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HIGH BLOOD PRESSURE TREATMENT #5 – Citrulline, November 2022
“N of 1”
“N of 1” is shorthand for a study performed on only 1 person, usually oneself. It’s usually said with a little smile, reinforcing: “This was only my experience, but it was really interesting and it might work for others, which is why I am telling you about it.” I am delighted to share that my own recent “N of 1” experiment with a nutritional supplement may eventually take me off the list of people with a “High probably of suffering a stroke,” and it may also be an effective treatment for others with uncontrolled hypertension.

After mercilessly being tossed around like on a ferocious bronco for over 3 years while taking antihypertensive medications, then living with the background terror of having a debilitating stroke at anytime for over a year because of no longer taking any antihypertensive medication, all of that accumulated mental and physical distress and disability began fading in little less than 24 hours after taking a new-to-me nutritional supplement.

I knew after taking my first 3-gram dose of the sports performance-enhancing supplement, Citrulline malate, that that white powder with no reported side effects, could save my life. On the 7th day, after taking triple my starting amount in 3 doses and that same total amount in 2 portions the day before, I hoped I had the tool I needed to control my high blood pressure for the very first time in my life.

In first few days of my “N of 1” undertaking, we predicted that it would require weeks to months of experimentation and adaptation time for us to know for sure but, on the evening of Day 7, I declared myself as being on my way to being cured of hypertension. It was such an unlikely effect for a compound found in food, particularly in watermelon rind.

Two month later, the cure is still out of reach: the Citrulline nicely drops my blood pressure, but only for a few hours. Inexplicably, the time-release products shown online are no longer available, and they are what I need for my cure. Having no other prospect of controlling my hypertension, I’m pressing-on with my Citrulline experiments.

The Backstory
My situation with hypertension is as an “outlier” in that I am extremely intolerant of the 10 prescription medications I tried over 3 years; I became sick on all of them within hours or a couple of weeks of taking small doses. I’m not able to take any of them in large enough amounts on an ongoing basis for them to be viable treatments, alone or in combination with each other. In addition to testing 10 medications over the course of 3 years, I’d tried 8 alternative interventions, including supplements, acupuncture, and hypnosis; Citrulline was #9 on that list.

My intolerance to the medications is made more difficult by my blood pressure readings varying widely from minute to minute and day-to-day. I scoff at interventions promising to lower blood pressure by 3 or 4 points, like on a reduced salt diet, when my systolic, the upper number, varies by 20 mmHg in a sitting. I need a bigger effect for a treatment to work for me.

I stumbled upon Citrulline as a possible remedy for hypertension at the end of August, while still in Italy, when listening to a keto conference podcast, something I’d never done before. Jeff Gerber, an MD, and keto conference host, was interviewing Gabrielle Lyon, a doctor with a special interest in nutrition, especially in older women. Dr Gerber, in the last minutes of the 30-minute interview, brought up the subject of non-protein, amino acid supplements with vasodilator properties. Both doctors agreed that the products were legitimate sports performance enhancers and had been kicked-around as possibly being useful in controlling high blood pressure. That was all I needed to know to designate myself as a lab rat for an “N of 1” experiment with Citrulline.

Effect on My Blood Pressure
I often see blood pressure readings like 150/90 mmHg when sitting quietly around 7 pm, my usual time to check them. In the morning, when they typically run higher, an average reading of 170/100 will remind me of the hazards of my untreated hypertension.

I somewhat arbitrarily began taking the Citrulline malate after dinner, about 60 to 90 minutes before taking those nightly readings, and I was immediately seeing healthier numbers, like 140/85. At my internist’s office on the morning in which I increased my first dose to 4.5 grams an hour and a half before the appointment, my blood pressure was a stunning 130/82. Given both that it was a morning reading and having the reading taken in the doctor’s office, I would have expected higher numbers, even on the Citrulline malate. There was absolutely no question that the Citrulline was the fastest acting and most effective intervention I’d ever used for my hypertension, seemingly without side effects.

None of our online research gave a clue as to how long acting the supplement was, though it was quickly looking like it was effective for calming my blood pressure for less than 3 hours. Curiously, the decrease in my heart rate and muscle pain, and the improvements in my gut, associated with Citrulline seemed to persist until the next dose in 24 hours even though my hypertension improvement did not hold so long.

Nutritional Supplement Vasodilators
All 3 non-protein amino acids products, Arginine, Citrulline, & Citrulline malate, have been known to athletes as performance enhancers for decades because they are vasodilators; they are thought to cause the blood vessels to widen, increasing blood flow to muscles, and thereby improve training effectiveness and performance.

As vasodilators, their action is the same as erectile dysfunction treatments like Viagra and are used by some men for that purpose. Viagra, however, isn’t used for treating hypertension because there are too many side effects, at least according to my internist. I asked her about taking such a product for my hypertension because some medications in that class have long half-lives, which would be ideal for me, especially overnight.

Arginine was previously the most popular of the 3 supplements, but many athletes switched to Citrulline because, unlike Arginine, Citrulline isn’t metabolized in the liver before it goes into the bloodstream, giving more benefit for a given amount of supplement ingested. Citrulline is actually converted to arginine by the body, but it is more effective when ingested as Citrulline. Subsequently, the move has been to Citrulline malate because both components have performance benefits. I somewhat arbitrarily opted to begin my experimentation with Citrulline malate.

The malate, a form of malic acid, is not itself a vasodilator and instead is thought to enhance performance because it is a substrate for energy production in the cell. I wondered when I bought it how I would ever know if the malate mattered for me but decided to sort that out later. Stunningly, it was easy and unplanned: on our last hike to Flagstaff’s Elden Lookout at the end of September, I popped 3 Citrulline-only capsules for my 2nd dose of the day halfway to the top. I hadn’t wanted to stop on my timed event to fiddle with the Citrulline malate powder, so the capsules were perfect, or so I thought.

It wasn’t until chatting with Bill, who was waiting for me at the top of the trail, that I understood that the sudden global aching in my legs was likely due to the absence of the malate. I’d started the hike with some malate still on board and was pushing for a personal best time and, apparently, my leg muscles noticed the malate’s absence. It seemed incredible my muscles were so sensitive, so particular, but it was the best explanation.

Towards the end of the hike in the afternoon, it was time for another small dose of Citrulline and I paused to fiddle with the powdered malate form I had with me. Amazingly, when I hit the grades, there was no aching, no soreness in my legs like there had been in the morning even though we were nearing the end of our 10-mile hike. It was a very small experiment, but given we’d be doing our most difficult hiking day of the year in less than a week, neither of us would be succumbing to the ease of the Citrulline-only capsules as planned.

Citrulline, Estrogen, & Menopause
Reading further about Citrulline, has me now hypothesizing that my profound benefits from it may go back to deficits I acquired 17 years ago, which was when I had sudden-onset menopause from discontinuing birth control pills. The precipitous drop in my estrogen levels would have caused a big drop in my body’s production of nitric oxide, a substance essential in many of the body’s functions, including vasodilation. Because estrogen is used in the production of nitric oxide to trigger vasodilation, some researchers suggest that post-menopausal women supplementing with Citrulline for improved sports performance may need larger amounts than others to achieve benefit from it.

Aging itself is thought to decrease the production of nitric oxide, which occurs in many places, including the endothelium, the lining of the blood vessels. This lack of nitric oxide in the endothelium may also be a contributor to atherosclerosis.

The more I read about Citrulline as a vasodilator, the more I believed that my current hypertension was related to the “downward spiral” of my wellness that began 17 years ago when my estrogen levels plummeted. I had almost every menopause symptom in the book, and it took 4 to 5 years on hormone replacement therapy (HRT), at ever increasing levels, and tinkering with supplement use guided by a naturopath, to begin restoring my lost vitality. My HRT regime continues to be about 4 times the standard amount that is sufficient for some women, though even that amount is well below normal female adult levels, and I still have troublesome break-through hot flashes.

I suspect that some of my vitality is gone forever because of having had a long-term, low estrogen ‘illness’ compounded by aging, but my current hypothesis is that the Citrulline is unraveling some of that metabolic burden from the sudden and persistent drop in my estrogen levels years ago.

It’s well known in the medical literature that estrogen is very important in the creation of nitric oxide, which is a vital compound with many functions in the body, including regulating blood pressure. The drop in estrogens, and subsequently, nitric oxide production, are considered significant contributors to the fact that 75% of post-menopausal women have high blood pressure.

I immediately developed significant muscle pain with menopause that was dismissed as a “new disease” in me, chronic pain that I’d reluctantly accepted as my new normal due to menopause. Shortly after that dismissive diagnosis, muscle and joint pain with menopause began appearing in the medical literature, though there were no suggestions about how to treat it. The magic of Citrulline for me is that it creates the nitric oxide that went missing with the drop in my estrogen levels and it increases blood flow everywhere in the body, especially noticeable in the muscles.

That backdrop of 17 years of muscle pain was suddenly all but gone after one dose of Citrulline malate. I used to ache when just sitting around; now I don’t get my usual aching that begins within hours of doing anything and persists for days. I could never significantly improve my strength with resistance training because I always became so sore and stiff, even with modest resistance, that I couldn’t make any progress. I’d resorted to spending several hours almost every morning doing self massage with a massage gun and a massage ball, as well as doing yoga and Qi Gong, to coax my body to physically engaging in the day. Practically in hours of taking the Citrulline, I went from feeling like a victim of low-grade chronic pain to cooing to myself about how good my body felt, how good I felt in my body.

Ever-hopeful, I cautiously began doing a 10-minute, daily HIIT or high-intensity interval training routine, and with the Citrulline on board, I didn’t disable myself. I felt the pleasant buzz of using my muscles well but had no aches, pains, or hobbling stiffness that was always a consequence of a new activity. I also began casually using dumbbells for a few minutes each day and, likewise, wasn’t incapacitated from the excursion into intense muscle use.

Bill also immediately noticed I was more “pinky” in my face—a sensitive measure of increased blood flow and perfusion in the tissues. At first, I thought my sunscreen was letting me down and I was getting a bit of sunburn, but it didn’t take long to understand that the additional color was coming from the inside, not the outside.

Almost immediately with the big drop in my estrogen levels years ago, I developed ‘excessive flexion tension’ or contraction of my entire body. At my first massage after the estrogen withdrawal, my sports massage guy said, “Can’t you relax?!” Well, no, I couldn’t, but I didn’t know why. Each night in bed for almost all of these 17 years, I’ve done my best to soften the flexion, the curling inwards at all my joints. I aim to partially straighten my arms, legs, wrists, fingers, and neck to counter the tendency to curl into a ball. Taking the Citrulline has removed that flexion tension from my body, which I notice both in standing and in bed.

I also am presuming that the acid reducers I was prescribed to treat my GERD 2 years after my sudden onset menopause that was akin to being surgically induced, was made worse by the poor blood flow to my gut. My body’s pattern of intolerance of the many proton-pump inhibitors and H2 blockers was the same as with antihypertensive medications. All the drugs made me terribly sick, and I was chronically ill from trying one drug after another for several years and, seemingly, my gut never fully recovered from the series of insults. I have to wonder if those medications would have been better tolerated with increased blood flow to my gut with Citrulline on board.

The Effects
“Wow, wow, wow!” I started feeling a boost from the Citrulline the first full day after my previous evening dose, even before I established that it improved my hypertension. Jet lag and then days of asthma from wildfire smoke prevented me from fully moving into the new internal space that was manifesting itself from using the supplement, but I also trusted it would be there when I emerged a week later, and it was indeed there to greet me. By Day 10, when I was largely recovered from jet lag and the asthma, I was noticing delightful ‘upgrades’ throughout my body from taking Citrulline malate.

My chronically unhappy gut purred with the Citrulline on board, presumably because of improved blood supply to it. I was noticing:
..a large reduction in gas and intestinal cramping
..”normal” stools described by one health care provider, as in “a single, long, dark brown ‘sinker’ each day” and by another as resulting in a “single wipe” bowel movement
..significant reduction in distention and bloating
..readily able to drink the nephrologist-prescribed 2+ liters of water per day vs my typical 1.25 to 1.5 liter limit in tolerance for drinking fluids

Cognitive Function
..restored executive functioning
..thinking more clearly in general
..improved short term and long term memory
..improved word-finding
..chronic drowsiness with driving diminished, even with sleep deprivation of jet lag
..shifting from feeling like I’ve been living life in the back seat for 17 years and have now moved to the front seat

Muscle Aches
..chronic muscle aching, even with little activity, disappeared
..less muscle soreness with exercise
..increased exercise tolerance because of reduced discomfort while exercising and in background soreness
..feeling stronger, more capable
..reduced muscle cramping in bed
..massage gun use dropped from as much as 90” per day on my legs to 10”

Improved Sense of Wellbeing
..more confident
..more optimistic
..more energetic
..more willing to get up and move
..sustaining good posture felt more achievable

Heart Rate Stabilization
Even with my blood pressure rising and falling with each dose of Citrulline malate, my chronically high heart rate settled down. My gut improvement likewise was steady throughout the blood pressure fluctuations.

With this years-long history of wild swings in my blood pressure, I was astonished to see how predictable and unvarying my readings were in the first days on Citrulline malate during the few hours it was active.

Practical Matters
I ordered my Citrulline malate online from Amazon, with many brands to choose from. At my early and current 9 gram/day dose, it costs me about 50 cents per day. It’s a bit of a nuisance to take something 3 times a day, especially a powder, but I know I can do that. The powder form is bulky, and I’ll be looking at packing pounds of it in my suitcase for 3 months of travel overseas each summer. The powder is fluffy but compresses, so I carefully weigh each dose on a delicate jeweler’s scale designed for small quantities rather than relying on using a scoop.

The FDA does not regulate supplements like Citrulline but, interestingly, it is on their radar as a “medical food.” Citrulline is a life-saving treatment for babies with a particular “inborn error of metabolism,” and for that use, is monitored by the FDA.

Bill’s Story
Day 1
Bill took a 3-gram dose of Citrulline malate with water in the late afternoon and monitored his blood pressure several times over the next several hours. He didn’t note a change in his blood pressure, nor did he notice any other effects. Having his blood pressure go lower could have been disastrous. The not-surprising news was good, it meant that he could safely begin experimenting with the supplement to assess if it had any happy surprises for him, and it did.

Day 2
The next morning, Bill weighed another 3-gram dose from my tub of Citrulline malate before exiting our trailer to make the Elden Lookout hike to 9300’ (2800 m). Starting at 7,000’ (2100 m), meant that Bill already had ibuprofen on board for his altitude intolerance. He took-off to the Lookout and when I found him at the top almost 2 hours later, 10 minutes ahead of me, he was beaming with delight. He felt great and was all smiles.

Having completed the hardest 3 miles of the 10-mile hike, we headed out together for another hour of walking to our lunch perch on a ridge. There, Bill sat at 9,000’ (2700 m), declaring “I feel perky!” Bill NEVER feels perky at that elevation, no matter how much ibuprofen he takes. Actually, I don’t recall Bill ever describing himself as feeling perky.

The “perky” comment was made about 3 hours after taking the Citrulline malate. During our long lunch, he reported what he perceived as the beneficial shifts from the supplement: his mood was buoyant, he felt calm and relaxed, he lacked the brain fog that is typical for him at elevation, and he felt energetic. While we were descending, somewhere between 4 and 4 ½ hours his after the morning dose, Bill could feel the relative euphoria fade.

Back at the trailer, soon after taking his second dose for the day, the typical deep weariness from the hike began to diminish and he was better able to organize himself for our usual chores, like cooking dinner. His mood took an upturn and he noticed he was again thinking more clearly. Based on carefully timing the effects of the supplement after he took the second dose, he likely experienced performance benefits in the morning in as little as 15. Trainers, however, claim you must take Citrulline 60-90 minutes before you workout to gain any benefit.

Day 3
The next morning, Bill took another 3 grams of the white powder from the tub 45 minutes after arising. In 11 minutes, he started experiencing the buzz he always hoped for from a cup of coffee, though he estimated it had about 10 times the effect of caffeine. His mood and RPMs shot up and he was a whirlwind of productivity for about 3 hours, which is when the fun effects of his augmented waking-up began waning. Bill has struggled his entire life to wake-up and get going in the morning, with that process sometimes taking 4 or more hours.

Surprisingly, the next morning, he woke-up ready to go without the boost from the Citrulline malate. He presumed he had a bit of carry-over from the previous afternoon’s 4 pm dose of 2 grams, even though the overt effects diminished after 4 hours. In a couple of hours, he threw-out his treasured cup of coffee, not liking the way it made him feel, which was a little jittery and unsettled.

After substituting a cup of no-caffeine tea for his coffee and about 3 hours of high productivity, he was longing for a little more energy, so took a 2-gram suspension of the Citrulline malate. Sure enough, in about 10 minutes, he got the boost he was looking for and went bustling about. That met his needs for the day, until about 4 pm, when he started dragging. His tiredness wasn’t surprising, even though it had been a rest day for us, because 4 pm is the metabolic low for the day for most of us. In the spirit of being a good lab rat, Bill took his smallest dose yet, 1 gram of Citrulline malate or about 650 mg of citrulline. Even this small dose gave him the lift he wanted in about 10 minutes, though it began to fade in
about 2 hours. Not a bad effect given it was now about 90 minutes before our bedtime.

Day 4
Bill had more spunk upon arising than he usually had, though missed the prior fun buzz of Citrulline. After about 3 hours, he took a 2-gram dose hoping for some added pizzazz, which wasn’t forthcoming. By the time we left for our hike more than an hour later, he noted his mood was elevated over earlier in the morning and he had a comfortable sense of wellbeing. Bill was faster yet on the same hike to the Lookout and felt strong and cheery all day and into the evening.

A month into experimenting with the Citrulline malate, Bill still loves its effects. The pop-up he gets with each dose varies from day to day, but he is convinced that overall, it improves his quality of life. At the time of this writing, he was taking 3 grams twice a day, once upon arising and once in the middle of the afternoon.

The above are our two “N of 1” experiments and I have no idea of how to predict who else might benefit or could be harmed by Citrulline malate.

Should you choose to be your own lab rat, proceed with caution. I had zero dizziness or lightheadedness, even when a 3-gram dose of Citrulline dropped my blood pressure by 30-40 mmHg/20 mmHg in an hour, but that was me. Bill had no blood pressure changes.

There are few studies on the use of Citrulline and they are all on small numbers of people, like 35, for short durations, and that isn’t likely to change because there is no return on the investment, there is no way to make money from the research. The only way to know if it is safe and beneficial for you is to try it.

Best not to take Citrulline while you are taking antihypertensives or erectile dysfunction medications like Viagra.

Note that most of the published discussions of Citrulline are of Citrulline, not the Citrulline malate we use. By weight, Bill’s 6 grams of Citrulline malate per day gives him 4 grams of Citrulline.

What We’ve Been Reading
This is an easy-to-read, lay-press article that seems consistent with the medical research studies we’ve read:
(My Notes: Improves endurance & strength-based exercise; muscle soreness decreases 40% if taken 60” before exercise; used 3-6g day L-citrulline; 8g/day citrulline malate)

Here are two research articles with my notes:
Meta analysis
..longest study was 17 weeks
..3-9 g/day (decrease in diastolic only on > 6g/day
..older women were less responsive, perhaps due to low estrogen & therefore reduced transport of arginine into vasculature; women may need larger doses or longer duration of supplementation
Completely absorbed through gut, no liver metabolism
L-Citrulline = twice as potent as arginine and can increase growth hormone
L-Citrulline doses 2.7 - 8.4 g/day, 1-16 weeks
Greater reductions in blood pressure with durations > 6 weeks
No adverse effects

Unexpected Consequences: Improved Heat Tolerance (April 2023)
Bill and I walked separately on the sun-exposed Lake Mead Historic Rail Trail our last day there, April 30th. I was on the trail over 5 hours, starting when it was 85°, and finally ducking into our trailer when our weather station registered 100°, a reading that held for several hours. Bill started later, finished earlier, and walked a few less miles than I did, and we both felt fine when we finished.

I was anxious to shed my full sun coverage pants, shirt, gloves, and hat so that my sweat-coated skin could dry. I chugged a cup of cold water and settled-in for a passive, 10" back release on the floor. We chatted about our different experiences of the day on the same trail and noticed that neither of us were wasted like we usually were when out in the heat. Being in the extreme heat had been no big deal, it was just another walk. We were delighted and perplexed with that shared observation.

What was remarkable was what wasn't: it was like any other hike. We each simply stopped hiking when planned and went on with our day. It was like we'd been walking on a 75° day. Nothing was out of the ordinary that evening, overnight, or the next morning: there was not even a blip for that significant heat stress.

Usually, we would have been so heat stressed after such prolonged heat exposure that we would have cut our hike short, been miserable for hours afterwards, and perhaps unusually weary the next morning. We would have been chugging water all evening and up multiple times that night to pee. A week earlier in Colorado, we'd been hiking in snow, so we knew we weren't heat acclimated.

The next day while driving to Zion, I pressed Bill for his recollections of our many winters of walking in the heat in Palm Springs, which usually wasn't over 90°. We both had vivid memories of being miserably hot and stressed and couldn't imagine why we were now bullet-proof in the heat. The Citrulline malate we'd been taking since September seemed the only possible explanation, though it was an incredible possibility.

A bit of online searching while Bill was driving, revealed studies that had been done on poultry hoping to find that citrulline increased their heat tolerance and, preliminary studies indicated it did. It's a huge leap to infer from the physiological responses of chickens to humans, but it fit with our experience. By any published measure I saw online, we were old enough by years, or decades, to be ineffective with thermoregulation and yet we did extremely well in this environmental heat. We'll keep taking citrulline for other reasons and watch for our new super-hero responses to heat stress again, though we do try to avoid those conditions.