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Magnesium is essential for our health. It is a key cofactor for our energy regulation, and in plants it is the center of the chlorphyll molecule. Low magnesium in people is associated with depression. Among the treatments we provide at the IV Medical Center is Ketamine infusions. In the process of our treatments, we assess patients for toher medical conditions that may lead to refractory depression and http://cinziamazzamakeup.com/?x=farmacia-viagra-generico-a-Verona low magnesium is one of them.



Ketamine, an anesthetic and street drug known as “Special K” has garnered a lot of attention for it’s ability, in some, to relieve the symptoms of very severe depression in a matter of minutes. A recent study has demonstrated how it might work, but before you go signing up for a clinical trial (and there are currently many going on in the US), it’s important to understand the downsides to the drug. One major problem is that the effects wear off, usually within 10 days, leaving you just as depressed as before. It can cause urinary incontinence, bladder problems, addiction, and, with chronic use, it can worsen mental health problems, causing more depression, anxiety, and panic attacks.

Ketamine seems to have a remarkable, short term ability to heal the synapses injured by chronic stress. However, anything that acts that quickly and successfully usually has a long-term cost. All powerfully addictive drugs work on our own natural receptors and neurons. Cocaine, for example, causes immediate racing euphoria by inhibiting the natural neurotransmitter dopamine from being recycled, leaving bunches of dopamine in the synaptic cleft. In the very short term, you feel great. In the long term, you tax the system by driving the neurotransmitter system far out of balance in an aggressive way.

Nicotine has a similar effect on the alpha-7 nicotinic receptor. It activates it in a pleasing way, but unfortunately desensitizes the receptor so much that only nicotine will keep it firing. A nutrient found in foods such as egg yolks called choline activates the same receptor, but without desensitizing it.  Long term, regular ingestion of choline keeps the receptor functional and happy, helping with certain brain tasks. Long term, regular use of nicotine activates the receptor but forces you to take more nicotine to keep the receptor working, leaving you foggy-headed and less sharp if you go without cigarettes.

So is there a less dramatic, “natural” version of ketamine, something we can safely ingest every day, but might be a little depleted in our modern diets? Nothing taken in physiologic amounts would reverse a depression in half an hour like ketamine, but could another chemical we find in food and mineral water help with resilience to stress, synaptic repair, and make us more resistant to depression and anxiety symptoms? Sure—that chemical is the mineral magnesium. Magnesium, like ketamine, acts as an antagonist to the NMDA receptor, which means it is a counter to glutamate, the major excitatory neurotransmitter in the brain. The exact mechanisms are complex, but both ketamine and magnesium seem to help glutamate do its job, activating the receptor, without damaging the receptor with too much activation, which, chronically, leads to excitotoxicity, synaptic degradation, inflammation, and even cell death.

One of the exciting things about ketamine is that it works in some people with severe treatment resistant depression who have failed the traditional therapies. Treatment-resistant individuals tend to have lower intracellular magnesium levels than normal (1). Ketamine and magnesium may also work synergistically, complementing each other. Ketamine leads to an increase of intracellular magnesium, and ketamine will reverse the normally seen magnesium decreases after brain trauma (2). There is some evidence also that more standard antidepressant medications, such as imipramine, work in part by reversing the magnesium-depleting effects of chronic stress, suggesting that adding magnesium supplementation to standard antidepressant regimens might help the medications work better (at least in rodents) (3).

It’s great to see an interesting compound like ketamine be taken seriously and thoroughly studied for its action in serious, resistant depression. Ultimately its usefulness may be limited to hospitalized patients who can be closely monitored for the side effects, and who also may benefit the most from the quick mechanism of action, while the longer term risks may be outweighed by the short term benefit in such a critical, serious situation. I would love to see a much safer compound, the mineral magnesium, be studied as an adjunct treatment.

In the mean time, magnesium supplementation is generally safe for most folks with normal kidney function. Many folks eating a normal Western Diethave a low intake of the mineral (4). Those with bowel obstructions, very slow heart rate, or dangerously low blood pressure should not take it. Magnesium can interfere with the absorption of certain medicines (digoxin, nitrofurantoin, bisphosphanates, and some anti malaria drugs). Here are some excellent food sources of magnesium (though remember that both nuts and grains have phytates, which bind minerals, so the magnesium you absorb may not be quite as much as the magnesium you ingest.) Magnesium is also available in many mineral waters.


Lets digress over Choline. Choline has impact on decreasing schizophrenia in the children of mother’s who supplement the right amount during pregnancy:

Recently in the American Journal of Psychiatrya new paper was published tying nutrient supplementation in pregnant women to positive changes in the brains of their offspring. One of the nutrients that may be less predominant in our modern diets than in traditional diets is the phospholipid known as choline. Phospholipids are exceedingly important for brain development and neuron signaling.

In the current study, 100 pregnant women were randomized to receiving a daily choline supplement (equivalent to the amount of choline found in 3 large eggs) or placebo. After the babies were born, the choline babies continued to get a supplement equal to 100mg of choline daily (the institutes of medicine recommend total daily choline in infants to be 125mg daily), and at measurements of “cerebral inhibition” were taken at about one month and three months of age. Cerebral inhibition is a term used to describe the ability of the brain to tune out a stimulus that happens over and over. For example, if you are trying to work, and someone is running a jackhammer on the street outside, if you have intact cerebral inhibition, your brain will respond less and less to the sound of the jackhammer as it continues. Presumably this change would allow you to focus on more important things, such as the work at hand.

Source: http://www.flickr.com/photos/anniemole/5268772776/sizes/m/

In some brain disorders, such as schizophrenia, cerebral inhibition is impaired. For someone with schizophrenia, the signal from the jackhammer would be just as strong the second and the third and the seventh and the eighth times. You can imagine how you might be affected if you couldn’t tune anything out, if your brain was constantly taking in more stimulation and unable to sort through what was necessarily important or not. It could be this lack of cerebral inhibition (which begins with brain development in utero and early infancy) is one of the central causes of developing schizophrenia later on. The brain, so overwhelmed with stimuli, stops making sense of it, leading to psychosis and eventually the degeneration of neurons.

Cerebral inhibition is typically measured by a test called the p50 evoked potential. Electrodes are placed on the scalp, and then the subject is exposed to a sensory stimulus, in this case, paired sounds. With intact cerebral inhibition, the second time the brain processes the sound, the wave amplitude of the auditory evoked potential 50 milliseconds after the sound will be much less than the first time. (Go to this image from the American Journal of Psychiatry to see what the waveforms look like in healthy controls and subjects with schizophrenia.

P50 evoked potential abnormalities can be seen in infants, and genes that are associated with a higher risk of schizophrenia are also associated with these abnormal evoked potential tests. Choline is known to cross the placenta and help with the brain development of certain receptors that normalize cerebral inhibition. In the study of pregnant women receiving choline supplements, 76% of the infants whose mothers got choline had normal p50 evoked potential tests at age one month. Only 43% of the infants of the mothers who received placebo had tests consistent with intact cerebral inhibition. In addition, a gene known as CHRNA7 correlated with diminished cerebral inhibition in the placebo group of infants, but not in the choline group. That means that it is possible (though there is way too little data to know) the choline supplementation could reduce the risk of schizophrenia in these infants. The ScienceDaily write up of the study can be found here.

Schizophrenia risk is higher in the offspring of malnourished mothers. There is also a known gene that reduces choline levels that is associated with a higher risk of schizophrenia. Choline is also sequestered in the mother’s liver during trauma, anxiety, or depression, depriving the fetus. Measures of developmental delay and other developmental problems are also associated with later risk of schizophrenia.

Nicotine activates but also profoundly desensitizes the same receptor that choline seems to protect and activate (the alpha-7 nicotinic receptor). 90% of people with schizophrenia smoke, and smoking normalizes p50 evoked potential tests is schizophrenia. Smoking in mothers has been associated with poorer infant cerebral inhibition and later childhood behavioral problems, whereas choline has only been shown to be beneficial for brain development. One difference between the two compounds (among many!) is that choline does not desensitize the alpha-7 nicotinic receptor at all, leaving it active so it can play its presumed role in helping with intact cerebral inhibition.

While choline supplementation is the interest of researchers, I’m more interested in having pregnant women eat their meat and egg yolks, the best sources of choline in the diet. Egg yolks are jam packed with great nutrients for the brain, not only choline, but also B vitamins and other fatty acids important for nerve growth. Bananas also have more choline than you would expect for a fruit. Choline levels in the diet have fallen recently with folks restricting their egg and organ meat consumption. These traditional foods have some important nutrients that we don’t want to skimp on in our diets.


Choline supplementation during pregnancy presents a new approach to schizophrenia prevention

Choline, an essential nutrient similar to the B vitamin and found in foods such as liver, muscle meats, fish, nuts and eggs, when given as a dietary supplement in the last two trimesters of pregnancy and in early infancy, is showing a lower rate of physiological schizophrenic risk factors in infants 33 days old. The study breaks new ground both in its potentially therapeutic findings and in its strategy to target markers of schizophrenia long before the illness itself actually appears. Choline is also being studied for potential benefits in liver disease, including chronic hepatitis and cirrhosis, depression, memory loss, Alzheimer’s disease and dementia, and certain types of seizures.

Robert Freedman, MD, professor and chairman of the Department of Psychiatry, University of Colorado School of Medicine and one of the study’s authors and Editor of The American Journal of Psychiatry, points out, “Genes associated with schizophrenia are common, so prevention has to be applied to the entire population, and it has to be safe. Basic research indicates that choline supplementation during pregnancy facilitates cognitive functioning in offspring. Our finding that it ameliorates some of the pathophysiology associated with risk for schizophrenia now requires longer-term follow-up to assess whether it decreases risk for the later development of illness as well.”

Normally, the brain responds fully to an initial clicking sound but inhibits its response to a second click that follows immediately. In schizophrenia patients, deficient inhibition is common and is related to poor sensory filtering and familial transmission of schizophrenia risk. Since schizophrenia does not usually appear until adolescence, this trait — measurable in infancy — was chosen to represent the illness.

Half the healthy pregnant women in this study took 3,600 milligrams of phosphatidylcholine each morning and 2,700 milligrams each evening; the other half took placebo. After delivery, their infants received 100 milligrams of phosphatidylcholine per day or placebo. Eighty-six percent of infants exposed to pre- and postnatal choline supplementation, compared to 43% of unexposed infants, inhibited the response to repeated sounds, as measured with EEG sensors placed on the baby’s head during sleep.


viagra generico pagamento online a Firenze Journal Reference:

  1. Randal G. Ross et al.  go Perinatal Choline Effects on Neonatal Pathophysiology Related to Later Schizophrenia RiskAmerican Journal of Psychiatry, 2013; DOI: 10.1176/appi.ajp.2012.12070940
  2. Perinatal Choline Effects on Neonatal Pathophysiology Related to Later Schizophrenia Risk


Ketamine, magnesium and major depression–from pharmacology to pathophysiology and back.

Ketamine, magnesium and major depression e From pharmacology to pathophysiology and back


The glutamatergic mechanism of antidepressant treatments is now in the center of research to overcome the limitations of monoamine-based approaches. There are several unresolved issues. For the action of the model compound, ketamine, NMDA-receptor block, AMPA-receptor activation and BDNF release appear to be involved in a mechanism, which leads to synaptic sprouting and strengthened synaptic connections. The link to the pathophysiology of depression is not clear. An overlooked connection is the role of magnesium, which acts as physiological NMDA-receptor antagonist: 1. There is overlap between the actions of ketamine with that of high doses of magnesium in animal models, finally leading to synaptic sprouting. 2. Magnesium and ketamine lead to synaptic strengthening, as measured by an increase in slow wave sleep in humans. 3. Pathophysiological mechanisms, which have been identified as risk factors for depression, lead to a reduction of (intracellular) magnesium. These are neuroendocrine changes (increased cortisol and aldosterone) and diabetes mellitus as well as Mg(2+) deficiency. 4. Patients with therapy refractory depression appear to have lower CNS Mg(2+) levels in comparison to health controls. 5. Experimental Mg(2+) depletion leads to depression- and anxiety like behavior in animal models. 6. Ketamine, directly or indirectly via non-NMDA glutamate receptor activation, acts to increase brain Mg(2+) levels. Similar effects have been observed with other classes of antidepressants. 7. Depressed patients with low Mg(2+) levels tend to be therapy refractory. Accordingly, administration of Mg(2+) either alone or in combination with standard antidepressants acts synergistically on depression like behavior in animal models.


On the basis of the potential pathophysiological role of Mg(2+)-regulation, it may be possible to predict the action of ketamine and of related compounds based on Mg(2+) levels. Furthermore, screening for compounds to increase neuronal Mg(2+) concentration could be a promising instrument to identify new classes of antidepressants. Overall, any discussion of the glutamatergic system in affective disorders should consider the role of Mg(2+)


So back to the magnesium and Ketamine issue: As above, Low magnesium seems to be present in individuals who are depressed and have sleeping disorders. The magnesium is not the type measured by standard blood tests as most magnesium is intracellular. Magnesium may play an important role by antagomizing the NMDA receptors as does Ketamine. Our deficient diets in Magnesium may be increasing our rates of depression!

Magnesium as the original Chill Pill

Source: http://www.flickr.com/photos/derekskey/3219004793/

Magnesium is a vital nutrient that is often deficient in modern diets. Our ancient ancestors would have had a ready supply from organ meats, seafood, mineral water, and even swimming in the ocean, but modern soils can be depleted of minerals and magnesium is removed from water during routine municipal treatment. The current RDA for adults is between 320 and 420mg daily, and the average US intake is around 250mg daily.

Does it matter if we are a little bit deficient? Well, magnesium plays an important role in biochemical reactions all over your body.  It is involved in a lot of cell transport activities, in addition to helping cells make energy aerobically or anaerobically. Your bones are a major reservoir for magnesium, and magnesium is the counter-ion for calcium and potassium in muscle cells, including the heart. If your magnesium is too low, you can experience muscle cramps, arrythmias, and even sudden death. Ion regulation is everything with respect to how muscles contract and nerves send signals. In the brain, potassium and sodium balance each other. In the heart and other muscles, magnesium pulls some of the load.

That doesn’t mean that magnesium is unimportant in the brain. Au contraire!In fact, there is an intriguing article entitled Rapid recovery from major depression using magnesium treatment, published in Medical Hypothesis in 2006. Medical Hypothesis seems like a great way to get rampant (but referenced) speculation into the PubMed database. Fortunately, I don’t need to publish in Medical Hypothesis, as I can engage in such speculation in my blog, readily accessible to Google. Anyway, this article was written by George and Karen Eby, who seem to run a nutrition research facility out of an office warehouse in Austin, Texas – and it has a lot of interesting information about our essential mineral magnesium.

Magnesium is an old home remedy for all that ails you, including “anxiety, apathy, depression, headaches, insecurity, irritability, restlessness, talkativeness, and sulkiness.” In 1968, Wacker and Parisi reported that magnesium deficiency could cause depression, behavioral disturbances, headaches, muscle cramps, seizures, ataxia, psychosis, and irritability – all reversible with magnesium repletion.

Stress is the bad guy here, in addition to our woeful magnesium deficient diets. As is the case with other minerals such as zinc, stress causes us to waste our magnesium like crazy – I’ll explain a bit more about why we do that in a minute.

Let’s look at Eby’s case studies from his paper:

A 59 y/o “hypomanic-depressive male”, with a long history of treatable mild depression, developed anxiety, suicidal thoughts, and insomnia after a year of extreme personal stress and bad diet (“fast food”). Lithium and a number of antidepressants did nothing for him. 300mg magnesium glycinate (and later taurinate) was given with every meal. His sleep was immediately restored, and his anxiety and depression were greatly reduced, though he sometimes needed to wake up in the middle of the night to take a magnesium pill to keep his “feeling of wellness.” A 500mg calcium pill would cause depression within one hour, extinguished by the ingestion of 400mg magnesium.

A 23 year-old woman with a previous traumatic brain injury became depressed after extreme stress with work, a diet of fast food, “constant noise,” and poor academic performance. After one week of magnesium treatment, she became free of depression, and her short term memory and IQ returned.

A 35 year-old woman with a history of post-partum depression was pregnant with her fourth child. She took 200mg magnesium glycinate with each meal. She did not develop any complications of pregnancy and did not have depression with her fourth child, who was “healthy, full weight, and quiet.”

A 40 year-old “irritable, anxious, extremely talkative, moderately depressed” smoking, alchohol-drinkingcocaine using male took 125mg magnesium taurinate at each meal and bedtime, and found his symptoms were gone within a week, and his cravings for tobacco, cocaine, and alcoholdisappeared. His “ravenous appetite was supressed, and … beneficial weight loss ensued.”

Eby has the same question about the history of depression that I do – why is depression increasing? His answer is magnesium deficiency. Prior to the development of widespread grain refining capability, whole grains were a decent source of magnesium (though phytic acid in grains will bind minerals such as magnesium, so the amount you eat in whole grains will generally be more than the amount you absorb). Average American intake in 1905 was 400mg daily, and only 1% of Americans had depression prior to the age of 75. In 1955, white bread (nearly devoid of magnesium) was the norm, and 6% of Americans had depression before the age of 24. In addition, eating too much calcium interferes with the absorption of magnesium, setting the stage for magnesium deficiency.

Beyond Eby’s interesting set of case studies are a number of other studies linking the effects of this mineral to mental health and the stress response system. When you start to untangle the effects of magnesium in the nervous system, you touch upon nearly every single biological mechanism for depression. The epidemiological studies (1) and some controlled trials (2)(3) seem to confirm that most of us are at least moderately deficient in magnesium. The animal models are promising (4). If you have healthy kidneys, magnesium supplementation is safe and generally well-tolerated (up to a point)(5), and many of the formulations are quite inexpensive. Yet there is a woeful lack of well-designed, decent-sized randomized controlled trials for using magnesium supplementation as a treatment or even adjunctive treatment for various psychiatric disorders.

Let’s look at the mechanisms first. Magnesium hangs out in the synapse between two neurons along with calcium and glutamate. If you recall, calcium and glutamate are excitatory, and in excess, toxic. They activate the NMDA receptor. Magnesium can sit on the NMDA receptor without activating it, like a guard at the gate. Therefore, if we are deficient in magnesium, there’s no guard. Calcium and glutamate can activate the receptor like there is no tomorrow. In the long term, this damages the neurons, eventually leading to cell death. In the brain, that is not an easy situation to reverse or remedy.

And then there is the stress-diathesis model of depression, which is the generally accepted theory that chronic stress leads to excess cortisol, which eventually damages the hippocampus of the brain, leading to impaired negative feedback and thus ongoing stress and depression and neurotoxicity badness. Murck tells us that magnesium seems to act on many levels in the hormonal axis and regulation of the stress response. Magnesium can suppress the ability of the hippocampus to stimulate the ultimate release of stress hormone, it can reduce the release of ACTH (the hormone that tells your adrenal glands to get in gear and pump out that cortisol and adrenaline), and it can reduce the responsiveness of the adrenal glands to ACTH. In addition, magnesium can act at the blood brain barrier to prevent the entrance of stress hormones into the brain. All these reasons are why I call magnesium “the original chill pill.”

If the above links aren’t enough to pique your interest, depression is associated with systemic inflammation and a cell-mediated immune response. Turns out, so is magnesium deficiency. In addition, animal models show that sufficient magnesium seems to protect the brain from depression and anxiety after traumatic brain injury (6), and that the antidepressants desipramine and St. John’s Wort (hypericum perforatum) seem to protect the mice from the toxic effects of magnesium deficiency and its relationship to anxious and depressed behaviors (4).

The overall levels of magnesium in the body are hard to measure. Most of our body’s magnesium is stored in the bones, the rest in the cells, and a very small amount is roaming free in the blood. One would speculate that various mechanisms would allow us to recover some needed magnesium from the intracellular space or the bones if we had plenty on hand, which most of us probably don’t. Serum levels may be nearly useless in telling us about our full-body magnesium availability, and studies of levels and depression, schizophrenia, PMS, and anxiety have been all over the place (7). There is some observational evidence that the Mg to Ca ratio may be a better clue. Secondly, the best sources of magnesium in the normal Western diet are whole grains (though again, phytates in grains will interfere with absorption), beans, leafy green veggies, and nuts. These happen to be some of the same sources as folate, and folate depletion is linked with depression, so it may be a confounding factor in the epidemiological studies.

Finally, magnesium is sequestered and wasted via the urine in times of stress. I’m speculating here, but in a hunter-gatherer immediate stress sort of situation, maybe we needed our neurons to fire on all cylinders and our stress hormones to rock and roll through the body in order for us to survive. Presumably we survived or didn’t, and then the stressor was removed, and our paleolithic diets had plenty of magnesium to replace that which went missing. However, it may not be overall magnesium deficiency causing depression and exaggerated stress response – it may just be all that chronic stress, and magnesium deficiency is a biomarker for chronic stress. But it doesn’t hurt to replete one’s magnesium to face the modern world, and at least the relationships should be studied thoroughly. Depression is hugely expensive and debilitating. If we could alleviate some of that burden with enough mineral water… we should know whether that is a reasonable proposition.

As I mentioned before, there are only a few controlled trials of magnesium supplementation and psychiatric disorders. A couple covered premenstrual dysphoria, cravings, and other symptoms (8)(9). Another small study showed some improvement with magnesium supplementation in chronic fatigue syndrome (10). Two open-label studies showed some benefit in mania (11)(12). There is another paper that postulates that magnesium deficiency could exacerbate the symptoms of schizophrenia. However, there is nothing definitive. Which is, of course, quite troubling. How many billions of dollars have we spent on drug research for depression, bipolar disorder, and schizophrenia, when here is a cheap and plausibly helpful natural remedy that hasn’t been properly studied?

So everyone get out there and take some magnesium already!  Whew.  Well, just a few more things to keep in mind before you jump in.

There are some safety considerations with respect to magnesium supplementation. If you have normal kidney function, you do not have myasthenia gravis, bowel obstruction, or bradycardia, you should be able to supplement without too many worries. In addition, magnesium interferes with the absorption of certain pharmaceuticals, including dixogin, nitrofurantoin, bisphosphanates, and some antimalaria drugs. Magnesium can reduce the efficacy of chloropromazine, oral anticoagnulants, and the quinolone and tetracycline classes of antibiotics.

Magnesium oxide is the cheapest readily available formulation, as well as magnesium citrate, which is more likely to cause diarrhea in excess. (In fact, magnesium is a great remedy for constipation). The oxide is not particularly bioavailable, but the studies I’ve referenced above suggest that you can top yourself off after about a month of daily supplementation. Those with short bowels (typically due to surgery that removes a large section of bowel) may want to supplement instead with magnesium oil. You can also put some Epsom salts in your bath. In addition to diarrhea, magnesium can cause sedation, and symptoms of magnesium toxicity (again, quite unlikely if your kidneys are in good shape) are low blood pressure, confusion, arrythmia, muscle weakness, and fatigue. Magnesium is taken up by the same transporter as calcium and zinc, so they can fight with each other for absorption. Jaminet and Jaminet recommend total daily levels (between food and supplements) of 400-800mg. Most people can safely supplement with 200-350mg daily without any problems (again, don’t proceed without a doctor’s supervision if you have known kidney disease or if you are elderly).

People looking for good (but not all paleo) food sources can go here (also a good link for more information on the other formulations of magnesium – there are many!), here, and here.


Following are some foods and the amount of magnesium in them:[23]


http://buy-generic-clomid.com/clomid_and_ovulation.html MAGNESIUM  

Magnesium Webpage as below


follow site Summary

Magnesium plays important roles in the structure and the function of the human body. The adult human body contains about 25 grams of magnesium. Over 60% of all the magnesium in the body is found in the skeleton, about 27% is found in muscle, 6% to 7% is found in other cells, and less than 1% is found outside of cells (1).


Magnesium is involved in more than 300 essential metabolic reactions, some of which are discussed below (2).

Energy production

The metabolism of carbohydrates and fats to produce energy requires numerous magnesium-dependent chemical reactions. Magnesium is required by the adenosine triphosphate (ATP)-synthesizing protein in mitochondria. ATP, the molecule that provides energy for almost all metabolic processes, exists primarily as a complex with magnesium (MgATP)(3).

Synthesis of essential molecules

Magnesium is required for a number of steps during synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. Several enzymes participating in the synthesis of carbohydrates and lipids require magnesium for their activity. Glutathione, an important antioxidant, requires magnesium for its synthesis (3).

Structural roles

Magnesium plays a structural role in bone, cell membranes, and chromosomes (3).

Ion transport across cell membranes

Magnesium is required for the active transport of ions like potassium and calcium across cell membranes. Through its role in ion transport systems, magnesium affects the conduction of nerve impulses, muscle contraction, and normal heart rhythm (3).

Cell signaling

Cell signaling requires MgATP for the phosphorylation of proteins and the formation of the cell-signaling molecule, cyclic adenosine monophosphate (cAMP). cAMP is involved in many processes, including the secretion of parathyroid hormone (PTH) from the parathyroid glands (see the articles on Vitamin D and Calcium for additional discussions regarding the role of PTH) (3).

Cell migration

Calcium and magnesium levels in the fluid surrounding cells affect the migration of a number of different cell types. Such effects on cell migration may be important in wound healing (3).

Nutrient interactions


High doses of zinc in supplemental form apparently interfere with the absorption of magnesium. One study reported that zinc supplements of 142 mg/day in healthy adult males significantly decreased magnesium absorption and disrupted magnesium balance (the difference between magnesium intake and magnesium loss) (4).


Large increases in the intake of dietary fiber have been found to decrease magnesium utilization in experimental studies. However, the extent to which dietary fiber affects magnesium nutritional status in individuals with a varied diet outside the laboratory is not clear (2, 3).


Dietary protein may affect magnesium absorption. One study in adolescent boys found that magnesium absorption was lower when protein intake was less than 30 grams/day, and higher protein intakes (93 grams/day vs. 43 grams/day) were associated with improved magnesium absorption in adolescents (5).

Vitamin D and calcium

The active form of vitamin D (calcitriol) may slightly increase intestinal absorption of magnesium (6). However, it is not clear whether magnesium absorption is calcitriol-dependent as is the absorption of calcium and phosphate. High calcium intake has not been found to affect magnesium balance in most studies. Inadequate blood magnesium levels are known to result in low blood calcium levels, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (2, 3).


Magnesium deficiency in healthy individuals who are consuming a balanced diet is quite rare because magnesium is abundant in both plant and animal foods and because the kidneys are able to limit urinary excretion of magnesium when intake is low. The following conditions increase the risk of magnesium deficiency (1):

  • Gastrointestinal disorders: Prolonged diarrhea, Crohn’s diseasemalabsorption syndromesceliac disease, surgical removal of a portion of the intestine, and intestinal inflammation due to radiation may all lead to magnesium depletion.
  • Renal disorders (magnesium wasting): Diabetes mellitus and long-term use of certain diuretics (see Drug interactions) may result in increased urinary loss of magnesium. Multiple other medications can also result in renal magnesium wasting (3).
  • Chronic alcoholism: Poor dietary intake, gastrointestinal problems, and increased urinary loss of magnesium may all contribute to magnesium depletion, which is frequently encountered in alcoholics.
  • Age: Several studies have found that elderly people have relatively low dietary intakes of magnesium (7, 8). Intestinal magnesium absorption tends to decrease with age and urinary magnesium excretion tends to increase with age; thus, suboptimal dietary magnesium intake may increase the risk of magnesium depletion in the elderly (2).

Although severe magnesium deficiency is uncommon, it has been induced experimentally. When magnesium deficiency was induced in humans, the earliest sign was decreased serum magnesium levels (hypomagnesemia). Over time, serum calcium levels also began to decrease (hypocalcemia) despite adequate dietary calcium. Hypocalcemia persisted despite increased secretion of parathyroid hormone (PTH), which regulates calcium homeostasis. Usually, increased PTH secretion quickly results in the mobilization of calcium from bone and normalization of blood calcium levels. As the magnesium depletion progressed, PTH secretion diminished to low levels. Along with hypomagnesemia, signs of severe magnesium deficiency included hypocalcemia, low serum potassium levels (hypokalemia), retention of sodium, low circulating levels of PTH, neurological and muscular symptoms (tremor, muscle spasms, tetany), loss of appetite, nausea, vomiting, and personality changes (3).

The Recommended Dietary Allowance (RDA)

In 1997, the Food and Nutrition Board of the Institute of Medicine increased the recommended dietary allowance (RDA) for magnesium, based on the results of recent, tightly controlled balance studies that utilized more accurate methods of measuring magnesium (2Table 1). Balance studies are useful for determining the amount of a nutrient that will prevent deficiency; however, such studies provide little information regarding the amount of a nutrient required for chronic disease prevention or optimum health.

Table 1. Recommended Dietary Allowance (RDA) for Magnesium
Life Stage Age Males (mg/day) Females (mg/day)
Infants 0-6 months 30 (AI) 30 (AI)
Infants 7-12 months 75 (AI) 75 (AI)
Children 1-3 years 80 80
Children 4-8 years 130 130
Children 9-13 years 240 240
Adolescents 14-18 years 410 360
Adults 19-30 years 400 310
Adults 31 years and older 420 320
Pregnancy 18 years and younger 400
Pregnancy 19-30 years 350
Pregnancy 31 years and older 360
Breast-feeding 18 years and younger 360
Breast-feeding 19-30 years 310
Breast-feeding 31 years and older 320

Disease Prevention

Metabolic syndrome

Low magnesium intakes have been associated with the diagnosis of metabolic syndrome. The concomitant presentation of several metabolic disorders in an individual, including dyslipidemia, hypertensioninsulin resistance, and obesity, increases the risk for type 2 diabetes mellitus and cardiovascular disease. Systemic inflammation, which contributes to the development of metabolic disorders, has been inversely correlated with magnesium intakes in a cross-sectional study of 11,686 middle-aged women; the lowest prevalence of metabolic syndrome was found in the group of women with the highest quintile of magnesium intakes (median intake, 422 mg/day) (9).

Hypertension (high blood pressure)

Large epidemiological study studies suggest a relationship between magnesium and blood pressure. However, the fact that foods high in magnesium (fruit, vegetables, whole grains) are frequently high in potassium and dietary fiber has made it difficult to evaluate the independent effects of magnesium on blood pressure. A prospective cohort study of more than 30,000 male health professionals found an inverse association between dietary fiber, potassium, and magnesium and the development of hypertension over a four-year period (10). In a similar study of more than 40,000 female registered nurses, dietary fiber and dietary magnesium were each inversely associated with systolic and diastolic blood pressures in those who did not develop hypertension over the four-year study period, but neither dietary fiber nor magnesium was related to the risk of developing hypertension (11). The Atherosclerosis Risk in Communities (ARIC) study examined dietary magnesium intake, magnesium blood levels, and risk of developing hypertension in 7,731 men and women over a six-year period (12). The risk of developing hypertension in both men and women decreased as serummagnesium levels increased, but the trend was statistically significant only in women.

However, circulating magnesium represents only 1% of total body stores and is tightly regulated; thus, serum magnesium levels might not best reflect magnesium status. A recent prospective study that followed 5,511 men and women for a median period of 7.6 years found that the highest levels of urinary magnesium excretion corresponded to a 25% reduction in risk of hypertension, but plasma magnesium levels were not correlated with risk of hypertension (13). In cohort of 28,349 women followed for 9.3 years, the risk of hypertension was 7% lower for those with the highest magnesium intakes (434 mg/day vs. 256 mg/day) (14). The relationship between magnesium intake and risk of hypertension suggests that magnesium supplementation might play a role in preventing hypertension; however, randomized controlled trials are needed to assess whether supplemental magnesium might help prevent hypertension in high-risk individuals.

Diabetes mellitus

Public health concerns regarding the epidemics of obesity and type 2 diabetes mellitus and the prominent role of magnesium in glucose metabolism have led scientists to investigate the relationship between magnesium intake and type 2 diabetes mellitus. A prospective study that followed more than 25,000 individuals, 35 to 65 years of age, for seven years found no difference in incidence of diabetes mellitus when comparing the highest (377 mg/day) quintile of magnesium intake to the lowest (268 mg/day) (15). However, inclusion of this study in a meta-analysis of eight cohort studies showed that risk of type 2 diabetes was inversely correlated with magnesium intake (15). A second meta-analysis found that an increase of 100 mg/day in magnesium intake was associated with a 15% decrease in the risk of developing type 2 diabetes (16). The most recent meta-analysis of 13 observational studies, published in the last 15 years and including almost 540,000 individuals and 24,500 new cases of diabetes, found higher magnesium intakes were associated with a lower risk of diabetes (17).

Insulin resistance, which is characterized by alterations in both insulin secretion by the pancreas and insulin action on target tissues, has been linked to magnesium deficiency. An inverse association between magnesium intakes and fasting insulin levels was evidenced in a meta-analysis of 11 cohort studies that followed more than 36,000 participants without diabetes (18). It is thought that pancreatic β-cells, which regulate insulin secretion and glucose tolerance, could become less responsive to changes in insulin sensitivity in magnesium-deficient subjects (19). A randomizeddouble-blindplacebo-controlled trial, which enrolled 97 individuals (without diabetes and with normal blood pressure) with significant hypomagnesemia (serum magnesium level ≤0.70 mmoles/L), showed that daily consumption of 638 mg of magnesium (from a solution of magnesium chloride) for three months improved the function of pancreatic β-cells, resulting in lower fasting glucose and insulin levels (20). Increased insulin sensitivity also accompanied the correction of magnesium deficiency in patients diagnosed with insulin resistance but not diabetes (21). Another study found that supplementation with 365 mg/day of magnesium (from magnesium aspartate hydrochloride) for six months reduced insulin resistance in 47 overweight individuals even though they displayed normal values of serum and intracellular magnesium (22). This suggests that magnesium might have additive effects on glucose tolerance and insulin sensitivity that go beyond the normalization of physiologic serum concentrations in deficient individuals.

Cardiovascular disease

A number of studies have found decreased mortality from cardiovascular disease in populations who routinely consume “hard” water. Hard (alkaline) water is generally high in magnesium but may also contain more calcium and fluoride than “soft” water, making the cardioprotective effects of hard water difficult to attribute to magnesium alone (23). One large prospective study (almost 14,000 men and women) found a significant trend for increasing serum magnesium levels to be associated with decreased risk of coronary heart disease (CHD) in women but not in men (24). However, the risk of CHD in the lowest quartile of dietary magnesium intake was not significantly higher than the risk in the highest quartile in men or women. This prospective study was included in a meta-analysis of 14 studies that found a 22% lower risk of CHD (but not fatal CHD) per 200 mg/day incremental intake in dietary magnesium (25). In another prospective study, which followed nearly 90,000 female nurses for 28 years, women in the highest quintile of magnesium intake had a 39% lower risk of fatal myocardial infarction (but not nonfatal myocardial infarction) compared to those in the lowest quintile (>342 mg/day versus <246 mg/day) (26). Higher magnesium intakes were associated with an 8%-11% reduction in stroke risk in two meta-analyses of prospective studies, each including over 240,000 participants (27, 28). Additionally, a meta-analysis of 13 prospective studies in over 475,000 participants reported that the risk of total cardiovascular events, including stroke, nonfatal myocardial infarction, and CHD, was 15% lower in individuals with higher intakes of magnesium (29). Finally, a meta-analysis of six prospective studies found no association between magnesium intake and cardiovascular mortality risk (30). However, a recent prospective study that followed 3,910 subjects for 10 years found significant correlations between hypomagnesemia and all-cause mortality, including cardiovascular-related mortality (31). Presently, well-controlled intervention trials are required to assess the benefit of magnesium supplementation in the prevention of cardiovascular disease.


Occurrence of hypomagnesemia has been reported in patients who suffered from a subarachnoid hemorrhage caused by the rupture of a cerebral aneurysm (32). Poor neurologic outcomes following an aneurysmal subarachnoid hemorrhage (aSAH) have been linked to inappropriate calcium-dependent contraction of arteries (known as cerebral arterial vasospasm), leading to delayed cerebral ischemia (33). Magnesium sulfate is a calcium antagonist and potent vasodilator that has been considered in the prevention of vasospasm after aSAH. Several randomized controlled trials have assessed the effect of intravenous (IV) magnesium sulfate infusions. A meta-analysis of nine randomized controlled trials found that magnesium therapy after aSAH significantly reduced vasospasm but failed to prevent neurologic deterioration or decrease the risk of death (34). The most recent meta-analysis of 13 trials in 2,413 aSAH patients concluded that the infusion of magnesium sulfate had no benefits in terms of neurologic outcome and mortality, despite a reduction in the incidence of delayed cerebral ischemia (35). At present, the data advise against the use of intravenous magnesium in clinical practice for aSAH patients after normalization of their magnesium status.

Complications of heart surgery

Atrial arrhythmia is a condition defined as the occurrence of persistent heart rate abnormalities that often complicate the recovery of patients after cardiac surgery. The use of magnesium in the prophylaxis of postoperative atrial arrhythmia after coronary artery bypass grafting has been evaluated as a sole or adjunctive agent to classical antiarrhythmic molecules (namely, β-blockers and amiodarone) in several prospective, randomized controlled trials. A meta-analysis of 21 intervention studies showed that intravenous magnesium infusions could significantly reduce postoperative atrial arrhythmia in treated compared to untreated patients (36). However, a meta-analysis of five randomized controlled trials concerned with rhythm-control prophylaxis showed that intravenous magnesium added to β-blocker treatment did not decrease the risk of atrial arrhythmia compared to β-blocker alone and was associated with more adverse effects (bradycardia and hypotension) (37). Presently, the findings support the use of β-blockers and amiodarone, but not magnesium, in patients with contraindications to first-line antiarrhythmics.


Although decreased bone mineral density (BMD) is the primary feature of osteoporosis, other osteoporotic changes in the collagenous matrix and mineral components of bone may result in bones that are brittle and more susceptible to fracture. Magnesium comprises about 1% of bone mineral and is known to influence both bone matrix and bone mineral metabolism. As the magnesium content of bone mineral decreases, apatite crystals of bone become larger and more brittle. Some studies have found lower magnesium content and larger apatite crystals in bones of women with osteoporosis compared to women without the disease (38). Inadequate serum magnesium levels are known to result in low serum calcium levels, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (calcitriol), all of which can lead to increased bone loss (see the articles on Vitamin D and Calcium). A study of over 900 elderly men and women found that higher dietary magnesium intakes were associated with increased BMD at the hip in both men and women. However, because magnesium and potassium are present in many of the same foods, the effect of dietary magnesium could not be isolated (39). A cross-sectional study in over 2,000 elderly individuals reported that magnesium intake was positively associated with total-body BMD in white men and women but not in black men and women (40). More recently, a large cohort study conducted in almost two-thirds of the Norwegian population found the level of magnesium in drinking water was inversely correlated with risk of hip fracture (41).

Few studies have addressed the effect of magnesium supplementation on BMD or osteoporosis in humans. In a small group of postmenopausal women with osteoporosis, magnesium supplementation of 750 mg/day for the first six months followed by 250 mg/day for 18 more months resulted in increased BMD at the wrist after one year, with no further increase after two years of supplementation (42). A study in postmenopausal women who were taking estrogen replacement therapy and also a multivitamin found that supplementation with an additional 500 mg/day of magnesium and 600 mg/day of calcium resulted in increased BMD at the heel compared to postmenopausal women receiving only estrogen replacement therapy (43). Evidence is not yet sufficient to suggest that supplemental magnesium could be recommended in the prevention of osteoporosis unless normalization of serum magnesium levels is required. Moreover, it appears that high magnesium levels could be harmful to skeletal health by interfering with the action of the calciotropic hormones, PTH and calcitriol (44). Presently, the potential for increased magnesium intake to influence calcium and bone metabolism warrants more research with particular attention to its role in the prevention and treatment of osteoporosis.

Disease Treatment

The use of pharmacologic doses of magnesium to treat specific diseases is discussed below. Although many of the cited studies utilized supplemental magnesium at doses considerably higher than the tolerable upper intake level (UL), which is 350 mg/day set by the Food and Nutrition Board (see Safety), it is important to note that these studies were all conducted under medical supervision. Because of the potential risks of high doses of supplemental magnesium, especially in the presence of impaired kidney function, any disease treatment trial using magnesium doses higher than the UL should be conducted under medical supervision.

Pregnancy complications

Preeclampsia and eclampsia

Preeclampsia and eclampsia are pregnancy-specific conditions that may occur anytime after 20 weeks of pregnancy through six weeks following birth. Approximately 7% of pregnant women in the US develop preeclampsia-eclampsia. Preeclampsia (sometimes called toxemia of pregnancy) is defined as the presence of elevated blood pressure (hypertension), protein in the urine, and severe swelling (edema) during pregnancy. Eclampsia occurs with the addition of seizures to the triad of symptoms and is a significant cause of perinatal and maternal death (45). Although cases of preeclampsia are at high risk of developing eclampsia, one-quarter of eclamptic women do not initially exhibit preeclamptic symptoms (46). For many years, high-dose intravenous magnesium sulfate has been the treatment of choice for preventing eclamptic seizures that may occur in association with preeclampsia-eclampsia late in pregnancy or during labor (47, 48). A systematic review of seven randomized trials compared the administration of magnesium sulfate with diazepam (a known anticonvulsant) treatment on perinatal outcomes in 1,396 women with eclampsia. Risks of recurrent seizures and maternal death were significantly reduced by the magnesium regimen compared to diazepam. Moreover, the use of magnesium for the care of eclamptic women resulted in newborns with higher Apgar scores; there was no significant difference in the risk of preterm birth and perinatal mortality (46). Additional research has confirmed that infusion of magnesium sulfate should always be considered in the management of preeclampsia and eclampsia to prevent initial and recurrent seizures (49).

Perinatal neuroprotection

While intravenous magnesium sulfate is included in the medical care of preeclampsia and eclampsia, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support its use in two additional situations: specific conditions of short-term prolongation of pregnancy and neuroprotection of the fetus in anticipated premature delivery (50). The relationship between magnesium sulfate and risk of cerebral damage in premature infants has been assessed in observational studies. A meta-analysis of six case-control and five prospective cohort studies showed that the use of magnesium significantly reduced the risk of cerebral palsy, as well as mortality (51). However, the high degree of heterogeneity among the cohort studies and the fact that corticosteroid exposure (which is known to decrease antenatal mortality) was higher in the cases of children exposed to magnesium compared to controls imply a cautious interpretation of the results. However, a meta-analysis of five randomized controlled trials, which included a total of 6,145 babies, found that magnesium therapy given to mothers delivering before term decreased the risk of cerebral palsy and gross motor dysfunction, without modifying the risk of other neurologic impairments or mortality in early childhood (52). Another meta-analysis conducted on five randomized controlled trials found that intravenous magnesium administration to newborns who suffered from perinatal asphyxia could be beneficial in terms of short-term neurologic outcomes, although there was no effect on mortality (53). Nevertheless, additional trials are needed to evaluate the long-term benefits of magnesium in pediatric care.

Cardiovascular disease

Hypertension (high blood pressure)

While results from intervention studies have not been entirely consistent (2), the latest review of the data highlighted a therapeutic benefit of magnesium supplements in treating hypertension. A recent meta-analysis examined 22 randomizedplacebo-controlled trials of magnesium supplementation conducted in 1,173 individuals with either a normal blood pressure (normotensive) or hypertension, both treated or untreated with medications. Oral supplementation with magnesium (mean dose of 410 mg/day; range of 120 to 973 mg/day) for a median period of 11.3 months significantly reduced systolic blood pressure by 2-3 mm Hg and diastolic blood pressure by 3-4 mm Hg (54); a greater effect was seen at higher doses (≥370 mg/day). The results of 19 of the 22 trials included in the meta-analysis were previously reviewed together with another 25 intervention studies (55). The systematic examination of these 44 trials suggested a blood pressure-lowering effect associated with supplemental magnesium in hypertensive but not in normotensive individuals. Magnesium doses required to achieve a decrease in blood pressure appeared to depend on whether subjects with high blood pressure were treated with antihypertensive medications, including diuretics. Intervention trials on treated subjects showed a reduction in hypertension with magnesium doses from 243 mg/day to 486 mg/day, whereas untreated patients required doses above 486 mg/day to achieve a significant decrease in blood pressure. While oral magnesium supplementation may be helpful in hypertensive individuals who are depleted of magnesium due to chronic diuretic use and/or inadequate dietary intake (56), several dietary factors play a role in hypertension. For example, adherence to the DASH diet — a diet rich in fruit, vegetables, and low-fat dairy and low in saturated and total fats — has been linked to significant reductions in systolic and diastolic blood pressures (57). See the article in the Spring/Summer 2009 Research Newsletter, Dietary and Lifestyle Strategies to Control Blood Pressure.

Myocardial infarction (heart attack)

Results of a meta-analysis of randomizedplacebo-controlled trials indicated that an intravenous (IV) magnesium infusion given early after suspected myocardial infarction(MI) could decrease the risk of death. The most influential study included in the meta-analysis was a randomized, placebo-controlled trial in 2,316 patients that found a significant reduction in mortality (7.8% all-cause mortality in the experimental group vs. 10.3% all-cause mortality in the placebo group) in the group of patients given intravenous magnesium sulfate within 24 hours of suspected myocardial infarction (58). Follow-up from one to five years after treatment revealed that the mortality from cardiovascular disease was 21% lower in the magnesium treated group (59). However, a larger placebo-controlled trial that included more than 58,000 patients found no significant reduction in five-week mortality in patients treated with intravenous magnesium sulfate within 24 hours of suspected myocardial infarction, resulting in controversy regarding the efficacy of the treatment (60). A US survey of the treatment of more than 173,000 patients with acute MI found that only 5% were given IV magnesium in the first 24 hours after MI, and that mortality was higher in patients treated with IV magnesium compared to those not treated with magnesium (61). The most recent systematic review of 26 clinical trials, including 73,363 patients, concluded that IV magnesium likely does not reduce mortality following MI and thus should not be utilized as a treatment (62). Thus, the use of IV magnesium sulfate in the therapy of acute MI remains controversial.

Endothelial dysfunction

Vascular endothelial cells line arterial walls where they are in contact with the blood that flows through the circulatory system. Normally functioning vascular endothelium promotes vasodilation when needed, for example, during exercise, and inhibits the formation of blood clots. Conversely, endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities. In cardiovascular disease, chronic inflammation is associated with the formation of atherosclerotic plaques in arteries. Atherosclerosis impairs normal endothelial function, increasing the risk of vasoconstriction and clot formation, which may lead to heart attack or stroke (reviewed in 63). Research studies have indicated that pharmacologic doses of oral magnesium may improve endothelial function in individuals with cardiovascular disease. A randomizeddouble-blindplacebo-controlled trial in 50 men and women with stable coronary artery disease found that six months of oral magnesium supplementation (730 mg/day) resulted in a 12% improvement in flow-mediated vasodilation compared to placebo (64). In other words, the normal dilation response of the brachial (arm) artery to increased blood flow was improved. Magnesium supplementation also resulted in increased exercise tolerance during an exercise stress test compared to placebo. In another study of 42 patients with coronary artery disease who were already taking low-dose aspirin (an inhibitor of platelet aggregation), three months of oral magnesium supplementation (800 to 1,200 mg/day) resulted in an average 35% reduction in platelet-dependent thrombosis, a measure of the propensity of blood to clot (65). Additionally, a study in 657 women participating in the Nurses’ Health Study reported that dietary magnesium intake was inversely associated with E-selectin, a marker of endothelial dysfunction (66)In vitro studies using human endothelial cells have provided mechanistic insights into the association of low magnesium concentrations, chronic inflammation, and endothelial dysfunction (67). Finally, since magnesium can function as a calcium antagonist, it has been suggested that it could be utilized to slow down or reverse the calcification of vessels observed in patients with chronic kidney disease. The atherosclerotic process is often accelerated in these subjects, and patients with chronic kidney disease have higher rates of cardiovascular-related mortality compared to the general population (68). Additional studies are needed to assess whether magnesium may be of benefit in improving endothelial function in individuals at high risk for cardiovascular disease.

Diabetes mellitus

Magnesium depletion is commonly associated with both insulin-dependent (type 1) and non-insulin dependent (type 2) diabetes mellitus. Reduced serum levels of magnesium (hypomagnesemia) have been reported in 13.5% to 47.7% of individuals with type 2 diabetes (69). One cause of the depletion may be increased urinary loss of magnesium, which results from increased urinary excretion of glucose that accompanies poorly controlled diabetes. Magnesium depletion has been shown to increase insulin resistance in a few studies and may adversely affect blood glucose control in diabetes (70). One study reported that dietary magnesium supplements (390 mg/day of elemental magnesium for four weeks) improved glucose tolerance in elderly individuals (71). Another small study in nine patients with type 2 diabetes reported that supplemental magnesium (300 mg/day for 30 days), in the form of a liquid, magnesium-containing salt solution, improved fasting insulin levels but did not affect fasting glucose levels (72). Yet, the most recent meta-analysis of nine randomizeddouble-blind, controlled trials concluded that oral supplemental magnesium may lower fasting plasma glucose levels in individuals with diabetes (73). One randomized, double-blind, placebo-controlled study in 63 individuals with type 2 diabetes and hypomagnesemia found that those taking an oral magnesium chloride solution (638 mg/day of elemental magnesium) for 16 weeks had improved measures of insulin sensitivity and glycemic control compared to those taking a placebo (74). Large-scale, well-controlled studies are needed to determine whether magnesium supplementation has any long-term therapeutic benefit in patients with type 2 diabetes. However, correcting existing magnesium deficiencies may improve glucose metabolism and insulin sensitivity in those with diabetes.

Migraine headaches

Individuals who suffer from recurrent migraine headaches have lower intracellular magnesium levels (demonstrated in both red blood cells and white blood cells) than individuals who do not experience migraines (75). Additionally, the incidence of ionized magnesium deficiency has been found to be higher in women with menstrualmigraine compared to women who don’t experience migraines with menstruation (76). Oral magnesium supplementation has been shown to increase intracellular magnesium levels in individuals with migraines, leading to the hypothesis that magnesium supplementation might be helpful in decreasing the frequency and severity of migraine headaches. Two early placebo-controlled trials demonstrated modest decreases in the frequency of migraine headaches after supplementation with 600 mg/day of magnesium (75, 77). Another placebo-controlled trial in 86 children with frequent migraine headaches found that oral magnesium oxide (9 mg/kg body weight/day) reduced headache frequency over the 16-week intervention (78). However, there was no reduction in the frequency of migraine headaches with 485 mg/day of magnesium in another placebo-controlled study conducted in 69 adults suffering migraine attacks (79). The efficiency of magnesium absorption varies with the type of oral magnesium complex, and this might explain the conflicting results. Although no serious adverse effects were noted during these migraine headache trials, 19% to 40% of individuals taking the magnesium supplements have reported diarrhea and gastric (stomach) irritation.

The efficacy of magnesium infusions was also investigated in a randomized, single-blind, placebo-controlled, cross-over trial of 30 patients with migraine headaches (80). The administration of 1 gram of intravenous (IV) magnesium sulfate ended the attacks, abolished associated symptoms, and prevented recurrence within 24 hours in nearly 90% of the subjects. While this promising result was confirmed in another trial (81), two additional randomized, placebo-controlled studies found that magnesium sulfate was less effective than other molecules (e.g., metoclopramide) in treating migraines (82, 83). The most recent meta-analysis of five randomized, double-blind, controlled trials reported no beneficial effect of IV magnesium for migraine in adults (84). However, the effect of magnesium should be examined in larger studies targeting primarily migraine sufferers with hypomagnesemia (85).


The occurrence of hypomagnesemia may be greater in patients with asthma than in individuals without asthma (86). Several clinical trials have examined the effect of intravenous (IV) magnesium infusions on acute asthmatic attacks. One double-blindplacebo-controlled trial in 38 adults with acute asthma, who did not respond to initial treatment in the emergency room, found improved lung function and decreased likelihood of hospitalization when IV magnesium sulfate was infused compared to a placebo (87). However, another placebo-controlled, double-blind study in 48 adults reported that IV infusion of magnesium sulfate did not improve lung function in patients experiencing an acute asthma attack (88). A systematic review of seven randomized controlled trials (five adult and two pediatric) concluded that IV magnesium sulfate is beneficial in patients with severe, acute asthma (89). In addition, a meta-analysis of five randomized placebo-controlled trials, involving 182 children with severe asthma, found that IV infusion of magnesium sulfate was associated with a 71% reduction in the need for hospitalization (90). In the most recent meta-analysis of 16 randomized controlled trials (11 adult and 5 pediatric), IV magnesium sulfate treatment was associated with a significant improvement of respiratory function in both adults and children with acute asthma treated with β2-agonists and systemic steroids (91). At present, available evidence indicates that IV magnesium infusion is an efficacious treatment for severe, acute asthma; however, oral magnesium supplementation is of no known value in the management of chronic asthma (92-94). Nebulized, inhaled magnesium for treating asthma requires further investigation. A meta-analysis of eight randomized controlled trials in asthmatic adults showed that nebulized, inhaled magnesium sulfate had benefits with respect to improved lung function and decreased hospital admissions (91). However, a recent systematic review of 16 randomized controlled trials, including adults, children, or both, found little evidence that inhaled magnesium sulfate, along with a β2-agonist, improved pulmonary function in patients with acute asthma (95).


Food sources

A large US national survey indicated that average magnesium intake is about 350 mg/day for men and about 260 mg/day for women — significantly below the current recommended dietary allowance (RDA). Magnesium intakes were even lower in men and women over 50 years of age (8). Such findings suggest that marginal magnesium deficiency may be relatively common in the US.

Since magnesium is part of chlorophyll, the green pigment in plants, green leafy vegetables are rich in magnesium. Unrefined grains (whole grains) and nuts also have high magnesium content. Meats and milk have an intermediate content of magnesium, while refined foods generally have the lowest. Water is a variable source of intake; harder water usually has a higher concentration of magnesium salts (2). Some foods that are relatively rich in magnesium are listed in Table 2, along with their magnesium content in milligrams (mg). For more information on the nutrient content of foods, search the USDA food composition database.

Table 2. Some Food Sources of Magnesium
Food Serving Magnesium (mg)
Cereal, all bran ½ cup 112
Cereal, oat bran ½ cup dry 96
Brown rice, medium-grain, cooked 1 cup 86
Fish, mackerel, cooked 3 ounces 82
Spinach, frozen, chopped, cooked ½ cup 78
Almonds 1 ounce (23 almonds) 77
Swiss chard, chopped, cooked ½ cup 75
Lima beans, large, immature seeds, cooked ½ cup 63
Cereal, shredded wheat 2 biscuits 61
Peanuts 1 ounce 48
Molasses, blackstrap 1 tablespoon 48
Hazelnuts 1 ounce (21 hazelnuts) 46
Okra, frozen, cooked ½ cup 37
Milk, 1% fat 8 fluid ounces 34
Banana 1 medium 32


Magnesium supplements are available as magnesium oxide, magnesium gluconate, magnesium chloride, and magnesium citrate salts, as well as a number of amino acidchelates, including magnesium aspartate. Magnesium hydroxide is used as an ingredient in several antacids (96).



Adverse effects have not been identified from magnesium occurring naturally in food. However, adverse effects from excess magnesium have been observed with intakes of various magnesium salts (i.e., supplemental magnesium) (6). The initial symptom of excess magnesium supplementation is diarrhea — a well-known side effect of magnesium that is used therapeutically as a laxative. Individuals with impaired kidney function are at higher risk for adverse effects of magnesium supplementation, and symptoms of magnesium toxicity have occurred in people with impaired kidney function taking moderate doses of magnesium-containing laxatives or antacids. Elevated serum levels of magnesium (hypermagnesemia) may result in a fall in blood pressure (hypotension). Some of the later effects of magnesium toxicity, such as lethargy, confusion, disturbances in normal cardiac rhythm, and deterioration of kidney function, are related to severe hypotension. As hypermagnesemia progresses, muscle weakness and difficulty breathing may occur. Severe hypermagnesemia may result in cardiac arrest (2, 3). The Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper intake level (UL) for magnesium at 350 mg/day (Table 3); this UL represents the highest level of daily supplemental magnesium intake likely to pose no risk of diarrhea or gastrointestinal disturbance in almost all individuals. The FNB cautions that individuals with renal impairment are at higher risk for adverse effects from excess supplemental magnesium intake. However, the FNB also notes that there are some conditions that may warrant higher doses of magnesium under medical supervision (2).

Table 3. Tolerable Upper Intake Level (UL) for Supplemental Magnesium
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 65
Children 4-8 years 110
Children 9-13 years 350
Adolescents 14-18 years 350
Adults 19 years and older 350
*Source of intake should be from food and formula only.

Drug interactions

Magnesium interferes with the absorption of digoxin (a heart medication), nitrofurantoin (an antibiotic), and certain anti-malarial drugs, which could potentially reduce drug efficacy. Bisphosphonates (e.g., alendronate and etidronate), which are drugs used to treat osteoporosis, and magnesium should be taken two hours apart so that the absorption of the bisphosphonate is not inhibited. Magnesium has also been found to reduce the efficacy of chlorpromazine (a tranquilizer), penicillamine, oral anticoagulants, and the quinolone and tetracycline classes of antibiotics. Because intravenous magnesium has increased the effects of certain muscle-relaxing medications used during anesthesia, it is advisable to let medical staff know if you are taking oral magnesium supplements, laxatives, or antacids prior to surgical procedures. High doses of furosemide (Lasix) and some thiazide diuretics (e.g., hydrochlorothiazide), if taken for extended periods, may result in magnesium depletion (96, 97). Moreover, long-term use (three months or longer) of proton-pump inhibitors (drugs used to reduce the amount of stomach acid) may increase the risk of hypomagnesemia (98, 99). Many other medications may also result in renal magnesium loss (3).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the latest RDA for magnesium intake (400-420 mg/day for men and 310-320 mg/day for women). Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement may ensure an intake of at least 100 mg of magnesium/day. Few multivitamin/mineral supplements contain more than 100 mg of magnesium due to its bulk. Because magnesium is plentiful in foods, eating a varied diet that provides green vegetables, whole grains, and nuts daily should provide the rest of an individual’s magnesium requirement.

Older adults (>50 years)

Older adults are less likely than younger adults to consume enough magnesium to meet their needs and should therefore take care to eat magnesium-rich foods in addition to taking a multivitamin/mineral supplement daily. Since older adults are more likely to have impaired kidney function, they should avoid taking more than 350 mg/day of supplemental magnesium without medical consultation (see Safety).



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NOVA Health Recovery  <<< Ketamine infusion center in Alexandria, Virginia 703-844-0184  – consider ketamine for addiction treatment

CAll 703-844-0184 for an immediate appointment!

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.


Ketamine center in Fairfax, Virginia    << Ketamine infusions

NOVA Health Recovery – KETAMINE SYSTEMS<< Link

703-844-0184 NOVA Health Recovery Ketamine Infusion Center – Beat depression and Anxiety. https://novahealthrecovery.com/

Each year, 13 to 14 million people in America suffer from major depression. Of those numbers who seek treatment, about 30-40% don’t get any better or recover through using the standard depression medications prescribed by healthcare professionals.

Untreated depression puts someone at a greater risk of alcohol and drug abuse, hospitalization and attempted suicide. However, there’s a growing body of research which shows there is a new reason to hope, and it’s the anesthesia drug ketamine.

Ketamine is a popular illicit party drug because it provides the user with hallucinogenic effects. The medication is used in only a handful of clinics around the United States, people who weren’t helped by standard psychiatric treatments are receiving a series of ketamine infusions to help ease the effects of their depression. Ketamine has also been used in emergency rooms to help curb suicidal thoughts, which means the drug is a potential lifesaver.

Ketamine is a fast-acting drug, the effects peak, often within hours, and healthcare providers who give it to a patient at a therapeutic dose say its side effects are brief and mild in most people. The drug hasn’t been studied for long-term safety and effectiveness and the Food and Drug Administration hasn’t approved it to treat depression.

Medical experts do not yet fully understand all the ways ketamine works, but it does work differently than antidepressants such as Zoloft, Prozac and Effexor. The way the drug works might explain why people who don’t respond to traditional treatment methods respond so well to ketamine.

It’s important to remember that no matter how successful ketamine may prove to be, one single treatment isn’t enough to cure depression. To successfully treat depression, a medical professional will need to address all aspects of a person’s disease from the biological, psychological to social and environmental angles.

A Brief History of Ketamine
Ketamine is an anesthetic that has been used on both humans and animals for over 52 years.  Unlike other anesthetics, it doesn’t depress patients’ breathing or circulatory systems and it is very fast-acting.

How Is Ketamine Used
Because of its effectiveness and safety when delivered appropriately, ketamine is being used more in the following ways: treating depression and other mood disorders and pain conditions including Complex Regional Pain Syndrome (CPRS/RSD).  Leading institutions such as Yale University, The National Institute of Mental Health, and  Massachusetts General Hospital have completed research that demonstrates the efficacy and safety of ketamine infusion treatments for these conditions.

The Visit
The medicine is given very slowly over 40 minutes.  Most people can expect to be with us for about 90 minutes.  You will leave treatment without side effects and you should not experience side effects between treatments.​

In As Little As One Treatment
Ketamine treatments may free you from depression, OCD, PTSD, anxiety, CRPS/RSD, fibromyalgia & other chronic pain conditions.

Ketamine Infusion for Depression, Bipolar Disorder or PTSD?

Ketamine could be the bridge for somebody who is suicidal because if they are given the drug and it’s effective for 3 days, the person could be hooked up with outpatient resources, other medications and psychotherapy.

Not all cases of suicidal thoughts are linked to depression, post-traumatic stress disorder, borderline personality disorder and alcohol and other substance abuse issues can also account for some suicides. Further research is needed to determine how ketamine can be utilized for treatment of depression and other psychiatric disorders.

Does Ketamine Infusion Work for Depression?

Social Anxiety and Ketamine:

Approximately one-third to one-half of all people with Social Anxiety Disorder (SAD) do not experience adequate clinical benefits from using the current treatment methods for SAD. These treatments include conventional approaches like selective serotonin reuptake inhibitors or SSRIs or cognitive behavioral therapy. Failing to relieve anxiety in patients with social anxiety disorder is a source of distress, substantial morbidity and it decreases the quality of a person’s life over the long term.

Feeling shy or uncomfortable in certain public situations isn’t an indication of a social anxiety disorder, particularly if these emotions are present in young children. A person’s comfort level in social situations will vary and depend on the individual’s personality and life experiences. Some people are naturally reserved and other people are outgoing, some are a mixture of both.  In contrast to everyday nervousness, social anxiety disorder includes distress, avoidance and unease that interferes with one’s daily life, routine, work, school and other activities.

There’s been new evidence from neuroimaging and pharmacological studies which support the importance of glutamate abnormalities in the pathogenesis of social anxiety disorder. In a previous clinical study, an elevate glutamate to creatinine ratio was found in the anterior cortex of social anxiety disorder patients when compared with healthy control subjects.

Ketamine is a potent agonist of the N-methyl-D-aspartate receptor is a major glutamate receptor in the brain. The drug is normally used as an anesthetic because of its dissociative properties. In a multitude of controlled clinical studies, ketamine has proven to be an effective treatment for reducing symptoms of depression and anxiety. Ketamine has produced a rapid antidepressant effect in unipolar and bipolar depression and the effects peak 1-3 days following infusion and is observed long after the drug has been metabolized and excreted by the body.

The results of several studies involving ketamine infusion show the medication may have significant anxiolytic effects. For patients with major depressive disorders or social anxiety disorder, the drug has shown strong and significant reductions in co-morbid anxiety symptoms. If you want to find out more information about how ketamine infusion may work for you, please contact us at 703-844-0184 – NOVA Health Recovery



Ketamine is a drug that was developed more than 50 years ago to be used as anesthesia during surgery, and it has also been used as an illicit street drug. Recently, ketamine has been found to be a valuable and extremely effective treatment for depression, anxiety, PTSD, OCD and certain pain disorders, like fibromyalgia.

Our Ketamine treatment center in Bowie MD offer infusions on an outpatient basis and following a consultation with medical staff it can be determined if the medication is appropriate and safe for a person. A patient using ketamine infusion therapy is monitored during the process by a clinical coordinator to ensure a smooth, supportive and successful treatment process.

Because the effects of a ketamine infusion are short-lived, patients will usually receive a series of infusions over a series of 2-3 weeks. Ketamine infusions for PTSD is an off-label use and it means the Food and Drug Administration has not approved the drug for this particular use. However, the drug’s safety and effectiveness have been demonstrated in multiple research studies and off-label prescribing is a common and necessary practice in the medical world.

Unlike most of the common antidepressant medications that may take weeks or months before a patient and doctor can even determine if it works, ketamine infusions yield positive results within hours or days. Many patients will know within the first few hours or days if ketamine is working for them or not. The most common experience when using ketamine infusions is no side effects between treatments, so it is a good option for those with treatment-resistant depression or those who have troublesome side effects from other medications commonly prescribed.

Ketamine Safety and Tolerability In Clinical Trials For Treatment-resistant Depression

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in DepressionA preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department

Ketamine for Depression: Where Do We Go from Here?

A Systematic Review of Ketamine for Complex Regional Pain Syndrome

The Promise of Ketamine For Treatment-resistant Depression: Current Evidence and Future Directions

Ketamine-Induced Optimism: New Hope for the Development of Rapid-Acting Antidepressants

Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial

Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression

Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression

NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

A review of ketamine in affective disorders:Current evidence of clinical efficacy,limitations of use and pre-clinical evidence on proposed mechanisms of action

Intravenous Ketamine for the Treatment of Mental Health Disorders: A Review of Clinical Effectiveness and Guidelines

Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder​

Researchers find new ways of managing clinical and seasonal depression

Areas we Serve:

Maryland (MD):

Bethesda 20814 – Bethesda 20816 – Bethesda 20817 – Chevy Chase 20815 – Colesville 20904 – Cabin John 20815 – Glen Echo 20812 – Gaithersburg 20855 – Gaithersburg 20877- Gaithersburg 20878 – Gaithersburg 20879 – Garrett Park 20896 – Kensington 20895 – Montgomery Village 20886 – Olney 20830 – Olney 20832 – Potomac 20854 – Potomac 20859 – Rockville 20850 – Rockville 20852 – Rockville 20853 – Silver Spring 20903 – Silver Spring 20905 – Silver Spring 20906 – Silver Spring 20910 – Takoma Park 20912 – Wheaton 20902


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Northern Virginia:

McLean 22101- McLean 22102 – McLean 22106 – Great Falls 22066 – Arlington 22201 – Arlington 22202 – Arlington 22203 – Arlington 22205 – Falls Church 22041 – Vienna 22181 – Alexandria 22314 – 22308 -22306 -22305 -22304  Fairfax – 20191 – Reston – 22009 – Springfield – 22152  22015  Lorton 22199

Fairfax, Va

2303 –  22307 – 22306 – 22309 – 22308 22311 – 22310 – 22312

22315 -22003 – 20120 – 22015 – 22027 20121 – 22031 –  20124

22030 – 22033 – 22032 – 22035 – 22039 22041 – 22043

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22102 – 20171 – 20170 – 22124 – 22151 22150 – 22153

22152 – 20191 – 20190 – 22181- 20192 22180 – 20194 –  22182

Woodbridge – 22191 – 22192 -22193 -22194 – 22195

Springfield – 22150 – 22151 -22152-22153-22154-22155 -22156 – 22157 -22158 -22159 -22160 – 22161

Front Royal 22630

Warren County 22610 22630 22642 22649

Fredericksburg Va 22401 22402 – 22403 – 22404 -22405 -22406 -22407 -22408 – 22412

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20105    Aldie      Loudoun County 20106  Amissville            Culpeper County 20107 Arcola   Loudoun County

20108    Manassas            Manassas City 20109       Sudley Springs   Prince William County

20109    Manassas            Prince William County 20110       Manassas            Manassas City

20111    Manassas            Prince William County 20111       Manassas Park  Prince William County

20112    Manassas            Prince William County 20113       Manassas Park  Manassas Park City

20115    Marshall               Fauquier County 20116  Marshall               Fauquier County

20117    Middleburg        Loudoun County 20118  Middleburg        Loudoun County

20119    Catlett  Fauquier County – 20120 Sully Station    Fairfax County

20120    Centreville          Fairfax County – 20121   Centreville          Fairfax County

20122    Centreville          Fairfax County – 20124   Clifton   Fairfax County

20128    Orlean  Fauquier County -20129                Paeonian Springs             Loudoun County

20130    Paris      Clarke County

20131    Philomont           Loudoun County 20132  Purcellville          Loudoun County

20134    Hillsboro              Loudoun County 20134  Purcellville          Loudoun County

20135    Bluemont            Clarke County 20136       Bristow Prince William County

20137    Broad Run           Fauquier County 20138  Calverton            Fauquier County

20139    Casanova             Fauquier County 20140  Rectortown        Fauquier County

20141    Round Hill            Loudoun County 20142  Round Hill            Loudoun County

20143    Catharpin            Prince William County

20144    Delaplane            Fauquier County20146   Ashburn               Loudoun County

20147    Ashburn               Loudoun County 20148  Brambleton        Loudoun County

20148    Ashburn               Loudoun County 20151  Chantilly               Fairfax County

20151    Fairfax  Fairfax County 20152      South Riding       Loudoun County

20152    Chantilly               Loudoun County 20152  Fairfax  Loudoun County

20153    Chantilly               Fairfax County 20153      Fairfax  Fairfax County

20155    Gainesville          Prince William County 20156       Gainesville          Prince William County

20158    Hamilton              Loudoun County 20159  Hamilton              Loudoun County

20160    Lincoln  Loudoun County 20160  Purcellville          Loudoun County

20163    Sterling Loudoun County 20164  Sterling Loudoun County

20165    Potomac Falls    Loudoun County 20165  Sterling Loudoun County

20166    Dulles    Loudoun County 20166  Sterling Loudoun County

20167    Sterling Loudoun County 20168  Haymarket          Prince William County

20169    Haymarket          Prince William County 20170       Herndon              Fairfax County

20171    Oak Hill Fairfax County 20171      Herndon              Fairfax County

20172    Herndon              Fairfax County 20175      Leesburg             Loudoun County

20176    Lansdowne         Loudoun County 20176  Leesburg             Loudoun County

20177    Leesburg             Loudoun County 20178  Leesburg             Loudoun County

20180    Lovettsville         Loudoun County 20181  Nokesville           Prince William County

20182    Nokesville           Prince William County 20184       Upperville           Fauquier County

20185    Upperville           Fauquier County 20186  Warrenton          Fauquier County

20187    New Baltimore  Fauquier County 20187  Vint Hill Farms   Fauquier County 20187  Warrenton          Fauquier County

20188    Vint Hill Farms   Fauquier County 20188  Warrenton          Fauquier County

20190    Reston  Fairfax County 20190      Herndon              Fairfax County

20191    Reston  Fairfax County 20191      Herndon              Fairfax County

20194    Reston  Fairfax County 20194      Herndon              Fairfax County

20195    Reston  Fairfax County 20195      Herndon              Fairfax County

20197    Waterford           Loudoun County 20198  The Plains            Fauquier County

Loudon County:

Loudoun County, VA – Standard ZIP Codes

20105 | 20117 | 20120 | 20129 | 20130 | 20132 | 20135 | 20141 | 20147 | 20148 | 20152 | 20158 | 20164 | 20165 | 20166 | 20175 | 20176 | 20180 | 20184 | 20189 | 20197 | 22066

Ashburn, VA – Standard ZIP Codes
20147 20148
Leesburg, VA – Standard ZIP Codes
20175 20176
Sterling, VA – Standard ZIP Codes
20164 20165 20166

Waterford, VA 20197

Dulles, VA – Standard ZIP Codes
20166 20189
Purcellville, VA – Standard ZIP Codes
Chantilly, VA – Standard ZIP Codes
20151 20152

Mcclean, Va Zip codes: 220432204622066,221012210222207


Ketamine Infusions |Ketamine Depression | Ketamine doctors in Virginia | Fairfax Ketamine | 703-844-0184 | Ketamine and depression treatment 22303 22307 22306 22309 22308 22311 22310 22312 22315 22003 20120 22015 22027 20121 22031 20124 22030 22033 22032 22035 22039 22041 22043 22042 22046 22044 22060 22066 20151 22079 20153 22101 22102 20171 20170 22124 22151 22150 22153 22152 20191 20190 22181 20192 22180 20194 22182

NOVA Health Recovery  <<< Ketamine infusion center in Alexandria, Virginia 703-844-0184  – consider ketamine for addiction treatment

CAll 703-844-0184 for an immediate appointment!

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.


Ketamine center in Fairfax, Virginia    << Ketamine infusions

NOVA Health Recovery – KETAMINE SYSTEMS<< Link

Ketamine | Fairfax, Virginia | 703-844-0184 | Ketamine infusions for depression | Dr. Sendi | Ketamine for alcoholism and drug abuse Ketamine in Maryland |IV ketamine treatments| NOVA Health Recovery |




Ketamine for resistant depression: Outstanding promise, outstanding issues.

Outstanding Promise.

Ketamine has been around for many years, firstly as a dissociative anaesthetic and then as a psychedelic drug. But it might become best known for it’s powerful antidepressant properties (Berman et al 2000Zarate et al 2006). Compared to existing antidepressants, which take around 2 weeks to work, ketamine exerts a large antidepressant effect on the first day of treatment.

depression ketamine murrough

Figure 1: The antidepressant effect of ketamine over 6 treatment sessions. The improvement on day 1 (measured using the MADRAS scale) was predictive of the response achieved following the sixth treatment session.

The robust antidepressant effect of ketamine also occurs in patients who have not found relief with existing drugs or with ECT. In the latest study to be reported, 24 patients with treatment-resistant depression underwent up to 6 sessions of intravenous ketamine (0.5mg/Kg in 40 mins) over ~2 weeks. Over 70% of patients responded to ketamine, and the overall reduction in depression was large and rapid (Murrough et al 2013) (Figure 1).

Outstanding Issues.

To date a major issue has been the lack of persistence of the antidepressant effect. In previous studies, involving a single ketamine treatment, depression returned within one week of the session or less. In the study by Murrough et al, this was extended to an average of 18 days. This is an improvement, but further work will be needed to solve the problem of the relatively short-lived antidepressant effect of ketamine.

An understanding of the mechanism by which ketamine alleviates depression may be necessary if we are to extend the duration of it’s beneficial effects. Pre-clinical work suggests that ketamine boosts the health and integrity of synapses and neuronal networks. Much of the action is believed to take place within dendritic spines, and involves local protein synthesis (Duman et al 2012) (Figure2).

ketamine mechanism
Ketamine | Ketamine virginia | Fairfax Ketamine | Ketamine infusions | 703-844-0184

Figure 2: The antidepressant effects of ketamine may depend upon activation of mTOR and local protein synthesis in dendritic spines.

Two molecules of relevance are mTOR and GSK-3. Ketamine enhances local protein synthesis by activating mTOR and by inhibiting GSK-3. [GSK-3 inhibits mTOR]. A drug, such as lithium, which inhibits GSK-3 might enhance the antidepressant effect of ketamine. This has now been demonstrated in pre-clinical studies (Liu et al 2013). The clinical question, which will now be addressed in trials is whether lithium treatment extends and enhances the antidepressant effects of ketamine. Lithium has been used for treatment-resistant depression for many years, and has a good evidence base (Bauer et al 2010) so that the combination of ketamine and lithium presents as an interesting and relatively straightforward strategy for stubborn depression.

However it is somewhat odd that the proposed mechanism for ketamine involves new protein synthesis and synaptogenesis (which take time, and are sustained) whereas the clinical effects of ketamine are very rapid (and transient). Other mechanisms may have more explanatory power. For instance a recent fMRI study showed that ketamine decreased the connectivity of limbic and prefrontal regions which are known to be overactive in depression (Scheidegger et al 2012). More provocatively, it appears that the antidepressant effect of ketamine depends upon the extent of the acute psychological reaction produced by the drug. Although the dissociative/psychedelic properties of ketamine are sometimes regarded as unwanted “side-effects”, a recent paper showed that the acute psychedelic and subsequent antidepressant effects are related (Sos et al 2013).


Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression.



Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder.


In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients.


Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen´s d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point.


The substantial relationship between ketamine’s antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine’s action, trough NMDA receptors, shared by both ketamine’s clinical effects.

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

Lithium’s Emerging Role in the Treatment of refractory major depression episodes – augmentation of antidepressants

Subanesthetic ketamine decreases the incentive-motivational value of reward-related cues.

The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers.

Signaling Pathways Underlying the Rapid Antidepressant Actions of Ketamine


Cognitive disorders: the role of dendritic spines.

Cognitive disorders: the role of dendritic spines.


Neuronal plasticity:

A major contribution of neuroscience to the humanities is the knowledge that the structure of the brain is moulded by the experiences the mind goes through – the phenomenon known as plasticity. It means that the circuits of the brain are sculpted by habitat, schooling, language, relationships, and culture, as well as by the unfolding genetic programme. The action occurs below the micrometre scale – at synapses (the points of connection between neurons) – and involves the exquisite choreography of a number of molecular machines. These molecular processes are so fundamental for cognition that their failure (whether driven by gene mutation or by harsh environments) results in neuropsychological disability. A major locus of plasticity (and hence, cognitive disability) is the dendritic spine.

pyramidal neuron

The dendrites of pyramidal neurons express thousands of dendritic spines. P=pyramidal neuron.

Principal neurons in the brain, such as cortical pyramidal neurons, express tens of thousands of small protruberances on their dendritic trees. These structures (dendritic spines) receive excitatory information from other neurons, and are highly dynamic. They can adjust their responsiveness to glutamate (the major excitatory neurotransmitter), becoming stronger (potentiation) or weaker (depression), as local circumstances dictate. This strengthening (LTP) or weakening (LTD) can be transient, or persist over long periods and as such, serves as an ideal substrate for learning and memory at synapses and in circuits. Potentiated spines increase in size, and express more AMPA glutamate receptors, whilst the opposite pattern occurs in synaptic depression to the extent that spines can be ‘absorbed’ back into the dendritic tree.

Over the course of childhood, dendritic spines (excitatory synapses) increase in number, but their numbers are ‘pruned’ back during adolescence to reach a plateau. Enriched environments have been shown to increase spine density, impoverished environments the opposite. In common psychiatric disorders, spine density is altered. For example, the most robust histological finding in schizophrenia is a reduction of spine density in the frontal cortex, auditory cortex and the hippocampus. In major depression, spines (and dendrites) are lost in the hippocampus. In autism, spine density actually increases. Finally, in Alzheimer’s and other dementias there is a catastrophic, and progressive loss of cortical and sub-cortical spines.


The molecular biology of dendritic spines involves hundreds of proteins, but the outlines are now reasonably well understood. Scaffolding proteins [such as PSD95, shank(s), AKAP, stargazin and homer(s)] provide structural support and provide orientatation for membrane bound receptors, ion-channels and their downstream signalling pathways. The scaffold (post-synaptic density), facilitates effective signalling by ensuring that the correct protein partners are in close apposition. The scaffold is also tethered to proteins which bridge the synaptic cleft (cell adhesion molecules) and to bundles of actin filaments which provide the structure and force for spine enlargement (and retraction).

dendritic spine

Spine plasticity is fundamental for learning and memory. The shuttling of AMPA receptors underlies early phase plasticity. Modification of the actin cytoskeleton and local protein synthesis underlie long term plastic changes.

There is a constant remodelling of the actin cytoskeleton within the spine in response to synaptic and network signalling. Remodelling is via small, cytoplasmic G-proteins from the RHOfamily. Some family members promote the growth and stabilisation of actin filaments, whereas others promote actin disassembly. Mutations in the proteins which regulate actin dynamics are a cause of learning disability. Finally local protein synthesis (and degradation) occurs within dendritic spines, is tightly controlled and is essential for plasticity. Abnormalities in local protein synthesis within the spine underlie learning disability syndromes such as fragile X, neurofibromatosis and tuberous sclerosis.

Spine pathology:

Recent years have seen glutamate synapses move to centre stage in neuropsychiatry. This is not surprising given the role of pyramidal neurons (glutamate containing neurons) in information processing, and the role of glutamate transmission in learning and memory [see link]. But it is remarkable that so many psychological and cognitive disorders appear to ‘coalesce’ at dendritic spines.

The enclosed vector-graphic image [click here] highlights a selection of some of the proteins which are now known to be involved in autism, learning disability and schizoprenia.

Research will continue to decipher the complexity (and beauty) of the dendritic spine, but potential treatments are starting to emerge for disorders like fragile X, (which until recently were thought to be not amenable for drug treatment, as was the case for schizophrenia until the 1950s). Molecular neuroscientists will, almost certainly, continue to uncover more treatment targets. The task for psychiatry, as ever, is to keep abreast of neuroscience in all it’s complexity (and beauty).

Glutamate & GABA for psychiatrists

Rapid Dissemination of Information
Glutamate and GABA are the archetypal ‘fast’ transmitters. If a neuron in the brain ‘wishes’ to communicate rapidly with another cell, the chances are that it will utilise glutamate or GABA. Of course, glutamate neurons exert an excitatory influence on the cells they contact, whereas GABA, at least on first glance, is inhibitory.

Fast transmitters bind to receptors on membrane-spanning ion channels. An ion-channel is in constant flux between various conformations: e.g. open, closed, desensitised. Binding of fast transmitter ‘causes’ the ion channel to snap open for brief periods, and ions rush down their concentration gradients causing an abrupt, short-lived, change in the local membrane potential of the post-synaptic cell (Figure 1). From start to finish the whole process is over within tens of milliseconds, and constitutes a discrete electrical signal (termed an excitatory or inhibitory post-synaptic potential; EPSP, IPSP).

nmda receptor

Figure 1. The NMDA Receptor mediates an EPSP.

Neurotransmission v neuromodulation
Fast transmission, as a concept, pre-supposes slow transmission. The classical slow transmitters are the monoamines, e.g. noradrenaline and dopamine. These substances are used as transmitters by neurons within specific brainstem nuclei, whose axons project to numerous subcortical structures and large areas of cortex. There are relatively few monoamine neurons (tens of thousands), but their projections show massive arborisation within the ‘higher centres’ and the limbic system. Anatomically, glutamate and GABA signalling is characterised by point-to-point communication between narrowly separated (and tethered) pre-synaptic and post-synaptic elements, whereas for monoamine systems, the release sites (boutons) and post-synaptic receptors are not necessarily in close proximity. In contrast to glutamate and GABA, which convey a fast, discrete, short-lived electrical signal, monoamines evoke slower-onset, diffuse, longer-duration biochemical changes in their target neurons. Monoamine systems are not optimised for the rapid dissemination of specific information, but instead for modulating those neurons that are.

Ensemble formation and Gestalts
Pyramidal neurons (the principal output neuron of the hippocampus and cortex) use glutamate as a transmitter to communicate rapidly with neurons in ‘lower centres’ such as the striatum, thalamus, pontine nuclei and the cord although most communication is with other pyramidal neurons. Pyramidal neurons organise themselves into ensembles. This process, in which pyramidal neurons fire in synchrony for brief periods of time is thought to be essential for object perception and for movement, speech and thinking.

Consider a pyramidal neuron ‘sitting’ at resting-membrane-potential (-70mV). It receives tens of thousands of excitatory (glutamate) inputs on its dendritic spines, (dynamic structures that are moulded by experience over a lifetime). A single excitatory input (by itself) has little overall impact on the pyramidal neuron. But when numerous EPSP’s from a multitude of inputs arrive ‘synchronously’, the depolarisation may be sufficient for the pyramidal neuron to fire an action potential (AP). In short, the pyramidal neuron is recruited (by the ensemble) into joining the ensemble.

It can be grasped that for AP firing to occur in a pyramidal neuron, there has to be a convergence of excitatory information from numerous sources. Excitatory inputs come from various thalamic nuclei and from stellate cells (in primary sensory cortices), although the overwhelming majority come from other pyramidal neurons. Regardless of the source, timing is key. In order to generate enough depolarisation to trigger an AP, inputs must arrive (and summate) within the same narrow time window (of the order of milliseconds).

Precise Timing and cortical dynamics
The output of a pyramidal neuron (AP spiking) is finely controlled. Precise timing is so fundamental for cortical processing that various auxiliary neurons appear to be tasked with a pacemaker role. These neurons utilise GABA as a transmitter. Classical neuroscience conceptualised GABA containing neurons as nothing more than inhibitory interneurons – this is no longer tenable. There are various populations of GABA containing neuron, which have been classified according to their morphology, their location in the cortex, which proteins they use to sequester calcium, and their electrophysiological properties. Some are even excitatory. For simplicity, we shall restrict ourselves to a simple classification based upon where the GABA neuron contacts the pyramidal neuron (Figure 2).

glutamate and gaba neurons

Figure 2. A pyramidal neuron receives inhibitory GABA-ergic input to its dendrites. GABA pacemakers synapse on the soma and axon initial segment.


Contacts formed with the dendrites of pyramidal neurons function as inhibitory interneurons in the classical sense (i.e. they oppose excitatory drive), whereas GABA neurons targeting the soma or the proximal axon (of the pyramidal neuron) function as pacemakers. We can consider how these GABA pacemaker neurons are optimised for their task. Firstly they have very fast dynamics, swifter for example than the pyramidal neurons that they make contact with. Secondly, they provide a very strong and reliable signal to the pyramidal neuron by engulfing the soma or the proximal axon with numerous terminals. A strong, brief, recurrent signal to the soma and proximal axon creates a series of time windows, which determine precisely when the pyramidal neuron fires. Thirdly, individual pacemaker neurons make contact with numerous local pyramidal neurons. And finally, groups of pacemaker neurons are connected by electrical synapses (gap junctions) so that they can function as an interconnected single entity, a syncytium. For completion, pyramidal neurons make strong, reliable synapses (excitatory) with pacemaker neurons.

It is readily apparent that the interconnectivity of pyramidal neurons and GABA interneurons favours the emergence of oscillations, with successive, precisely timed periods of integration followed by periods of AP discharge. Experiments have shown that the population of neurons in an active ensemble generate the rhythm, whilst the rhythm puts precise constraints upon when an individual neuron can fire.

Systems and levels
For slow, diffuse modulators such as noradrenaline, it makes sense to talk of a system. To recap, noradrenaline [NA] is synthesized by no more than tens of thousands of neurons, confined to discrete nuclei within the brainstem, and is ‘sprayed’ from en-passant boutons over large territories of CNS tissue, in a hormone-like manner. Crucially, the release patterns of noradrenaline [and other neuromodulators] can be clearly mapped onto distinct behavioural states, the most marked differences arising in the sleep-state [noradrenaline – ‘off’] versus the waking-state [noradrenaline – ‘on’]. Since the extracellular concentrations of noradrenaline [and other neuromodulators] can inform directly about higher brain/mind levels, the idea of a noradrenergic system has utility.

Glutamate and GABA are too ubiquitous as fast point-to-point transmitters for the term ‘system’ to be applicable in the same way. Particular patterns of behaviour cannot be mapped onto the release of GABA or glutamate at a specific locus. All we can say is that neurons in an ensemble use glutamate and GABA to communicate with each other. Whereas transient fluctuations in the extracellular concentrations of GABA/glutamate do not reveal anything about behaviour, the dynamics of neuronal ensembles correspond with distinct behavioural states. Again the sleep wake-cycle is illustrative. Oscillatory activity generated by the ensemble can be mapped unambiguously onto the sleep-state and the waking-state.

Learning & Memory
In the 1970s it became clear that excitatory connections onto pyramidal neurons could be made stronger, if they were subjected to particular patterns of input. This was the first experimental support for an idea that can be traced back to Ramon y Cajal – the idea that synapses are modifiable (plastic) and that such plasticity might serve as the physical basis of memory.

There are various forms of plasticity, but the most widely studied is NMDA-dependent long-term potentiation (LTP). In the early 1980’s, researchers based in Bristol showed that NMDA receptor antagonists could block the initiation of LTP [and subsequent behavioural experiments, (most famously, by Richard Morris in Edinburgh) showed that such drugs could inhibit new learning].

NMDA receptor channels are found at the heads of dendritic spines, adjacent to the glutamate terminal. AMPA receptor channels are found in the same locale. When activated, both receptor channels produce an excitatory-post-synaptic-potential (EPSP). In the case of the AMPA receptor, the EPSP is mediated by sodium ions flowing into the spine. For NMDA receptors, the EPSP is mediated by a combination of sodium and calcium ions. [It is the calcium signal that initiates LTP (Figure 3). Early-phase LTP is mediated by phosphorylation of AMPA receptors (increasing their conductance) and by insertion of new AMPA receptors into the post-synaptic membrane].

long term potentiation

Long Term Potentiation (LTP) is induced by NMDA receptor activation. The mechanism of early-phase LTP involves the enhancement of AMPA receptor conductances and insertion of new AMPA receptors into the post-synaptic membrane.

AMPA and NMDA receptor channels differ in one other key property. The NMDA channel is voltage-dependent. At membrane potentials less than -50mV, the NMDA channel remains closed, even if glutamate is bound to the receptor. For the NMDA channel to snap open, the membrane potential must be already depolarised to at least -30mV. So two conditions are necessary for NMDA conductance; binding of glutamate and membrane depolarisation. For this reason, the NMDA receptor is said to be a coincidence detector (or in engineering terms, an AND gate).

Sufficient post-synaptic depolarisation can occur from backward-propagating action potentials (APs) or from temporally or spatially summated excitatory input to a dendritic branch. Research in the last decade has revealed that the timing of pre-synaptic activity (glutamate release) and of post-synaptic activity (post-synaptic-depolarisation) is critical in determining whether synaptic strength will be altered. Pre and post synaptic ‘events’ must occur within approximately 20 milliseconds, otherwise synaptic strength remains unchanged. This form of plasticity, known as Spike-Timing-Dependent-Plasticity (SDTP), is likely to become increasingly relevant as we begin to conceptualise ‘micro-circuit’ abnormalities in major neurodevelopmental disorders. Two final points about SDTP will be made here. Plasticity is bidirectional (potentiation or depression) depending on the order of pre and post-synaptic events. And conventional modulators such as dopamine can impact upon the timing rules and alter the direction of the plasticity, (LTP or LTD).

Some Psychiatry: The K-Hole and beyond
Ketamine, a drug that has attracted the attention of psychiatrists in the past few decades, ‘blocks’ the NMDA channel. It has been used as a model psychosis, and latterly has been demonstrated to have acute anti-depressant properties. (It certainly impairs new learning, as would be expected).

Downstream of NMDA blockade, there is no clear consensus as to how ketamine produces a psychosis. Counter-intuitively (for a glutamate antagonist), ketamine increases the excitability (spiking) of pyramidal neurons. Ketamine also increases the power of gamma band (~40 Hz oscillations) and some have proposed that ‘kernels’ of ‘abnormal’ gamma underlie the psychotic-like effect.

But the behavioural pharmacology of ketamine is far from straightforward. Rating-scales used in schizophrenia research, are probably not ideal for capturing the nuances of the drug. Those who have taken a more phenomenological approach [in the sense of ‘bracketing-out’ existing assumptions, whilst focussing on clear descriptions] have identified a much richer and more complex behavioural psychopharmacology, which includes euphoria, near-death experiences, the cessation of time, the dissolution of the ego, and the experience of being immersed in fractal geometries or boundless oneness (Jansen K, Ketamine: Dreams & Realities 2000).

Close observation reveals the dose-dependent emergence of an oneroid (dream-like) state, and other catatonic features (ambitendency, posturing) but not a classic paranoid psychosis. Researchers have also tended to assume that ketamine can ‘cause’ negative symptoms, but reports of euphoria, terror and awe are inconsistent with this categorisation. Motor output (which includes speech of course) is certainly restricted following ketamine, but because the concurrent inner world is a kaleidoscope of strange, mystical and fantastic experiences with extremes of emotion, the overall picture is far removed from the negative syndrome.

Nevertheless, ketamine is frequently championed as the most convincing drug-model of schizophrenia because it can induce negative symptoms, on a rating scale. The irony perhaps is that the ketamine experience might actually be more schizophrenia-like than many of its proponents have suggested. Ketamine elicits phenomena, which are now very rarely encountered in psychiatric clinics, given the modern-day domination of the softer, paranoid form of the illness.


Paul Janssen’s genius was in predicting that a drug which blocked the effects of amphetamine in animals, would be an effective treatment for those cases of schizophrenia that resembled an amphetamine psychosis (characterised by agitation, hallucinations and delusions)[link]. That drug was haloperidol, and that class of drug (D2 dopamine receptor antagonists) changed the landscape of psychiatry.

Janssen’s logic would also suggest that a drug which inhibited the effects of ketamine in animals, would be an effective treatment for those cases of schizophrenia which resemble ketamine-elicited psychopathology (characterised by bizarre, inaccessible dream-like states, and psychotic motor phenomena. i.e. cases where ECT becomes a sensible option). A pharmacological antagonist of ketamine (in animals) proved to be ineffective against human paranoid schizophrenia. Perhaps this could have been predicted, by closer attention to the phenomenology of ketamine. The question now is whether ‘The Lilly compound‘ has efficacy against non-paranoid schizophrenia?

Natural antidepressants & new brain cells

New Brain Cells

In the last decade it has become clear that new cells can form in the adult brain. This happens in a region known as the hippocampal complex. The hippocampal complex is found deep inside either temple and is crucial for memory and emotion. The hippocampal complex inhibits the human stress response, but can itself be damaged by persistent stress, leading to a vicious cycle in which the stress response is amplified further and depression ensues.

hippocampus from nieuwenhuys et al

The hippocampal complex is found in the temporal lobe, and has a crucial role in regulating the stress response.

Experimental work suggests that neurogenesis (the birth of new neurons) in the hippocampal complex is vital for the action of conventional antidepressant drugs. Exercise and enriched environments also promote neurogenesis, whilst stress has the opposite effect.The current picture is that hippocampal health (including the birth of new neurons) is essential for protecting the organism against the effects of stress, so that if hippocampal functioning is compromised, anxiety and depression can emerge.


Natural Antidepressants

There has been recent interest in the antidepressant properties of a natural molecule called curcumin. This substance is found in the herb turmeric. As well as a foodstuff, turmeric has been used for centuries in traditional Indian medicine (Ayurveda). In pre-clinical studies, curcumin exhibited clear antidepressant effects.


Research has focused on the mechanism of action of curcumin. Remarkably it appears that curcumin can also increase the birth of new neurons in the hippocampal complex. This is an intriguing finding which hints at the possibility of a new class of antidepressant drug.

A new paper from researchers at King’s College London provides an excellent summary of work in this area. The full paper can be read here.


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Here is an interesting piece regarding the rapid effects of Ketamine on reversing depression, in specific, making events more pleasurable through modulating the action of Glutamate in the brain.

This article was written by Dr. Zarate:

Ketamine and depression – NIH

Highlight: Ketamine: A New (and Faster) Path to Treating Depression

Two charts show the effect of ketamine or placebo on the Hamilton Depression Rating Scale.

Left: Change in the 21-item Hamilton Depression Rating Scale (HDRS) following ketamine or placebo treatment.
Right: Proportion of responders showing a 50 percent improvement on the HDRS following ketamine or placebo treatment.34

Source: Carlos Zarate, M.D., Experimental Therapeutics and Pathophysiology Branch, NIMH

The most commonly used antidepressants are largely variations on a theme; they increase the supply within synapses of a class of neurotransmitters believed to play a role in depression. While these drugs relieve depression for some, there is a weeks-long delay before they take effect, and some people with “treatment-resistant” depression do not respond at all.

The delay in effectiveness has suggested to scientists that the medication-induced changes in neurotransmitters are several steps away from processes more central to the root cause of depression. One possibility for a more proximal mechanism is glutamate, the primary excitatory, or activating, neurotransmitter in the brain. Preliminary studies suggested that inhibitors of glutamate could have antidepressant-like effects, and in a seminal clinical trial, the drug ketamine—which dampens glutamate signaling—lifted depression in as little as 2 hours in people with treatment-resistant depression.34

The discovery of rapidly acting antidepressants has transformed our expectations—we now look for treatments that will work in 6 hours rather than 6 weeks. But ketamine has some disadvantages; it has to be administered intravenously, the effects are transient, and it has side effects that require careful monitoring. However, results from clinical studies have confirmed the potential of the glutamate pathway as a target for the development of new antidepressants. Continuing research with ketamine has provided information on biomarkers that could be used to predict who will respond to treatment.35Clinical studies are also testing analogs of ketamine in an effort to develop glutamate inhibitors without ketamine’s side effects that can then be used in the clinic.36 Ketamine may also have potential for treating other mental illnesses; for example, a preliminary clinical trial reported that ketamine reduced the severity of symptoms in patients with PTSD. 37 Investigation of the role of glutamate signaling in other illnesses may provide the impetus to develop novel therapies based on this pathway.

One of the imperatives of clinical research going forward will be to demonstrate whether the ability of a compound to interact with a specific brain target is related to some measurable change in brain or behavioral activity that, in turn, can be associated with relief of symptoms. In a study of ketamine’s effects in patients in the depressive phase of bipolar disorder, ketamine restored pleasure-seeking behavior independent from and ahead of its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom—loss of interest in pleasurable activities—which lasted up to 14 days.38 Brain scans traced the agent’s action to boosted activity in areas at the front and deep in the right hemisphere of the brain. This approach is consistent with the NIMH’s RDoC project, which calls for the study of functions—such as the ability to seek out and experience rewards—and their related brain systems that may identify subgroups of patients with common underlying dysfunctions that cut across traditional diagnostic categories.

The ketamine story shows that in some instances, a strong and repeatable clinical outcome stemming from a hypothesis about a specific molecular target (e.g., a glutamate receptor) can open up new arenas for basic research to explain the mechanisms of treatment response; basic studies can, in turn, provide data leading to improved treatments directed at that mechanism. A continuing focus on specific mechanisms will not only provide information on the potential of test compounds as depression medications, but will also help us understand which targets in the brain are worth aiming at in the quest for new therapies.

PET scan data superimposed on anatomical MRI

PET scans revealed that ketamine rapidly restored bipolar depressed patients’ ability to anticipate pleasurable experiences by boosting activity in the dorsal anterior cingulate cortex (yellow) and related circuitry. Picture shows PET scan data superimposed on anatomical MRI.38


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I also threw in a reprint of the article from NIH regarding strategic principle #2 to find biomarkers of mental health disorders:

Highlight: GPS for the Brain? BrainSpan Atlas Offers Clues to Mental Illnesses

Image from BrainSpan Atlas shows the location and expression level of the gene TGIF1 in a brain from 21 weeks postconception.

The recently created BrainSpan Atlas of the Developing Human Brain incorporates gene activity or expression (left) along with anatomical reference atlases (right) and neuroimaging data (not shown) of the mid-gestational human brain. In this figure, the location and expression level of the gene TGIF1 is shown in a brain from 21 weeks postconception.

Source: Allen Institute for Brain Science

Technologies have come a long way in mapping the trajectory of mental illnesses. Early efforts provided information on anatomical changes that occur over the course of development. In a step that has been hailed as providing a “GPS for the brain,” the BrainSpan Atlas of the Developing Brain, a partnership among the Allen Institute for Brain Science, Yale University, the University of Southern California, and NIMH—has created a comprehensive 3-D brain blueprint.25 The Atlas details not only the anatomy of the brain’s underlying structures, but also exactly where and when particular genes are turned on and off during mid-pregnancy—a time during fetal brain development when slight variations can have significant long-term consequences, including heightened risk for autism or schizophrenia.26 Knowledge of the location and time when a particular gene is turned on can help us understand how genes are disrupted in mental illnesses, providing important clues to future treatment targets and early interventions. The Atlas resources are freely available to the public on the Allen Brain Atlas data portal. Already, the BrainSpan Atlas has been used to identify genetic networks relevant to autism and schizophrenia.27,28 In both of these studies, the fetal pattern of gene expression revealed relationships that could not be detected by studying gene expression in the adult brain. As most mental illnesses are neurodevelopmental, mapping where and when genes are expressed in the brain provides a fundamental atlas for charting risk.

Brain Atlas NIH