this beverage 30 minutes before a workout to increase performance and endurance. Whether this occurs is debatable. Caffeine and creatine I love caffeine; others share this love. Here’s a fun game: when you commute to work today, count the number of locations that can provide you with this beloved psychoactive substance. There is a substantial amount of research to suggest that caffeine can have positive effects on athletic performance.4 Some of the mechanisms of actions for this include reduction of fatigue by blocking adenosine receptors and potentiating muscle contractions.5 A recent meta-analysis found that coffee ingestion had an inverse association with depressive symptoms.6 It was noted that there was a 4% reduction in depression risk with each increase of 250ml of coffee ingestion. The optimal dose is thought to be 400ml of coffee daily.7 This effect was attributed to caffeine’s ability to modulate dopaminergic transmission and facilitate serotonin release. Sadly, there was no effect on depression with tea consumption. However, l-Theanine (a major psychoactive substance in tea) at a dose of 250mg/day had a beneficial effect on patients with major depressive disorder.8 It should be noted that most pre-workout supplements contain between 200-300mg of caffeine and 250mg l-theanine per dose. This is the same amount of caffeine in a 4-shot espresso or 500ml regular brewed coffee. Creatine is perhaps the most popular and studied supplement for increasing athletic performance. Regular supplementation has been shown to increase time to exhaustion with short-term highly-intensive activities (eg., weightlifting).9 This action is thought to be due to creatine’s ability to assist in rapid regeneration of ATP in muscles.9 As the greatest dietary source of creatine is from meat products, benefits of supplementation are even greater in vegetarians compared to omnivores.10 Also of note, vegetarian athletes who took 20gm of creatine for 5 days experienced improvements in working memory compared to meat eaters.11 Vegetarian diets have been associated with elevated risk of mental disorders (including anxiety and depression), but no causal role has been shown.12 A recent article summarized the effect that creatine has on improving the symptoms of depression.13 However the article noted that most of these studies were small, open label or studied creatine use in addition to other depression treatment options (i.e., SSRIs). This effect was thought to be due to increased local energy stores and efficiency of oxygen uptake. Although a recent study found that stroke survivors who participated in progressive resistance training experienced improvements in muscle strength and depression,14 those participants who took creatine only demonstrated an increase in a six minute walk speed. L-Citrulline and beta-alinine L-Citrulline is a non-essential amino acid that is thought to be helpful for exercise performance due to its ability to increase nitric oxide synthesis and buffer ammonia.15 However the aforementioned meta-analysis showed no benefit. L-Citrulline is converted into the body to form L-arginine, which is an amino acid associated with NO mediated vasodilation.16 L-Citrulline is more favourable for increasing levels of L-arginine, as L-arginine has greater intestinal elimination. In case you were wondering, yes L-arginine and L-citrulline are supplements used to help treat erectile dysfunction. And there is evidence to suggest that doses between 1500mg-6000mg are effective in treatment of mild to moderate ED17. While there is some evidence that arginine metabolism and NO play a role in depression,18 and arginine bioavailability is reduced in patients with MDD19, I could not find any studies with L-Citrulline or L-arginine in the treatment of depression. (In something completely unrelated, L-arginine supplementation showed favourable results in treating fatigue associated with COVID-19 infections.20 There are a few clinical trials underway testing L-arginine and its ability to restore mitochondria function in children with COVID19. ) Beta-alanine is another non-essential amino acid thought to be helpful in improving athletic performance. Beta-alanine has been shown to increase muscle stores of carnosine.21 While the exact mechanism is not known, it has been shown to increase performance in high-intensity exercise, possibly through pH buffering and improved contractile performance.22 There is also some evidence showing that regular ingestion of Beta-alanine (2.4gm/day) can improve cognitive function (if they were below average) and depression scores.23 In another short term study, 14 day supplementation of 12gm Beta-alanine was used on subjects undergoing stressful simulated military operations. While no changes in cognition was observed, subjective feelings of depression were reduced.24 Doses of beta-alanine in pre-workout supplements range from 2gm to 3.4 grams per dose. So why did I write this article? As pharmacists we are curious about drugs and their effects on the body. We are also fascinated by off-label use of these medications. The same principle goes for supplements. The more we know, the most we are able to help our patients make informed decisions. Anyone remember high-dose biotin as a treatment for progressive MS? A small patient size, long-term study showed it was effective for mobility25 and disability symptoms but not for visual concerns.26 Yet, people heard “biotin is helpful for MS.” References 1. Paolucci EM, Loukov D, Bowdish DME, Heisz JJ. Exercise reduces depression and inflammation but intensity matters. Biol Psychol. 2018 Mar;133:79-84. doi: 10.1016/j.biopsycho.2018.01.015. Epub 2018 Feb 3. PMID: 29408464. 2. Maughan RJ, Depiesse F, Geyer H; International Association of Athletics Federations. The use of dietary supplements by athletes. J Sports Sci. 2007;25 Suppl 1:S103-13. doi: 10.1080/02640410701607395. Erratum in: J Sports Sci. 2009 Apr;27(6):667. PMID: 18049988. 3. Brisebois M, Kramer S, Lindsay KG, Wu CT, Kamla J. Dietary practices and supplement use among CrossFit® participants. 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