Antipsychotics Might Cause Cognitive Impairment

Epistemic Statuspretty rough, a first pass

A friend of mine recounted a pretty terrifying description of his experience being on antipsychotics for years as a child:

Antipsychotics can make you dumber.  So can a lot of other medications.  But with antipsychotics it isn’t the normal sort of drug-induced dumbness – feeling tired, or distracted, or mentally sluggish, say.  It’s more qualitative than that.  It’s like your capacity for abstract thought is reduced.

And one of the consequences of this is that you may lose the ability to notice that you have lost anything.  You agree to give the new med a try, and you start taking it, and then when you see your prescriber again you don’t report any problems because you’ve lost the ability to form thoughtslike “my cognition has changed a lot recently, and the change coincided with the introduction of this new med.”

This can go on for years.  It did for me and for several people I know.

When I finally went off Risperdal – encouraged by my parents, I don’t remember really caring – it suddenly seemed obvious that I’d been cognitively altered for the past five years.  I didn’t remember the time before that very well (I had started Risperdal when I was about 10 years old), but there were objective indicators – for instance, I loved reading before Risperdal, and while on Risperdal I don’t think I read a single book cover-to-cover.

You’d think I would have noticed that I couldn’t read anymore.  Somehow I didn’t, for five years.  What did it feel like?  It’s hard to remember and also hard to describe.  Sort of a passivity.  The world acted upon me for mysterious reasons.  I did not draw correlations between present and past events, didn’t formulate ideas about the workings of things.  The present was simply given; I wasn’t frustrated when it refused to honor my theories.  “Reading is hard” was a datum, and was unpleasant, but I was not really surprised by it, or frustrated in the “this wasn’t supposed to happen!” way of abstract-reasoning-creatures.  It was a given datum and all I did was hope that given data would be pleasant and not unpleasant.

I think people should know that antipsychotics can do this.  They still may be worth trying, in certain situations.  But taking an antipsychotic is a special sort of decision, one that interferes with decision-making itself, like choosing to listen to the Sirens.

There are also cases of antipsychotics causing autistic catatonia, in which an autistic person, upon treatment with antipsychotics, suddenly loses speech and motor skills.  See examples: personal narrative,  case study, case study.

So, a natural question is: does this happen often? Do antipsychotics actually cause cognitive problems?

And here I’m referring to long-term cognitive problems. Many medications, including most atypical antipsychotics, are sedating; nobody thinks as clearly when they’re sleepy.  But when you stop taking a sedative, you generally become alert again. Do antipsychotics have any permanent effects?

Now, a major confounder is that schizophrenia causes cognitive impairment in itself, and antipsychotics seem to slightly relieve those problems.

Overall, atypical antipsychotics seem to help cognition in schizophrenia

One study of 533 patients having their first psychotic episode and randomized to either risperidone or haloperidol found that, on both drugs, there were slight but significant improvements in most cognitive tests after 3 months of treatment and patients did not significantly worsen on any tests.[1]

The CATIE trial, a randomized trial of 1460 schizophrenics given various antipsychotics, found significant (p < 0.001) improvement in a composite score consisting of speed, reasoning, working memory, verbal memory, and vigilance on all antipsychotic meds.[2]

There are dozens of studies like this. A meta-study found that various atypical antipsychotics were found to improve cognitive functioning in roughly half of studies, most of which were short-term (6 weeks).[3]

Typical Vs. Atypical Side Effects

“Typical” antipsychotics are older drugs, like haloperidol, whose primary effect is dopamine antagonism, while “atypical” antipsychotics are newer drugs, like risperidone, olanzapine, clozapine, and quetiapine, with a wider variety of targets including serotonin agonist, anticholinergic, and antihistamine effects.  The atypical drugs are often believed to be safer because they aren’t as likely to cause the motor disorders (extrapyramidal effects and tardive dyskinesia — that is, Parkinson’s-like stiffness and involuntary twitching movements) that the older drugs did, but the newer drugs often have other side effects (like sedation and large amounts of weight gain).

Clozapine is associated with an average of 14-25 pounds of weight gain over a period of several months of treatment; over 50% of patients become overweight when treated with clozapine.  A year of high-dose olanzapine causes an average of 26 pounds of weight gain.  Risperidone and quetiapine are associated with a weight gain of 4-5 pounds over the course of 5-6 weeks, and remaining stable over long-term use.[4] At the higher end of weight gain, this is no longer a cosmetic issue, but a serious diabetes risk.

Recently, it’s been observed that “atypical” antipsychotics can cause motor problems too, and their safety advantages have been overstated.

The CATIE study found that 8% of patients on olanzapine or risperidone had extrapyramidal symptoms. All agents, typical and atypical, had rates of tardive dyskinesias of 13-17% after a year of follow-up. Akasthisia rates for atypical antipsychotics are in the 10-20% range, compared to 20-52% with typical neuroleptics.[5]

While older studies found that atypical antipsychotics had lower rates of extrapyramidal effects than typical antipsychotics, these studies were comparing the new drugs to high-dose haloperidol, and the difference disappears when you compare to low-dose haloperidol or other typical antipsychotics (such as perphenazine, whose side effects are milder.)  The CATIE trial, which randomized schizophrenics to olanzapine, quetiapine, risperidone, perphenazine, or ziprasidone, found no differences in the incidence of extrapyramidal side effects. 12-month Parkinsonism rates were 37-44% for the four atypical antipsychotics and 37% for perphenazine. Akasthisia rates were 26-35% for the atypical antipsychotics and 35% for perphenazine.  Tardive dyskinesia was rarer, but also not different — 1.1%-4.5% for the atypical antipsychotics and 3.3% for perphenazine.[6]

In a meta-study, second-generation antipsychotics had significantly less use of antiparkinson medication than haloperidol (RR’s 0.17 for clozapine to 0.7 for risperidone), but not significantly less compared to low-potency typical antipsychotics (like perphenazine). Atypical antipsychotics caused significantly more weight gain than haloperidol, but not compared to low-potency typical antipsychotics.  Atypical antipsychotics caused the same amount of sedation as haloperidol and low-potency typical antipsychotics — except that clozapine causes more sedation than everything else.[7]

In other words, it’s definitely not true that the new drugs are safer than the old drugs across the board. Lower doses or better choices in the old drugs would have a comparable or strictly better side effect profile.

As a rough rule of thumb, the stronger the antihistamine effects, the more sedation and weight gain (that’s clozapine and olanzapine), and the stronger the dopamine-antagonist effects, the more movement disorders there are (that’s haloperidol and risperidone).

Evidence that Antipsychotics Impair Cognitive Abilities

While the majority of studies of antipsychotics find improvements or no change on cognitive tests, there are some exceptions, particularly on tests that have to do with spatial or procedural learning.

A study of 25 patients, after being on risperidone for 6 weeks, and throughout a 1-year follow-up period, found that risperidone worsened spatial working memory in first-episode schizophrenia. [8]

Procedural learning is impaired after months of treatment with haloperidol and risperidone — schizophrenic patients are slower to learn the Tower of Toronto task (though no difference is apparent after 6 weeks of treatment).  Olanzapine caused much less cognitive impairment (p < 0.001).[9]

A comparison of treatment-naive first-episode schizophrenics vs. schizophrenics treated with risperidone for six weeks found that the untreated patients were no worse at a procedural learning task than controls, while the treated patients were significantly worse.  This indicates that the medication, and not the schizophrenia, is responsible for the impairment.[10]

In a study of 35 schizophrenic and 45 control patients given a procedural learning task, the patients randomized to haloperidol performed worse than controls, while those randomized to risperidone or clozapine did not.[12]

In a study of 20 patients on haloperidol, 20 on risperidone, and 19 healthy controls tested on psychomotor tests related to driving ability, the medicated patients were significantly worse than controls on all tests, and haloperidol was worse than risperidone.[11]

Note that procedural learning — remembering how to complete a task, usually physical/motor, by practice — is associated with activity in the striatum and basal ganglia, the part of the brain that produces dopamine. This seems to fit with the fact that antipsychotics, in particular the most dopamine-inhibiting ones, particularly impair procedural learning.

Evidence that Tardive Dyskinesia Comes With Cognitive Impairment

Out of 28 studies identified in a meta-study, 22  reported patients with tardive dyskinesia to be more impaired along at least one cognitive measure.  The most common findings were an association with decreased orientation and memory (13 studies).  The finding persists even in studies that controlled for anticholinergic side effects.  Orofacial tardive dyskinesia seems to be especially associated with cognitive impairment (beta=0.23 of association with performance on the Trail Making Test, a measure of executive function and task switching).[13]

If cognitive dysfunction is a symptom of tardive dyskinesia, that supports the hypothesis that antipsychotic drugs cause cognitive dysfunction.

Animal Evidence that Antipsychotics Cause Cognitive Impairment

Animal studies give a usefully different perspective than human studies because you can ethically give antipsychotics to healthy animals. It may be that antipsychotics both remediate the cognitive problems caused by schizophrenia and cause additional cognitive problems of their own; with animals, you can see the latter in isolation.

Monkeys develop working memory deficits after 1-4 months of haloperidol administration (P = 0.0000004) and recover when given a D1 agonist.[15]

If you give a rhesus monkey haloperidol, it performs worse on a working-memory task (in which, if you can remember which window had a flashing light earlier, you get a treat when you stick your face in), and the higher the dose, the worse the accuracy.[16]

Haloperidol, olanzapine, risperidol, quetiapine, and clozapine all worsened marmosets’ performance at an object-retrieval task relative to baseline. Lurasidone, on the other hand, improved performance.[17]

Evidence that Antipsychotics Shrink Brains

A meta-study of longitudinal MRI effects of antipsychotics on brain volumes found that ventricular volumes increased 7.7-10.9% in treated patients, compared to 1.4% in controls; and that gray-matter or whole-brain volume decreased 1.2-2.9% per year in patients compared to 0.4 to 1% in controls.  [Note that ventricles are fluid-filled spaces in the skull cavity: growing ventricles means a shrinking brain.]

But is this just the result of schizophrenia itself causing brain damage? The evidence suggests not. Two studies of drug-naive patients showed a decrease in brain volume after onset of antipsychotics; two showed no effect.  Studies of chronically ill, untreated patients in India show no difference in brain volume vs. controls.  There’s no difference in volume in the brains of “high-risk” (pre-psychosis) patients compared to controls, including in the subgroup that went on to develop psychosis.  It may be that the reduction in brain volume that has usually been associated with schizophrenia is instead caused by antipsychotic use.[14]

Longer-term and higher-dose use of antipsychotics is associated with more gray matter and white-matter shrinkage, even after adjusting for illness severity, substance abuse, and follow-up duration.[18]

Long-term (17-27 month) exposure to antipsychotics (olanzapine and haloperidol) in macaque monkeys resulted in an 8-11% reduction in brain weight.[19]

The fact that antipsychotic-naive schizophrenics do not show a progressive decline in brain volume, and the fact that treating macaques with antipsychotics does cause a decline in brain volume, has led psychiatrist Joanna Moncrieff to argue that antipsychotics do not exert a “neuroprotective” effect on schizophrenia, and that schizophrenia is not a degenerative brain disease — instead, she believes that antipsychotics treat symptoms and also cause much of the brain damage we observe in schizophrenics.[20]

Personal Views

Before I went to the literature on this, I had a pretty negative view on antipsychotics, heavily colored by the personal stories I’ve heard of them working out very badly, and the rare cases of severe side effects like neuroleptic malignant syndrome.  My view was also colored by the fact that they’re often used on children and psychiatric inpatients as a coercive mechanism, against the will of the patients, and whether or not they have any medically beneficial effect. My sympathies are always going to be with the victims of coercion who have, in many cases, pleaded eloquently to just be let alone.

On the other hand, schizophrenia is really bad. And, from what I can tell, we can be quite confident that antipsychotics reduce the positive symptoms (delusions and hallucinations).  I can believe there are situations where the benefits outweigh the costs.

I think the evidence that antipsychotics, including atypical antipsychotics, can cause cognitive impairment is pretty compelling.

Do they cause net cognitive impairment in schizophrenics? I don’t know.  Maybe they reduce negative symptoms enough to balance out the cognitive impairment.

Do they cause irreversible cognitive impairment? I don’t know.  I don’t think we have human evidence of what happens to brains when people go off antipsychotics, or take a dopamine agonist.

Is taking antipsychotics worse, or better, than leaving psychosis untreated? Can you split the difference by taking lower dosages or getting off meds sooner? I have no idea how I would even begin to answer this question, and the answer probably depends a lot on individual values.

Here’s stuff that I do think is sensible to do (keep in mind, I am not a doctor or any kind of psych professional):

  • Think about the tradeoffs of antipsychotics before you have a psychotic break. 
    • In some states, including California, you can write up a psychiatric advance directive in which you can specify what to do in the event you lose your mind, including medications you are not to be given.
  • Look up psychiatric meds that you’re prescribed and see what they do.
    • Sometimes antipsychotics will be prescribed for things besides psychosis, like depression or Tourette’s. Sometimes they work for those things! But they have the same kinds of side effect risks that they always do, and doctors don’t always tell you that.  Abilify? Is an antipsychotic! It can cause extrapyramidal side effects! It’s surprisingly common for people not to get told things like this.
  • Don’t take a judgmental, one-size-fits-all attitude unless you have correspondingly incredible data.
    • “Always meds!” and “Never meds!” are terrible oversimplifications. We don’t know what’s going on yet, so in the meantime, all anyone can do is to try to make the best judgments they can under conditions of colossal uncertainty (and often great stress).


[1]Harvey, Philip D., et al. “Treatment of cognitive impairment in early psychosis: a comparison of risperidone and haloperidol in a large long-term trial.” American Journal of Psychiatry 162.10 (2005): 1888-1895.

[2]Keefe, Richard SE, et al. “Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial.” Archives of general psychiatry 64.6 (2007): 633-647.

[3]Meltzer, Herbert Y., and Susan R. McGurk. “The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.” Schizophrenia bulletin 25.2 (1999): 233-256.

[4]Nasrallah, H. “A review of the effect of atypical antipsychotics on weight.” Psychoneuroendocrinology 28 (2003): 83-96.

[5]Shirzadi, Arshia A., and S. Nassir Ghaemi. “Side effects of atypical antipsychotics: extrapyramidal symptoms and the metabolic syndrome.” Harvard Review of Psychiatry 14.3 (2006): 152-164.

[6]Miller, Del D., et al. “Extrapyramidal side-effects of antipsychotics in a randomised trial.” The British Journal of Psychiatry 193.4 (2008): 279-288

[7]Leucht, Stefan, et al. “Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.” The Lancet 373.9657 (2009): 31-41.

[8]Reilly, James L., et al. “Adverse effects of risperidone on spatial working memory in first-episode schizophrenia.” Archives of General Psychiatry 63.11 (2006): 1189-1197.

[9]Purdon, Scot E., et al. “Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine, risperidone, and haloperidol.” Psychopharmacology 169.3-4 (2003): 390-397.

[10]Harris, Margret SH, et al. “Effects of risperidone on procedural learning in antipsychotic-naive first-episode schizophrenia.” Neuropsychopharmacology 34.2 (2009): 468-476.

[11]Soyka, Michael, et al. “Effects of haloperidol and risperidone on psychomotor performance relevant to driving ability in schizophrenic patients compared to healthy controls.” Journal of psychiatric research 39.1 (2005): 101-108.

[12]Scherer, Hélene, et al. “Procedural learning in schizophrenia can reflect the pharmacologic properties of the antipsychotic treatments.” Cognitive and behavioral neurology 17.1 (2004): 32-40.

[13]Waddington, J. L., et al. “Cognitive dysfunction in schizophrenia: organic vulnerability factor or state marker for tardive dyskinesia?.” Brain and cognition 23.1 (1993): 56-70.

[14]Moncrieff, J., and J. Leo. “A systematic review of the effects of antipsychotic drugs on brain volume.” Psychological medicine 40.09 (2010): 1409-1422

[15]Castner, Stacy A., Graham V. Williams, and Patricia S. Goldman-Rakic. “Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation.” Science 287.5460 (2000): 2020-2022.

[16]Bartus, Raymond T. “Short-term memory in the rhesus monkey: Effects of dopamine blockade via acute haloperidol administration.” Pharmacology Biochemistry and Behavior 9.3 (1978): 353-357.

[17]Murai, Takeshi, et al. “Effects of lurasidone on executive function in common marmosets.” Behavioural brain research 246 (2013): 125-131.

[18]Ho, Beng-Choon, et al. “Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia.” Archives of general psychiatry 68.2 (2011): 128-137.

[19]Dorph-Petersen, Karl-Anton, et al. “The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.” Neuropsychopharmacology 30.9 (2005): 1649-1661.

[20]Moncrieff, Joanna. “Questioning the ‘neuroprotective’hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia?.” (2011): 85-87.

Chronic Fatigue Syndrome

Epistemic Status: moderately confident. Spent several weeks on this in an effort to be more complete and careful than most of my lit reviews.

Chronic fatigue syndrome is something of a medical mystery. Some doctors question whether it’s a real disease at all. There are no well established treatments. We don’t know what causes it.

There’s a lot of evidence that CFS has something to do with immune and hormonal dysfunction, and is frequently associated with infectious diseases, particularly the Epstein-Barr virus and other herpes viruses (not all of which are sexually transmitted.)  There are also some immunotherapy options that seem to be effective in a subset of CFS patients, in particular corticosteroids.

Bottom Lines

Corticosteroids seem to help for a sub-population of CFS patients.  Rituximab, bacterial therapy, and intravenous immunoglobulin may also help for some CFS patients, but the evidence base is smaller or less consistent for those.

Chronic Fatigue and the HPA Axis

The hypothalamus/pituitary/adrenal (HPA) axis is a system of interconnected hormone signaling processes involved in the body’s response to stress. Cortisol, the “stress hormone”, is produced by the adrenal glands in response to signals from the pituitary gland and hypothalamus.

Cortisol suppresses inflammation, which is why it’s often used as a treatment in autoimmune diseases. It also promotes alertness and increases blood sugar, to ready the body for action.

There’s evidence that patients with chronic fatigue syndrome have lower cortisol levels, or are less able to produce cortisol in response to the appropriate stimuli.

There are a number of small studies showing that CFS patients have lower cortisol than healthy people.  14 CFS patients had significantly lower salivary cortisol levels compared to 26 cases of depression and 131 controls.[2]  In 15 CFS patients and 20 controls, mean salivary cortisol levels were significantly lower for CFS patients.[3] Urinary free cortisol was significantly lower in 121 CFS patients compared to 64 control patients.[4]  10 melancholic depressives had higher urinary free cortisol than 15 controls, while 21 CFS patients had lower urinary free cortisol.[5]  In 10 patients with CFS, 15 patients with major depression, and 25 healthy controls, baseline serum cortisol levels were highest in the depressives, lowest in the CFS patients, moderate in the controls.[6]

However, not all studies replicate the finding. In 22 CFS patients and 22 healthy controls, one study found no difference in urinary or salivary cortisol.[7] In another study of 10 CFS patients vs 10 controls, patients were slightly but significantly higher in salivary cortisol.[8]

One possible explanation for the discrepancy is that cortisol levels fluctuate greatly throughout the day, and in response to conditions that vary from day to day (food intake, stress, etc).  All these studies sampled patients over the course of a day or less. It’s not surprising that small studies should find discordant results, especially given the possibility that not all CFS patients are alike.

One finding that does seem consistent is that chronic fatigue patients have a blunted cortisol response to ACTH, the hormone produced by the pituitary that normally stimulates cortisol release, and they have an exaggerated drop in cortisol levels in response to challenge with corticosteroids (cortisol and its molecular analogues reduce ACTH levels in a negative feedback loop.)  So, even if cortisol is not always lower in CFS patients, it may be more sluggish to rise and quicker to decline.  In 21 CFS patients vs. 21 healthy controls, patients with CFS had normal baseline salivary cortisol but showed enhanced and prolonged suppression of salivary cortisol in response to dexamethasone challenge.[9]  Prednisolone challenge suppresses both salivary and urinary cortisol more in CFS patients (n=15) than controls (n=20).[11]

Upon challenge with ACTH, the increase in plasma cortisol was significantly less for 20 CFS subjects vs. 20 controls.[10]  In 22 CFS patients vs 14 controls, CFS patients also had a blunted DHEA response to ACTH; DHEA is a steroid hormone and androgen precursor, which is generally produced in response to exercise. In other words, the steroid-promoting effects of ACTH are weaker in CFS patients, while the cortisol-reducing negative feedback effects of corticosteroids are stronger.

Perhaps relatedly, CFS patients have blunted salivary cortisol response to awakening compared to healthy volunteers.[1]  Another study compares that female CFS patients have lower lower morning salivary cortisol than controls.[8] This may be related to the unrefreshing sleep and constant fatigue that CFS patients experience.

Finally, when there are hormonal differences in CFS patients, there are also clear anatomical differences. 8 CFS patients who had a subnormal cortisol response to ACTH challenge were found to have adrenal glands less than 50% the size of normal subjects’ adrenal glands.  In each case, the symptoms of fatigue were preceded by a viral infection.[12]  So in at least some cases, CFS patients have smaller glands than healthy people, which indicates that at least some of the time, CFS is associated with a damaged endocrine system.

Chronic Fatigue and Impaired NK Function

Studies find a variety of abnormalities in white blood cells in CFS patients, but the only really consistent results are impairment of NK (natural killer) cells’ function.  NK cells are cytotoxic (cell-killing) white blood cells involved in the innate immune response; they attack tumor cells and infected cells.

A study of 30 CFS patients and 69 controls found that NK cell cytotoxicity was 64% lower against tumor cell lines.[13]  In a family with 8 relatives with chronic fatigue syndrome, affected individuals had 62% lower NK activity levels (p = 0.008) against a tumor cell line than normal controls; unaffected relatives had intermediate NK activity levels.[14]  In a study of 41 CFS patients and 23 matched controls, the patients had significantly lower cytotoxic activity against EBV-infected cell lines and tumor cell lines, and patients also had significantly lower levels of NKH1+ NK cells, a subtype which comprises most of the NK cells in healthy people.[15]  A review article [16] explained that there are conflicting results in most immunological abnormalities in CFS; most studies, however, found reduced NK activity and reduced lymphoproliferative activities in response to antigens.  Of 17 studies that evaluated NK activity in CFS patients, 15 found reduced NK cytotoxicity in the CFS patients compared to controls, and a greater decrease in activity was associated with greater symptom severity.[17]

This suggests that CFS is characterized by a weakened immune system.

In general, NK deficiencies or reduced NK activity are associated with greater susceptibility to herpesviruses.[18] Reduced NK activity has also been found in major depression [19],  stress[20][21][22], bereavement [23], and sleep deprivation[24][25].

Chronic Fatigue and Herpesviruses

A number of studies have found that CFS is associated with elevated antibodies to viruses, particularly herpesviruses. It’s also often been found that CFS occurs with rapid onset, after a viral illness, and that there are outbreaks of CFS in locations where there have been disease outbreaks.  However, results are not entirely consistent between studies.

Negative Results

In a study of 548 CFS patients vs 30 healthy controls, CFS patients did not have significantly higher rates of positive titers on antibodies to HSV1, HSV2, Rubella, CMV, EBV, HHV-6, or Coxsackie.  This was a study of consecutive patients at a chronic fatigue clinic in Washington State.[26]

In another study of 100 CFS patients referred to the lab by doctors and 92 healthy controls, there were significantly higher rates in patients than controls of prevalence of antibodies to EBV viral capsid antigen, and prevalence of antibodies to EBV early antigen, but not to antibodies to EBV nuclear antigen; there was also no significant difference between patients and controls in who had high titers of antibodies.[27]

In a study of 26 patients from Atlanta with CFS and 50 healthy controls, there were no significant differences in the rate of prevalence of antibodies to any viruses, including HHV-6; the prevalence of antibodies in the controls was nearly 100% for all viruses tested.  Also, there was no significant difference in the antibody titers for any EBV antibodies (early antigen, nuclear antigen, or viral capsid.)[28]

In a study of four clusters of outbreaks of CFS in the Nevada/California area in the 1980’s, with 31 patients and 105 controls in total, there was no significant difference in the mean antibody titer to HHV-6, EBV-VCA, or EBV-EA.  Mean VCA GMT level for cases was 239.7 vs. 254.0 for controls, a non-significant difference.[29]

In 88 patients with CFS compared to 76 healthy blood donors in the Netherlands, there was no significant difference in geometric mean titer for EBV EA antibodies or EBV VCA antibodies. Mean VCA GMT level for patients was 39.5 vs. 38.0 for controls.[33]

For identical twin pairs discordant for CFS, the twin with CFS was no more likely to have serological evidence of virus than the twin without (including EBV and HHV-6).[39]

In 14 patients with CFS compared to 14 controls, there was no significant difference in EBV antibody titer.[40]

Positive Results

In a study of 259 patients associated with the Lake Tahoe outbreak in 1984, compared to 40 healthy controls, found active replication of HHV-6 in cell cultures from blood in 70% of patients compared to 20% of controls.  The reciprocal geometric mean titers for EBV VCA were significantly higher in the patient than control group (138.0 +/- 2.6 for the cases vs. 67.6 +/- 4.4 for the controls) but not for early antigen or nuclear antigen.  There was no significant difference in antibody titers for HHV-6, though.  Mean HHV-6 ELISA densities were 1905 for cases and 1288 for controls, a nonsignificant difference.[30]

In a study comparing 15 patients from the Lake Tahoe outbreak who had been sick for more than 2 months to 119 patients with less severe symptoms and 30 matched controls found that a significantly higher fraction of cases than non-case patients had EBV VCA antibodies at 160 or greater, and 320 or greater.  Reciprocal geometric mean titers for VCA were higher in case-patients than controls (254 vs. 115.)  After retesting across 3 laboratories, the only significant difference between case-patients and control-patients was EBV EA titer, with reciprocal geometric mean titers of 22 in cases vs. 9 in controls; VCA levels were not significantly different.[31]

In 58 CFS patients and 68 matched controls, 33 CFS patients (57%) had positive EBV VCA IgM titers, compared to 7% of controls.[32]  IgM titers to EBV are rare, are more likely to indicate active infection, and most studies find none at all.

In a study of 154 CFS patients and 165 controls from Flint and Boston, patients were significantly more likely than controls (p < 0.001) to have the presence of IgG and IgM antibodies to HHV-6, but not to have EBV-EA antibodies.[34]

In a study of 10 CFS patients with acute mononucleosis onset, 10 CFS patients without, and 42 healthy controls found significantly higher EBV IgG VCA antibody titers in all CFS patients relative to controls, as well as HHV-6 antibody titers.[35]

In 21 MS patients, 35 CFS patients, and 28 healthy controls, 75% of MS patients had elevated IgM titers to HHV-6 antibodies compared to 6.7% of healthy controls, and 71.4% elevated IgM titers to HHV-6 virus compared to 15% of controls.  However 60-80% of everyone had HHV-6 by PCR. CFS patients were more likely to have IgG responses to early HHV-6 antibodies than controls (65.2% vs 20%) and IgM responses to early HHV-6 antibodies than controls (54.3% vs. 8.0%).  This suggests a high level of HHV-6 reactivation in CFS and MS patients.[36]

In 13 patients with CFS and 13 healthy controls, serum antibodies for HHV-6 were significantly higher in the patients; 7 of the patients and none of the controls had HHV-6 DNA, as measured by PCR.[37]

A study of 36 CFS patients and 24 controls found that HHV-6A DNA was significantly more prevalent in CFS patients, while HHV-6B DNA was the same.[38]


HHV-6 High IgG levels

Study Cases (number) Controls (number)
Buchwald 1996 13% (295) 7% (30)
Patnaik 1995 40% (154) 8% (165)
Sairenji 1995 100% (20) 88% (26)
Ablashi 2000 71% (35) 0% (25)

HHV-6 High IgM levels

Patnaik 1995 60% (154) 4% (165)
Ablashi 2000 54% (35) 8% (25)


Yalcin 1994 53% (13) 0% (13)
Di Luca 1995 22% (36) 4% (24)
Koelle 2002 36% (22) 27% (22)

EBV-VCA High IgG levels

Buchwald 1996 8% (308) 3% (30)
Sumaya 1991 11.9% (42) 18% (100)
Swanink 1995 32% (88) 32% (76)
Sairenji 1995 20% (20) 0% (26)

EBV-VCA High IgM Levels

Lerner 2004 100% (33) 8% (50)

EBV-EA High IgG levels

Buchwald 1996 18% (308) 23% (30)
Sumaya 1991 47.6% (42) 69% (100)
Lerner 2004 79% (33) 30% (50)
Swanink 1995 8% (88) 8% (76)
Patnaik 1995 25% (154) 15% (15)
Sairenji 1995 45% (20) 0% (26)


EBV-NA positive

Buchwald 1996 95% (308) 93% (30)
Sumaya 1991 97.6% (42) 88% (100)
Swanink 1995 16% (88) 32% (76)


EBV-IgM elevated

Buchwald 1996 0.6% (310) 3% (30)


Sumaya 1991 182.5 (42) 181.2 (100)
Mawle 1995 89.0 (26) 83.6 (50)
Buchwald 1992 138 (134) 67.6 (27)
Holmes 1987 169 (15) 113 (30)
Levine 1992 239.7 (24) 254.0 (49)


Sumaya 1991 9.5 (42) 21.1 (100)
Mawle 1995 57.5 (26) 35.2 (50)
Buchwald 1992 40.7 (134) 12.6 (27)
Holmes 1987 22 (15) 9 (30)
Levine 1992 6.0 (24) 2.1 (49)


Sumaya 1991 21.7 (42) 13.8 (100)
Mawle 1995 26.4 (26) 21.1 (50)
Holmes 1987 53 (15) 36 (30)


Mawle 1995 1460 (26) 1715 (50)
Buchwald 1992 1905 (134) 1288 (27)
Levine 1992 132.6 (27) 87.9 (89)

The only serological differences that are consistently significantly different between CFS and normal patients are HHV-6 DNA (except for the twin study), HHV-6 IgM, and EBV-VCA IgM levels.  IgM, as opposed to IgG, levels, indicate active infection, as do viral DNA levels. This suggests that chronic fatigue patients are more likely than controls to have reactivated herpesviruses, but may not be more likely than controls to have had past exposure to herpesviruses.

Chronic Fatigue and Other Infections

There are some studies that have found associations between chronic fatigue syndrome and other types of bacterial and viral infection.


Mycoplasma bacterial species can survive for a long time inside cells, evade immune response, and resist treatment with antibiotics. They can cause a form of pneumonia and a sexually transmitted disease, and have been associated with various types of cancer.

In a study of 200 CFS patients and 100 controls, 52% of CFS patients had Mycoplasma infections compared to 7% of controls, and 30.5% of CFS patients had HHV-6 infections compared to 9% of controls, as measured by forensic PCR.[41]

In 100 CFS patients and 50 controls, 52% of CFS patients had PCR results positive for Mycoplasma genus, compared to 14% of controls (p < 0.0001).[42]

Other viruses

In 258 patients from Dubbo in rural Australia, exposed to Epstein-Barr virus, Ross River virus, or Q fever, 35% had a post-infective fatigue syndrome at 6 weeks and 12% at 6 months, at which point 11% (28 patients) met criteria for chronic fatigue syndrome. [43]

Out of 51 patients infected with acute Parvovirus B19, 5 went on to meet criteria for CFS.  Those with prolonged fatigue and CFS had significantly higher rates of serum B19 DNA.[44]

In 50 patients with postviral fatigue, 6 were associated with a local epidemic of Coxsackie virus, and 9 from a different viral epidemic of unknown cause; 30 had high antibody titers to Coxsackie virus, but none to other viruses.[45]

Chronic fatigue syndrome seems to frequently follow acute infections, and it is associated with high DNA levels of pathogens, often ones (like viruses or Mycoplasma bacteria) that can persist in the body indefinitely.

Corticosteroids Relieve CFS In A Sub-Population of Patients

In a study of 37 patients with chronic fatigue syndrome and 28 healthy controls, the CFS group had higher baseline cortisol levels but weaker cortisol responses to CRH and fenfluramine, and lower urinary cortisol levels.  In a subset of responders (8 out of 23 patients) treated with low-dose hydrocortisone for 28 days, the blunting of the cortisol response recovered, and CRH again caused a strong cortisol spike.  In these patients, fatigue dropped to the same level as the normal population.[46]

In a randomized trial of 32 CFS patients with no comorbid disorders, self-reported fatigue scores fell by 7.2 points in treatment group vs. 3.3 points in placebo group (p = 0.009), and 28% of treated patients reached normal levels of fatigue, compared to 9% of the placebo patients. This was a crossover study: patients received either hydrocortisone or placebo for one month, and then the reverse.[50]

Patients with CFS have higher DHEA levels than controls; there is a correlation between higher DHEA and more disability; untreated CFS patients have a blunted DHEA response to CRH challenge compared to controls and hydrocortisone-treaded CFS patients; basal levels of DHEA also went down after treatment with hydrocortisone.[47]

In a much older study from 1948, 53 patients with chronic mononucleosis, with “infectious mononucleosis cells” in the blood, presenting with weakness or ease of fatigue, responded only to a preparation of adrenal cortical extract (“cortalex”). “There was but little subjective improvement during the first week, but a definite feeling of well being developed during the second week and was quite definite during the third week. After this the medication was discontinued and the improvement usually continued. In a few patients it was necessary to increase the dose, or resume it after its discontinuance. Associated with the subjective improvement, there was a decrease in the size of the spleen.”[48]

However, when patients are not selected for having a blunted cortisol response, sometimes trials of corticosteroids on CFS don’t show positive results.

A crossover study of 80 patients given hydrocortisone and fludrocortisone found no significant difference from placebo in reported fatigue.  Note that the treatment group here did not see a larger response than placebo to an ACTH injection. So this negative result would still be consistent with the hypothesis that steroids work only when they recover the cortisol response to CRH or ACTH.[49]

A controlled study of 63 patients given low-dose hydrocortisone vs. placebo found no significant difference in wellness score over a period of 3 months, but significantly more patients  (53% vs 29%, p =0.04) experiencing an improvement of >5 points on the wellness score, which could be consistent with the drug being effective on a sub-population.[51]

Corticosteroids in Autoimmune Neurological Disorders

Chronic fatigue syndrome has similar symptoms and may have similar causes to other autoimmune neurological disorders such as multiple sclerosis and inflammatory neuropathies. Fatigue, muscle weakness, and brain fog, as well as high antibody titers for viruses, are found in these diseases. Corticosteroids are often standard treatments. This suggests that analogous treatment may be useful in CFS.

Corticosteroids (particularly methylprednisone) decreased by 63% the probability of the patient failing to recover from an exacerbation of multiple sclerosis, according to a Cochrane Review.[52]

IVIG and/or corticosteroids are standard treatment for chronic inflammatory demyelinating polyradiculoneuropathy.  Both significantly reduce disability scores.[53][54]

Demyelinating peripheral neuropathy responded to corticosteroids in six children, who regained strength and ability to walk.[55]

Corticosteroids (prednisolone) have significant positive effects on muscle strength and ability to function in daily life for patients with myasthenia gravis, an autoimmune neurological disorder.[56]

However, corticosteroids are ineffective in Guillain-Barre syndrome, another autoimmune demyelinating disease causing weakness and numbness. Standard treatment for Guillain-Barre is plasmapheresis and/or IVIG.[57]

Corticosteroids suppress inflammation, so they are often effective on autoimmune disorders which damage the nervous system through inflammatory damage. While it is not known what causes CFS, if it is an autoimmune disorder, it may respond to similar treatment.

IVIG Is Not Consistently Effective in CFS

Intravenous immunoglobulin is the practice of treating immunodeficiency disorders with a variety of antibodies via injection.

A 30-person randomized trial of IVIG in CFS, with a dose of 1 gm/kg, found no significant differences in symptoms between treatment and control by the 5-month follow-up point.[58]

A 99-patient controlled trial of IVIG vs. placebo infusion on CFS patients found no significant treatment effect on any self-reported symptom scores.[59]

A 71-patient randomized controlled trial of IVIG vs. placebo infusion found a barely-significant (p = 0.04) difference between placebo and IVIG on symptom scores.[64]

However, a 49-person study of patients with CFS treated with a dose of 2 gm/kg of IVIG, 40 of which had reduced T-cell counts or reduced response to skin-test antigens, found  43% of the treated group compared to 12% of controls noticed major reductions in their symptoms at the 3-month follow-up point after treatment.  The responders also noticed recovery of their cell-mediated immunity findings.[60]

It’s possible that for a sub-population of CFS patients with abnormally low T-cell counts or T-cell subtype counts, IVIG can be helpful; but it doesn’t seem to be helpful for CFS patients across the board.

Staphylococcus Toxin May Help CFS

In a randomized trial treating 100 fibromyalgia or CFS patients with staphylococcus toxin or placebo found that the treatment group had 65% responders (reduction of >50% of symptoms on a comprehensive rating scale) compared to 18% for placebo, p < 0.001. There was improvement at a p < 0.01 level in fatiguability, reduced sleep, failing memory, concentration difficulties, and sadness.[61]

Rituximab May Help CFS

Rituximab, an immunosuppressant drug that targets B cells, was found to improve fatigue scores in 67% of 30 patients in a randomized trial, compared to 13% of placebo. (p = 0.003). There were no adverse effects except a worsening of psoriasis in two patients.[62]

In an open-label follow-up from the same lab, 18 out of 29 patients on maintenance rituximab therapy for 15 months had clinically significant responses.[63]


Reduced NK activity and viral reactivations naturally go together, and stress can cause both.  Cortisol usually inhibits NK activity, so long-term hypocortisolism might result in NK cells that become more sensitive to cortisol[65], a possible mechanism for how an impaired HPA axis could result in NK dysfunction and thence viral reactivation.  The picture that seems to be emerging is that prolonged stress and/or an acute viral infection can result in fatigue and immunocompromise. This would explain why there are often psychological comorbid factors.

If this is what’s going on, then the obvious intervention points would be to increase cortisol (particularly the phasic cortisol response to stress) and to increase NK activity.  Administering low dose corticosteroids seems to do reasonably well at the former. It’s not clear how to do the latter, but cytokines like IL-15 might work[66] and so might bacterial therapies like the staphylococcus toxin mentioned above.


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[27]Sumaya, Ciro V. “Serologic and virologic epidemiology of Epstein-Barr virus: relevance to chronic fatigue syndrome.” Review of Infectious Diseases 13.Supplement 1 (1991): S19-S25.

[28]Mawle, Alison C., et al. “Seroepidemiology of chronic fatigue syndrome: a case-control study.” Clinical Infectious Diseases 21.6 (1995): 1386-1389.

[29]Levine, Paul H., et al. “Clinical, epidemiologic, and virologic studies in four clusters of the chronic fatigue syndrome.” Archives of internal medicine 152.8 (1992): 1611-1616.

[30]Buchwald, Dedra, et al. “A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection.” Annals of internal medicine 116.2 (1992): 103-113.

[31]Holmes, Gary P., et al. “A cluster of patients with a chronic mononucleosis-like syndrome: is Epstein-Barr virus the cause?.” JAMA 257.17 (1987): 2297-2302.

[32]LERNER, A. MARTIN, et al. “IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome.” in vivo 18.2 (2004): 101-106.

[33]Swanink, Caroline MA, et al. “Epstein-Barr virus (EBV) and the chronic fatigue syndrome: normal virus load in blood and normal immunologic reactivity in the EBV regression assay.” Clinical infectious diseases 20.5 (1995): 1390-1392.

[34]Patnaik, Madhumita, et al. “Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome.” Journal of Infectious Diseases 172.5 (1995): 1364-1367.

[35]Sairenji, Takeshi, et al. “Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome.” Intervirology 38.5 (1995): 269-273.

[36]Ablashi, D. V., et al. “Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients.” Journal of Clinical Virology 16.3 (2000): 179-191.

[37]Yalcin, Safak, et al. “Prevalence of human herpesvirus 6 variants A and B in patients with chronic fatigue syndrome.” Microbiology and immunology 38.7 (1994): 587-590.

[38]Di Luca, D. A. R. I. O., et al. “Human herpesvirus 6 and human herpesvirus 7 in chronic fatigue syndrome.” Journal of clinical microbiology 33.6 (1995): 1660-1661.

[39]Koelle, David M., et al. “Markers of viral infection in monozygotic twins discordant for chronic fatigue syndrome.” Clinical Infectious Diseases 35.5 (2002): 518-525.

[40]Whelton, C. L., I. Salit, and H. Moldofsky. “Sleep, Epstein-Barr virus infection, musculoskeletal pain, and depressive symptoms in chronic fatigue syndrome.” The Journal of rheumatology 19.6 (1992): 939-943.

[41]Nicolson, G. L., R. Gan, and J. Haier. “Multiple co‐infections (Mycoplasma, Chlamydia, human herpes virus‐6) in blood of chronic fatigue syndrome patients: association with signs and symptoms.” Apmis 111.5 (2003): 557-566.

[42]Vojdani, A., et al. “Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome.” FEMS Immunology & Medical Microbiology 22.4 (1998): 355-365.

[43]Hickie, Ian, et al. “Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.” Bmj 333.7568 (2006): 575.

[44]Kerr, Jonathan R., et al. “Chronic fatigue syndrome and arthralgia following parvovirus B19 infection.” The Journal of Rheumatology 29.3 (2002): 595-602.

[45]Hickie, Ian, et al. “Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.” Bmj 333.7568 (2006): 575.

[46]Cleare, A. J., et al. “Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy.” The Journal of Clinical Endocrinology & Metabolism 86.8 (2001): 3545-3554.

[47]Cleare, A. J., V. O’Keane, and J. P. Miell. “Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome.” Psychoneuroendocrinology 29.6 (2004): 724-732.

[48]Isaacs, Raphael. “Chronic infectious mononucleosis.” Blood 3.8 (1948): 858-861.

[49]Blockmans, Daniel, et al. “Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study.” The American journal of medicine 114.9 (2003): 736-741.

[50]Cleare, Anthony J., et al. “Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial.” The Lancet 353.9151 (1999): 455-458.

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[54]Hughes, Richard, et al. “Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy.” Annals of neurology 50.2 (2001): 195-201.

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Life Extension Possibilities

Epistemic Status: Pretty confident

This is my first pass of a lit review of life-extension interventions apart from caloric restriction, with a focus on things that work in mammals (rather than fruit flies or other invertebrates.)

Intervention Longevity Increase
Ames dwarf mice 50%
PAPP-A knockout mice 38%
Irs knockout mice 32% (female only)
AC5 knockout mice 32%
Low methionine diet 30%
High dose rapamycin 25%
High dose vitamin E 15% females, 40% males
Lower core body temperature 12% males, 20% females
Low dose rapamycin 10-18%
NGDA 10% (male only)
Statins + ACE inhibitors 9%
Selegiline 7%
Metformin 4-5%

Bottom Lines

  • Low methionine diets (roughly, vegan diets) work really well at extending life in mice, and there’s a plausible mechanism (avoiding homocysteine buildup) that they might work in humans as well.  If it worked as well on humans as it does on mice, the average person would live to over 100.
  • Rapamycin extends life in mice by quite a lot. Unfortunately it’s a strong immunosuppressant, so isn’t very safe to use as a drug.
  • There’s a lot of evidence that the IGF/insulin signaling/growth hormone metabolic pathway is associated with aging and short lifespan, and that inhibiting genes on that pathway results in longer lifespan.  IGF-receptor-inhibiting or growth-hormone-inhibiting drugs could be studied for longevity, but haven’t yet.
  • The MAO inhibitor selegiline extends life in both mice and dogs.
  • Metformin seems to work, and is currently being studied in a human trial.
  • NDGA, an antioxidant derived from the creosote bush, might work, but it’s also toxic.
  • Sirtuin drugs and resveratrol don’t work.

Low methionine

60 Fischer rats fed a low-methionine diet lived 30% longer than control rats. The low-methionine rats grew significantly less as well.[1]

80 female mice fed a low-methionine diet lived longer than control mice, at p < 0.02; they also were lower in weight, lower in IGF, insulin, glucose, and thyroxine, had fewer cataracts, and experienced less loss of liver function in response to injected acetaminophen.[2]’

Some tumors are dependent on methionine to grow and will not kill methionine-starved mice as fast.[28]

Homocysteine is biosynthesized from methionine.  Homocysteine levels rise as we age and are associated with many diseases of aging, such as heart disease, cancer, stroke, Alzheimer’s, and presbyopia. Genetic conditions that cause homocysteinuria in younger people cause similar problems: vascular thrombosis, intellectual disability, lens disclocation.  Homocysteine levels are also associated with depression[32] and schizophrenia.[33]  Homocysteine is toxic and reacts to “homocysteinylate” many different kinds of proteins, rendering them ineffective.[29]  It might also cause its damage through oxidation, impaired methylation, or other chemical mechanisms.[30]  If you give a rabbit homocysteine injections, it’ll develop atherosclerosis.[31]

Children with homocysteinuria have been successfully treated with low-methionine diets.[34][35][36] This is now the standard treatment for patients with genetic homocysteinuria who don’t respond to vitamin B supplementation. A low-methionine diet in humans consists of abstaining from meat, fish, and dairy, instead getting protein from soy and vegetables, and making up the caloric deficit with fat.

Growth Hormone and IGF Inhibition

Rats which were heterozygous for an antisense growth-hormone transgene lived 7-10% longer than control rats. They were also smaller and had lower levels of IGF. [3]

Ames dwarf mice lack growth hormone, prolactin, and TSH, and live about 50% longer than normal mice due to a Prop1 mutation.[22]

Humans with Prop1 mutations lack growth hormone and so have short stature, hypothyroid, cortisol deficiency, and failure to go through puberty.[37]  Humans with growth hormone receptor deficiency in Ecuador had short stature and were obese but had a much lower incidence of cancer and diabetes, and greater insulin sensitivity, than their normal relatives.  They did not have higher longevity because they had higher rates of alcoholism and accidents.[38]

Female mice missing an IGF receptor (Irs1 -/-) live 32% longer on average; male Irs1 -/- mice have no change in longevity.  These mice are insulin resistant but have reduced fat mass despite eating more.[23]  A cohort of Ashkenazi Jewish centenarians had female offspring with 35% higher IGF1 and 2.5 centimeters shorter than age- and sex-matched controls.  The centenarians had many mutations in the IGF1 receptor gene. The centenarians with mutations had higher IGF1 and a trend towards shorter height than those without.[39]

Pegvisomant is a growth hormone receptor antagonist used to treat acromegaly; it could be investigated as an anti-aging therapy.  Somatostatin analogs such as octreotide and pasireotide could also be investigated; somatostatin inhibits the release of growth hormone.  There are also IGF receptor kinase inhibitors being investigated for antitumor properties, such as NVP-AEW-541.


If started at 3 months of age (but not later), metformin increased mean lifespan of female SHR mice by 14%. It also delayed the onset of the first tumor by 22%.[4]

Metformin increases the mean lifespan of mice by 4-5%. Treated mice had lower cholesterol, lower LDL, and lower insulin.[7]


If fed to mice near the end of lifespan (600 days), rapamycin extends mean lifespan by 14% for females and 9% for males.[5]  Rapamycin fed to mice starting at 9 months extends median survival by 10% in males and 18% in females.[6]  Rapamycin fed to Her/neu homozygous (cancer-prone) mice caused 4% extension in mean lifespan and 12.4% increase in maximum lifespan.  Rapamycin-treated mice were 25% less likely to develop tumors.[8]

High-dose rapamycin given to mice at 9 months extends life by 23% in males and 26% in females.[9]

Rapamycin increases the lifespan of Rb1+/- mice ( a model of neuroendocrine tumors) by inhibiting the incidence of neuroendocrine tumors.  Mean lifespan increased by 9% in females and 14% in males. Treated mice were significantly less likely to have thyroid tumors, and had smaller tumors of all kinds.[15]


Nordihydroguaiaretic acid, an antioxidant derived from the creosote bush, increased mean lifespan by 12% in male but not female mice. Did not increase the proportion of extremely long-lived mice.[11]

NDGA increased median lifespan in male mice, but not female mice, by 8-10%.[12]

On the other hand, there have been reports of hepatitis and kidney damage from human consumption of NDGA or creosote.

High-dose Vitamin E

Male mice given tocopherol (an antioxidant) at a dose of 5g/kg of food from 28 weeks of age had 40% longer median lifespan than control, and 17% increased maximal lifespan; female mice given tocopherol had 15% increased median lifespan.[10]  Mice given tocopherol from 28 weeks and maintained in the cold (45 degrees Fahrenheit) lived 15% longer.[56]  On the other hand, high-dose vitamin E in humans, according to a meta-analysis, did not reduce all-cause mortality.[57]

Lower Core Body Temperature

Mice genetically engineered to overexpress the Hrct-UCP2 gene, which causes an 0.3-0.5 degree drop in core body temperature, had median lifespans increased by 12% in males and 20% in females.[13]  Lower core body temperature is one of the results of caloric restriction, and cooler humans tend to live longer and be less obese.[55]

Young Ovaries

Old mice transplanted with young mouse ovaries lived an average of 6% longer.[14]  In particular, mice ovariectomized before puberty and transplanted with ovaries at 11 months lived longer than intact mice, by 17%. Transplantation with ovaries at 11 months seems to shift the survival curve to the right, postponing aging.[54]


Male rats treated with deprenyl (aka selegiline, a Parkinson’s drug and MAO-B inhibitor) lived on average 35% longer than controls, according to a 1988 study.[16] However, later studies could never find an equally dramatic effect. Mice treated with selegiline starting at 18 months had no increase in survival.[17] Selegiline extends life in female but not male Syrian hamsters.[18] Fischer rats treated starting at 18 months with selegiline lived 7% longer.[19] Male Fischer rats treated starting at 12 months with selegiline lived 7% longer.[20] Female hamsters, but not male, treated with selegiline, lived significantly longer than controls.[24]

ACE Inhibitors

High dose ACE inhibition with ramipril doubled the lifespan of hypertensive rats, bringing it up to that of normal rats.[21] Statins + ramipril increased lifespan of long-lived mice by 9%.[53]

Ramipril is a standard drug for high blood pressure.

AC5 Knockout

Adenylyl cyclase 5 is primarily expressed in the heart and brain, and catalyzes the synthesis of cyclic AMP, an important second messenger which allows hormones to pass through the plasma membrane and activates protein kinases, in particular to regulate glucose and fat metabolism.

AC5 knockout mice have a median lifespan 32% longer than wild-type mice. Bones were less brittle, body weights were smaller, and GH levels were lower.[25]  AC5 knockout mice also have markedly attenuated responses to pain (heat, cold, mechanical, inflammation, and neuropathic.)[50]  The effects of morphine and mu or delta opioid receptor agonists are attenuated in AC5 knockout mice.[52] However, AC5 knockout mice had Parkinson’s-like motor symptoms.[51]

SIRT1 Activators

Sirtuin 1, determined by the SIRT1 gene, is downregulated in cells that have high insulin resistance, and increased in mice undergoing caloric restriction; mice with low levels of SIRT1 don’t live longer in response to caloric restriction, while mice with high levels mimic the caloric restriction phenotype. [49]

SRT1720, a SIRT1 activator, extends life by 8% in mice on a standard diet, and by 21.7% in mice fed a high-fat diet (who are generally shorter-lived).  SRT1720 also reduces the incidence of cataracts, improves glucose tolerance, and lowers LDL and cholesterol.[26]  SRT1720 reduces liver lipid accumulation in strains of mice bred for obesity and insulin resistance, and preserved liver function.[45]

A phase I trial of SRT1720 in elderly human volunteers found that it was safe and well-tolerated and reduced cholesterol, LDL, and triglycerides over the course of a month of treatment.[46]

However, a subsequent trial found that SRT1720 does not in fact activate SIRT except when SIRT is attached to a fluorophore (used for imaging), so it may be an artifact. This study also found that SRT1720 had no effect on glucose tolerance in mouse models of diabetes.[47]

The putative SIRT1 activator SRT2104 did not affect insulin or glucose in a randomized trial of type II diabetes.[48]

Investigation of the sirtuin drugs has shut down, due to these failures to replicate.

PAPP-A Knockout

Mice missing pregnancy-associated plasma protein A live 38% longer than control mice, not associated with changes in serum glucose, cholesterol, or dietary intake. Wild-type mice had many more tumors than knockout mice. (70% of wild-type vs. 15% of knockout had tumors.)[27]  Knockout mice are smaller than wild-type, and consume less food, though similar as a proportion of bodyweight; they also show more spontaneous physical activity. Knockout mice are not significantly different from wild-type in terms of insulin sensitivity, fasting glucose, or insulin levels.[42]  PAPP-A knockout mice do not demonstrate as much thymic atrophy in old age as wild-type mice: more immature thymus cells, more new T cells, less IGF1 expression, easier to activate T cells.  IGF-1 promotes differentiation of T cells, so releasing it slower could keep the thymus young longer.[43]  PAPP-A knockout and wild-type mice both gain similar amounts of subcutaneous fat on high-fat diets, but the knockout mice gain significantly less visceral fat; PAPP-A is most highly expressed in mesenteric fat.[44] PAPP-A may have some tissue-specific effects on promoting IGF-axis activity, without altering metabolism that much across the board.

PAPP-A encodes a metalloproteinase that cleaves insulin-like growth factor binding proteins.  These IGFBPs are inhibitors of IGF activity, and if you cleave them, the ability to inhibit IGF diminishes; so PAPP-A knockouts make IGF less bioavailable.[40]  PAPP-A is expressed in unstable atherosclerotic plaques but not in stable ones; serum PAPP-A levels are higher in patients with unstable angina or acute myocardial infarction than in patients with stable angina or controls, by about a factor of two.[41]



80% of dogs receiving selegiline, compared to 39% of elderly (age 10-15) dogs receiving placebo, survived to the end of the two-year study.[65]


Female dogs who had their ovaries removed lived no longer than male dogs, while dogs with ovaries were twice as likely as male dogs to achieve “exceptional” longevity (>13 years).[66]

IGF and Weight

IGF is positively correlated with weight, and negatively correlated with age, in dogs across various breeds.  Larger dogs live less long. [67]


FOXO3A Mutation

Homozygous minor mutations in the FOXO3A gene were associated with a 2.75 odds ratio of being in a cohort of long-lived men, compared to controls.  They were 29% more likely to be “healthy” at baseline (free of cardiovascular disease, cancer, stroke, Parkinson’s, and diabetes, able to pass a walking and a cognitive test). The mutations were 85% more common in people who lived to more than 100 than in people who died at 72-74.[58]  A German sample of long-lived people found that minor alleles were 1.53x as common in centenarians than controls.[59]

Insulin-like growth factor signaling inhibits FOXO3 activity, while oxidative stress activates FOXO3.  FOXO3 represses the mTOR pathway and promotes DNA repair.  It is also anti-inflammatory: suppresses IL-2 and IL-6, reduces proliferation of T cells and lymphocytes, reduces inflammation.[60]

FOXO3 is activated by AMPK.[61] You can do this via metformin in vitro — meanwhile changing glioma precursor cells into non-tumor cells.[62]  You can also do it with AICAR, an AMP analogue that stimulates AMPK.[63]  Note that AICAR reduces triglycerides, increases HDL, lowers blood pressure, and reverses insulin resistance in mice.[64]

Unsupported Musings

I don’t think antioxidants generally have come out looking too good for anti-aging, and there are a lot of counterexamples to the “aging is oxidative damage” hypothesis.

I think the growth-hormone-and-insulin-signaling cluster of life extension techniques and mutations is probably a real thing, and matches well to an explanation for why caloric restriction works. It also makes sense evolutionarily; in times of food abundance you want to reproduce, while in times of food scarcity you just want to survive the season, so it would make sense if you had two hormonal modes, “reproductive mode” and “survival mode.”

I also think there’s probably an mTOR mechanism, possibly just due to cancer, that explains the effectiveness of both rapamycin and the significance of the FOXO3 genes.  AMPK, which is produced by exercise, is upstream of both the mTOR stuff and the insulin-signaling stuff; this would explain why both exercise and metformin seem to be helpful for longevity.


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[25]Yan, Lin, et al. “Type 5 adenylyl cyclase disruption increases longevity and protects against stress.” Cell 130.2 (2007): 247-258.

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[29]Krumdieck, Carlos L., and Charles W. Prince. “Mechanisms of homocysteine toxicity on connective tissues: implications for the morbidity of aging.” The Journal of nutrition 130.2 (2000): 365S-368S.

[30]Perna, Alessandra F., et al. “Possible mechanisms of homocysteine toxicity.” Kidney International 63 (2003): S137-S140.

[31]McCully, Kilmer S., and Bruce D. Ragsdale. “Production of arteriosclerosis by homocysteinemia.” The American journal of pathology 61.1 (1970): 1.

[32]Tolmunen, Tommi, et al. “Association between depressive symptoms and serum concentrations of homocysteine in men: a population study.” The American journal of clinical nutrition 80.6 (2004): 1574-1578.

[33]Applebaum, Julia, et al. “Homocysteine levels in newly admitted schizophrenic patients.” Journal of psychiatric research 38.4 (2004): 413-416.

[34]Perry, ThomasL, et al. “Treatment of homocystinuria with a low-methionine diet, supplemental cystine, and a methyl donor.” The Lancet 292.7566 (1968): 474-478.

[35]Kolb, Felix O., Jerry M. Earll, and Harold A. Harper. ““Disappearance” of cystinuria in a patient treated with prolonged low methionine diet.” Metabolism 16.4 (1967): 378-381.

[36]Sardharwalla, I. B., et al. “Homocystinuria: a study with low-methionine diet in three patients.” Canadian Medical Association Journal 99.15 (1968): 731.

[37]Reynaud, Rachel, et al. “A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies.” The Journal of Clinical Endocrinology & Metabolism 89.11 (2004): 5779-5786.

[38]Guevara-Aguirre, Jaime, et al. “Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans.” Science translational medicine 3.70 (2011): 70ra13-70ra13.

[39]Suh, Yousin, et al. “Functionally significant insulin-like growth factor I receptor mutations in centenarians.” Proceedings of the National Academy of Sciences 105.9 (2008): 3438-3442.

[40]Lawrence, James B., et al. “The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A.” Proceedings of the National Academy of Sciences 96.6 (1999): 3149-3153.

[41]Bayes-Genis, Antoni, et al. “Pregnancy-associated plasma protein A as a marker of acute coronary syndromes.” New England Journal of Medicine 345.14 (2001): 1022-1029.

[42]Conover, Cheryl A., et al. “Metabolic consequences of pregnancy-associated plasma protein-A deficiency in mice: exploring possible relationship to the longevity phenotype.” Journal of Endocrinology 198.3 (2008): 599-605.

[43]Vallejo, Abbe N., et al. “Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A.” Proceedings of the National Academy of Sciences 106.27 (2009): 11252-11257.

[44]Conover, Cheryl A., et al. “Preferential impact of pregnancy-associated plasma protein-A deficiency on visceral fat in mice on high-fat diet.” American Journal of Physiology-Endocrinology and Metabolism 305.9 (2013): E1145-E1153.

[45]Yamazaki, Yu, et al. “Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice.” American Journal of Physiology-Endocrinology and Metabolism 297.5 (2009): E1179-E1186.

[46]Libri, Vincenzo, et al. “A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers.” PLoS One 7.12 (2012): e51395.

[47]Pacholec, Michelle, et al. “SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.” Journal of Biological Chemistry 285.11 (2010): 8340-8351.

[48]Baksi, Arun, et al. “A phase II, randomized, placebo‐controlled, double‐blind, multi‐dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes.” British journal of clinical pharmacology 78.1 (2014): 69-77.

[49]Cantó, Carles, and Johan Auwerx. “Caloric restriction, SIRT1 and longevity.” Trends in Endocrinology & Metabolism 20.7 (2009): 325-331.

[50]Kim, K‐S., et al. “Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase‐5.” Genes, Brain and Behavior 6.2 (2007): 120-127.

[51]Iwamoto, Tamio, et al. “Motor dysfunction in type 5 adenylyl cyclase-null mice.” Journal of Biological Chemistry 278.19 (2003): 16936-16940.

[52]Kim, Kyoung-Shim, et al. “Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action.” Proceedings of the National Academy of Sciences of the United States of America 103.10 (2006): 3908-3913.

[53]Spindler, Stephen R., Patricia L. Mote, and James M. Flegal. “Combined statin and angiotensin-converting enzyme (ACE) inhibitor treatment increases the lifespan of long-lived F1 male mice.” AGE 38.5-6 (2016): 379-391.

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Transcranial Direct Current Stimulation

Epistemic status: rough-draft, I wouldn’t be surprised if my conclusions reversed

tDCS consists of a pair of sponge electrodes on the head, through which constant current is placed, at about 0.029-0.08 mA per square centimeter. Locations vary based on the intended effect of the treatment.  Extending treatment is usually done by prolonging duration rather than increasing intensity, as higher currents cause more cutaneous pain. When done correctly, the stimulation is painless, and therefore can be compared to sham stimulation as a control.[1]

Bottom lines: there are some serious methodological flaws in tCDS studies.  “Sham” stimulation isn’t a perfect control, so some significant proportion of the effect may be placebo. And there’s quite significant variation in how much a given application of current increases the evoked potential in the brain.  Also, almost all the studies are quite small.

Given that, though, the effect sizes on working memory are quite good — comparable or better to the best nootropics (caffeine, modafinil, and amphetamine.)

As a treatment for depression, tCDS looks less impressive; aggregating the best-quality studies gives no net effect compared to sham stimulation.

As a treatment for chronic pain, tCDS looks quite good, though there’s not very many studies.


A study of 15 healthy females found a slight improvement on a working memory task from anodal stimulation to the DLPFC, but not from cathodal stimulation of the DLPFC, stimulation of M1, or sham stimulation.  Cohen’s d is 0.66. [2]

18 patients with Parkinson’s given 1-2 mA of tCDS to the DLPFC for 20 min found a 20% increase in correct answers on a 3-back task compared to sham stimulation for 2 mA.  Stimulation with 1 mA improved accuracy by only 5%. Stimulation of M1 had a significant improvement of reaction time but not accuracy. Cohen’s d is 3.5.[3]

32 patients given sham, anodal, or cathodal stimulation of the DLPFC or M1 found that accuracy on a word-memorization task was significantly better with anodal DLPFC stimulation than sham (88% correct vs. 80% correct), while cathodal stimulation was worse than sham.  Sham and M1 stimulation were similar.  Cohen’s d was 3.5. [7]

18 subjects given a verbal-associative task with anodal DLPFC tCDS vs sham or cathodal tCDS significantly improved mean scores (9 vs. 7 out of 12 correct). There was no effect on verbal fluency scores (a test of how many unique words one can produce in a short timespan).  Cohen’s d was 0.8.[8]

12 patients given a 2-back task with sham, anodal DLPFC tCDS, or transcranial random noise stimulation found a significant improvement in speed but not accuracy for 2-back anodal tCDS vs. sham.  Cohen’s d was 0 for accuracy, 0.36 for speed.[9]

10 Alzheimer’s patients treated with tCDS on the DLPFC and left temporal cortex found significantly more correct responses with tCDS vs sham on a memorization task (30 vs. 35 correct responses out of 55) but no improvement in Stroop or digit span tests.  Cohen’s d was 1.[12]

16 Parkinson’s patients given tCDS to the DLPFC significantly improved phonemic verbal fluency relative to sham and TPC stimulation (p < 0.002) but did not improve semantic verbal fluency.[17]

In a study of 12 healthy subjects given a naming task, reaction times were decreased with anodal tCDS to the DLPFC and increased with cathodal tCDS to the DLPFC.[18]

15 healthy subjects given a 3-back working memory task given anodal tCDS to the DLPFC significantly improved accuracy with tCDS vs sham (80% correct vs 69% correct).  Cohen’s d of 0.87.[18]

10 stroke patients given a 2-back working memory task, treated with anodal DLPFC tCDS or sham, found significant improvement in accuracy in anodal but not sham groups. Cohen’s d of 2.4.[19]

28 patients with major depression given a 2-back task given tCDS or sham on the DLPFC found a significant improvement in accuracy with the active version vs. sham: 58% vs 42% correct, p = 0.04, Cohen’s d about 4.[20]

58 healthy subjects given working memory training had an effect size of DLPFC tCDS vs. sham of 1.5 on digit span (p = 0.025) , 1.35 for Stroop accuracy, 1.3 on the CVLT, no effect on Raven’s.[21]

30 healthy older adults were given sham or real anodal tCDS to the left DLPFC and given a 3-back test; there was no significant effect of stimulation on working memory performance.[24]

37 patients with temporal lobe epilepsy had no improvement in working or episodic memory from anodal tCDS to the left DLPFC.[25]

Mean Cohen’s d for working memory accuracy, weighted by sample size: 1.5.

A meta-analysis of 16 studies of anodal DLPFC tCDS found a mean effect size of 0.14 for accuracy and 0.15 for reaction time.[22]

I’m not certain why I’m getting such different numbers, except that my “review” seems to have included different studies than the meta-analysis did.  If you averaged the results, you’d still get a mean effect size of 0.75, which corresponds to a strong effect.


10 aphasic stroke patients treated with anodal tCDS over Wernicke’s area vs. sham: significantly improved accuracy on a picture-naming task (40% vs 20% correct before training, and 70% vs 50% after training.)  Anodal tCDS also improved mean reaction time (1.8 sec vs 2.5 sec.)  The improvement persisted 3 weeks after treatment.[6]

In 10 healthy subjects, anodal tCDS over Broca’s area vs sham increased verbal fluency: mean number of words were 22 vs. 16, and mean number of syllables was 15 vs. 14.  There was no effect when the tCDS was switched to the right-hemisphere analogue of Broca’s area.[10]


A study of 17 patients with central pain due to traumatic spinal cord injury, given 2 mA of tCDS to the motor cortex M1 or sham tCDS found a significant improvement of pain scores — from a 7 (out of 9) to a 4.  The effects of consecutive sessions were cumulative.  There was no significant effect of treatment on anxiety or cognitive function.

32 female patients with fibromyalgia were treated with sham tCDS, tCDS of M1, or tCDS of the DLPFC.  M1 stimulation worked, sham and DLPFC did not. Out of a subjective improvement scale (where 2 is “much improvement”,  3 is “minimal improvement”, and 4 is “no change”, the group treated with M1 tCDS was at 2.5 and the sham group was at 3.5; the DLPFC group was at 3.  This was 2 mA, 20 min/day, for 5 days.[4]

41 female patients with fibromyalgia treated with tCDS on M1, DLPFC, or sham found that M1 stimulation significantly improved pain scores compared to DLPFC or sham: from about a 6 (which was baseline) to a 4.  No significant effect on depression scores.[11]

A meta-analysis of tCDS for chronic pain found a pooled effect size of 2.29 on pain symptoms.[23]


A meta-analysis of the use of tCDS in depression (directed to the DLPFC) found that the mean effect on depressive symptoms was significant: a Hedges’ g score of 0.743, significant at a p-value of 0.006. There’s a bit of a bias in the data: the Fregni and Boggio labs had significantly larger effect sizes than the other labs, and there was significant heterogeneity in results. Only a minority of patients (10-30%) were responders.  The average reduction in symptom severity was about 30%.[5]

Another meta-analysis of 6 RCTs of tCDS in depression found no significant effect of tCDS vs. sham on response rates or remission rates for depression.[13]

Blinding issues

There are more frequent reports of itching and burning with real than sham tCDS, suggesting that blinding may not be sufficient.[14]  Participants are able to guess more accurately than chance whether they are in the active or sham treatment.[15]

Other problems

The MEP (electrical activity change) due to tCDS is extremely variable both between individuals and within the same individual. The MEP effect of tCDS can be abolished by moving or thinking while the current is being administered.[16]


If you want to zap your brain, there are a variety of places that sell tCDS devices.

The Brain Stimulator is $59.95

The  stimulator is $249, plus headsets and cables.

The Apex is $139.99

The Fisher Wallace Stimulator is $699.

Soterix Medical makes the standard clinical-use device, for investigational use only.

And, of course, a lot of people make DIY versions.

Safety issue to keep in mind: high voltage to your brain is not good. Anything above 2 mA is outside the range of what’s been studied and probably a bad idea.  If it hurts your skin, it’s too strong. A TENS unit is too strong.  A 9-volt battery is too strong. Do not do the thing.


[1]Nitsche, Michael A., et al. “Transcranial direct current stimulation: state of the art 2008.” Brain stimulation 1.3 (2008): 206-223.

[2]Fregni, Felipe, et al. “Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory.” Experimental brain research 166.1 (2005): 23-30.

[3]Boggio, Paulo S., et al. “Effects of transcranial direct current stimulation on working memory in patients with Parkinson’s disease.” Journal of the neurological sciences 249.1 (2006): 31-38.

[4]Fregni, Felipe, et al. “A randomized, sham‐controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia.” Arthritis & Rheumatism 54.12 (2006): 3988-3998.

[5]Kalu, U. G., et al. “Transcranial direct current stimulation in the treatment of major depression: a meta-analysis.” Psychological medicine 42.09 (2012): 1791-1800.

[6]Fiori, Valentina, et al. “Transcranial direct current stimulation improves word retrieval in healthy and nonfluent aphasic subjects.” Journal of Cognitive Neuroscience 23.9 (2011): 2309-2323.

[7]Javadi, Amir Homayoun, and Vincent Walsh. “Transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex modulates declarative memory.” Brain stimulation 5.3 (2012): 231-241.

[8]Cerruti, Carlo, and Gottfried Schlaug. “Anodal transcranial direct current stimulation of the prefrontal cortex enhances complex verbal associative thought.” Journal of Cognitive Neuroscience 21.10 (2009): 1980-1987.

[9]Mulquiney, Paul G., et al. “Improving working memory: exploring the effect of transcranial random noise stimulation and transcranial direct current stimulation on the dorsolateral prefrontal cortex.” Clinical Neurophysiology 122.12 (2011): 2384-2389.

[10]Cattaneo, Z., A. Pisoni, and C. Papagno. “Transcranial direct current stimulation over Broca’s region improves phonemic and semantic fluency in healthy individuals.” Neuroscience 183 (2011): 64-70.

[11]Valle, Angela, et al. “Efficacy of anodal transcranial direct current stimulation (tDCS) for the treatment of fibromyalgia: results of a randomized, sham-controlled longitudinal clinical trial.” Journal of pain management 2.3 (2009): 353.

[12]Boggio, Paulo S., et al. “Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease.” Journal of Neurology, Neurosurgery & Psychiatry 80.4 (2009): 444-447.

[13]Berlim, Marcelo T., Frederique Van den Eynde, and Z. Jeff Daskalakis. “Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.” Journal of psychiatric research 47.1 (2013): 1-7.

[14]Kessler, Sudha Kilaru, et al. “Differences in the experience of active and sham transcranial direct current stimulation.” Brain stimulation 5.2 (2012): 155-162.

[15]O’connell, Neil E., et al. “Rethinking clinical trials of transcranial direct current stimulation: participant and assessor blinding is inadequate at intensities of 2mA.” PloS one 7.10 (2012): e47514.

[16]Horvath, Jared Cooney, Olivia Carter, and Jason D. Forte. “Transcranial direct current stimulation: five important issues we aren’t discussing (but probably should be).” Frontiers in systems neuroscience 8 (2014): 2.

[17]Pereira, Joana B., et al. “Modulation of verbal fluency networks by transcranial direct current stimulation (tDCS) in Parkinson’s disease.” Brain stimulation 6.1 (2013): 16-24.

[18]Ohn, Suk Hoon, et al. “Time-dependent effect of transcranial direct current stimulation on the enhancement of working memory.” Neuroreport 19.1 (2008): 43-47.

[19]Jo, Jung Mi, et al. “Enhancing the working memory of stroke patients using tDCS.” American Journal of Physical Medicine & Rehabilitation 88.5 (2009): 404-409.

[20]Oliveira, Janaina F., et al. “Acute working memory improvement after tDCS in antidepressant-free patients with major depressive disorder.” Neuroscience letters 537 (2013): 60-64.

[21]Richmond, Lauren L., et al. “Transcranial direct current stimulation enhances verbal working memory training performance over time and near transfer outcomes.” Journal of Cognitive Neuroscience (2014).

[22]Hill, Aron T., Paul B. Fitzgerald, and Kate E. Hoy. “Effects of anodal transcranial direct current stimulation on working memory: a systematic review and meta-analysis of findings from healthy and neuropsychiatric populations.” Brain stimulation 9.2 (2016): 197-208.

[23]Luedtke, Kerstin, et al. “Transcranial direct current stimulation for the reduction of clinical and experimentally induced pain: a systematic review and meta-analysis.” The Clinical journal of pain 28.5 (2012): 452-461.

[24]Nilsson, Jonna, Alexander V. Lebedev, and Martin Lövdén. “No significant effect of prefrontal tDCS on working memory performance in older adults.” Frontiers in aging neuroscience 7 (2015).

[25]Liu, Anli, et al. “Exploring the efficacy of a 5-day course of transcranial direct current stimulation (TDCS) on depression and memory function in patients with well-controlled temporal lobe epilepsy.” Epilepsy & Behavior 55 (2016): 11-20.

Vestibular Stimulation and Fat Loss

It is a strange but well replicated fact, that if you leave small animals in a centrifuge for a really long time, they lose a lot of fat.  Many of these experiments were done in the 1960’s and 1970’s as part of the study of the physiological effects of spaceflight.

Centrifugation makes animals smaller, leaner, more muscular, and denser-boned

If you put female rats in a centrifuge for 60 days, at 2.76 and 4.15 G (where G is the strength of Earth’s gravitational field), they lose 10% and 19% of their body weight, respectively, with reductions in the fat fractions of most components and increases in the water fraction of liver and gut.[1]

Female rats exposed to 3.5 or 4.7 G for one year showed “marked depletion of body-fat depots” and “significant decrease in kidney and liver lipids.”[2]

Chickens exposed to 1.75, 2.5, or 3 G for 24 weeks had significantly reduced body fat.[15]  The drop in body fat is linearly increasing in G, and also increases with body mass.[17]

Rabbits exposed to up to 2.5 G had a drop in body fat and increase in body water, even as their food consumption increased.[16]

Female rats centrifuged for 30 days at 2.76 or 3.18 G reduced body fat and fat-free body mass within the first week of centrifugation, without any difference depending on whether they were fed commercial chow, a high-fat diet, a high-protein diet, or fasted.[3]

The drop in body fat from centrifugation can be quite large; chickens went from 13% body fat to 3% body fat at 3G, and mice have a 55% drop in total body fat after 8 weeks of 2G exposure.[18]

Centrifuged mice have a drop in weight during the first few days, but slowly regain it.[10]  Hamsters born in centrifuges have a final body weight of about 30% lower than control hamsters.[13]

Female rats centrifuged for 810 days at 2.76 G grew more slowly than control rats, but had the same absolute muscle mass; they have thicker bones and larger muscles for their size than uncentrifuged rats.[4]  They also have denser bones.[6]  They have a higher proportion of slow-oxidating muscle fibers (the kind used in distance running and other endurance activities).[9]  Centrifuged dogs (subjected to 2G for 3 months) also have denser bones.[11]

Centrifuged rats also had more uptake of glucose into tissues and a stronger response to insulin than uncentrifuged rats; this is the opposite of “insulin resistance.”[5]  Centrifuged chickens also have higher glucose uptake.[14]

Centrifuged rats have a sharp decrease in body temperature at about 3 days, and a subsequent recovery of normal body temperature.[7]

Centrifuged rats have a prolonged decrease in locomotor activity and distorted circadian rhythms.[8]

Centrifugation alters the vestibular system

The vestibular system is involved in balance.

The microscopic structure of the lateral vestibular nucleus (where many vestibular nerve fibers enter the brain) is altered in chronically centrifuged rats.[12]  Centrifuged hamsters have impaired balance during swimming tests.[13]

Knockout mice that lack vestibular linear acceleration organs are known as “head-tilt mice.” They move normally, except for a head tilt, but cannot swim because they cannot orient to the gravitational force vector.  Head-tilt mice, when centrifuged at 2G, do not experience the changes that chronic centrifugation causes in wild-type mice: they do not have a drop in body temperature, body mass, or body fat percentage. While wild-type mice under 2G dropped from 16% to 8% body fat, head-tilt mice started out at 8% before centrifugation and did not change.  This implies that vestibular effects somehow cause the physiological changes associated with higher gravity.

Artificially stimulating the vestibular organs causes fat loss

A pilot study at the University of California San Diego’s Center for Brain and Cognition, one of whose authors was famed neuroscientist Vilayanur Ramachandran, tested galvanic stimulation of the vestibular nerves, a non-invasive procedure that involves passing current over the inner ear, on six overweight and obese subjects, with three controls, for a total of 40 hours, for an hour a day.  There was a significant 8.3% decrease in truncal fat and a nonsignificant decrease in total body fat.  Appetite was reduced, leptin was reduced, and insulin was increased.[19]

This is not a huge reduction in fat.  (It would be something like two pounds on me, over the course of a month.) On the other hand, this is a significantly lower “dose” of vestibular stimulation than centrifuged animals would receive. The animals that had body composition changes were centrifuged continuously over a period of months.  It may be possible to slowly increase the time spent receiving galvanic stimulation.

Vestibular stimulation may affect hormone levels

There are a few case studies from India of “controlled vestibular stimulation” (swinging on a swing) causing various changes in physiology. A college student for whom swinging resulted in significantly lower blood pressure, blood glucose, and cortisol[21], and an 83-year-old diabetic man for whom swinging resulted in significantly lower glucose and blood pressure [22].

The vestibular system modulates autonomic activity, and vestibular stimulation activates vagus nerves in the pancreas which stimulate insulin production. There seems to be a parasympathetic response to vestibular stimulation, which goes with increased insulin production and lower hunger, both of which would reduce fat.  (It also matches the intuitive observation that rocking and swinging is soothing: think of infants and rocking chairs.)

Other Vestibular Stimulation Weirdness

Galvanic vestibular stimulation also seems to reverse face blindness [23].


Galvanic vestibular stimulation is safe, if sometimes uncomfortable (causes motion sickness), and might have significant effects on body fat and other metabolic factors. It is probably worth investigating more on humans.

It’s trivial to set up; people who are interested in virtual reality frequently build their own vestibular stimulation rigs to increase the verisimilitude of immersive games.  This seems like something with a lot of potential for venturesome self-experimenters to try out as well as something to investigate seriously in clinical experiments.


[1]Pitts, G. C., L. S. Bull, and J. Oyama. “Effect of chronic centrifugation on body composition in the rat.” American Journal of Physiology–Legacy Content 223.5 (1972): 1044-1048.

[2]Oyama, J., and B. Zeitman. “Tissue composition of rats exposed to chronic centrifugation.” American Journal of Physiology–Legacy Content 213.5 (1967): 1305-1310.

[3]Pitts, G. C., L. S. Bull, and J. Oyama. “Regulation of body mass in rats exposed to chronic acceleration.” American Journal of Physiology–Legacy Content 228.3 (1975): 714-717.

[4]Amtmann, Eduard, and Jiro Oyama. “Effect of chronic centrifugation on the structural development of the musculoskeletal system of the rat.” Anatomy and embryology 149.1 (1976): 47-70.

[5]Daligcon, B. C., and J. Oyama. “Increased uptake and utilization of glucose by diaphragms of rats exposed to chronic centrifugation.” American Journal of Physiology–Legacy Content 228.3 (1975): 742-746.

[6]Jaekel, Erika, Eduard Amtmann, and Jiro Oyama. “Effect of chronic centrifugation on bone density of the rat.” Anatomy and embryology 151.2 (1977): 223-232.

[7]Oyama, J. I. R. O., WILLIAM T. Platt, and VARD B. Holland. “Deep-body temperature changes in rats exposed to chronic centrifugation.” American Journal of Physiology–Legacy Content 221.5 (1971): 1271-1277.

[8]Holley, Daniel C., et al. “Chronic centrifugation (hypergravity) disrupts the circadian system of the rat.” Journal of Applied Physiology 95.3 (2003): 1266-1278.

[9]Martin, W. D. “Time course of change in soleus muscle fibers of rats subjected to chronic centrifugation.” Aviation, space, and environmental medicine 49.6 (1978): 792-797.

[10]WUNDER, CHARLES C. “Survival of mice during chronic centrifugation.” Aerospace Med 33 (1962): 866-870.

[11]Amtmann, Eduard, Jiro Oyama, and Gerald L. Fisher. “Effect of chronic centrifugation on the musculoskeletal system of the dog.” Anatomy and embryology 149.1 (1976): 71-78.

[12]Johnson, J. E., W. R. Mehler, and J. Oyama. “The effects of centrifugation on the morphology of the lateral vestibular nucleus in the rat: a light and electron microscopic study.” Brain research 106.2 (1976): 205-221.

[13]Sondag, H. N. P. M., H. A. A. De Jong, and W. J. Oosterveld. “Altered behaviour in hamsters conceived and born in hypergravity.” Brain research bulletin 43.3 (1997): 289-294.

[14]Evans, J. W., and J. M. Boda. “Glucose metabolism and chronic acceleration.” American Journal of Physiology–Legacy Content 219.4 (1970): 893-896.

[15]Evans, J. W., A. H. Smith, and J. M. Boda. “Fat metabolism and chronic acceleration.” American Journal of Physiology–Legacy Content 216.6 (1969): 1468-1471.

[16]Katovich, MICHAEL J., and ARTHUR H. Smith. “Body mass, composition, and food intake in rabbits during altered acceleration fields.” Journal of Applied Physiology 45.1 (1978): 51-55.

[17]Smith, A. H., P. O. Sanchez, and R. R. Burton. “Gravitational effects on body composition in birds.” Life sciences and space research 13 (1974): 21-27.

[18]Fuller, Patrick M., et al. “Neurovestibular modulation of circadian and homeostatic regulation: vestibulohypothalamic connection?.” Proceedings of the National Academy of Sciences 99.24 (2002): 15723-15728.

[19]McGeoch, Paul D., Jason McKeown, and Vilayanur S. Ramachandran. “Modulation of Body Mass Composition using Vestibular Nerve Stimulation.” bioRxiv (2016): 087692.

[20]Yates, B. J., and A. D. Miller. “Physiological evidence that the vestibular system participates in autonomic and respiratory control.” Journal of Vestibular Research 8.1 (1998): 17-25.

[21]Sailesh, Kumar Sai, and R. Archana. “Controlled vestibular stimulation: A physiological method of stress relief.” Journal of clinical and diagnostic research: JCDR 8.12 (2014): BM01.

[22]Kumar, Sailesh Sai, R. Archana, and J. K. Mukkadan. “Controlled vestibular stimulation: Physiological intervention in diabetes care.” Asian Journal of Pharmaceutical and Clinical Research 8.4 (2015): 315-318.

[23]Wilkinson, David, et al. “Improvement of a face perception deficit via subsensory galvanic vestibular stimulation.” Journal of the International Neuropsychological Society 11.07 (2005): 925-929.

Cross-Sex Hormone Therapy: Female Hormones

Scope Of Report

For the purposes of this report, we’re looking at cross-gender hormone therapy for assigned-male-at-birth individuals — that is, estrogen and anti-androgens, as they are generally taken by transgender women and others seeking to feminize their bodies.  I’ll look into the evidence for the medical and psychological risks and benefits of these drugs.

Bottom Lines

  • hormone therapy consisting of estrogen and an anti-androgen is mostly safe: the biggest risk is cardiovascular problems
  • the anti-androgen cyproterone acetate is riskier than other anti-androgens: it’s associated with venous thromboembolism, hyperprolactinemia, and possibly impaired mood and cognitive ability. It can be substituted with spironolactone, or in some cases with no anti-androgen at all.
  • hormone therapy for trans women improves mood and agreeableness, reduces gender dysphoria, and has some feminizing effects on appearance
  • hormone therapy does change brain size but doesn’t impair cognitive performance
  • trying to get an “androgynous” outcome by taking anti-androgens without estrogen is a bad idea and does cause cognitive impairment and depression.

Risks of Hormone Therapy: Venous Thromboembolism

The most common risk of hormone therapy in trans women is venous thromboembolism. This is when a blood clot in a vein breaks loose and travels in the blood; if it reaches the lungs it is called a pulmonary embolism and can be very dangerous. About 5% of people with venous thromboembolisms die.[1]

In the largest study, 1076 individuals, the rate of venous thromboembolism is 1%; smaller studies find 5-6% rates.[2]  Some small studies (162 individuals) suggest that transdermal estrogen has less risk of venous thromboembolism than oral estrogen.

The risk of venous thromboembolism is also elevated in hormonal birth control, which, like hormone therapy, contains female hormones.  Current users of estrogen-containing birth control have about double the yearly risk of venous thromboembolism of female non-users. Birth control containing the progestin cyproterone acetate is associated with 1.88x the venous thromboembolism risk of birth control with other progestins.[3]  This is relevant because cyproterone acetate is also an anti-androgen sometimes used in cross-gender hormone therapy; avoiding cyproterone acetate could reduce the risk of venous thromboembolism.

Risks of Hormone Therapy: Osteoporosis

Estrogen is associated with osteoporosis: 25% of 100 transgender women had osteoporosis after more than 10 years of HRT, whereas transgender men did not.[2]

Risks of Hormone Therapy: Hyperprolactinemia

The anti-androgen cyproterone acetate can cause hyperprolactinemia.

High levels of the hormone prolactin can cause symptoms such as breast discharge, erectile dysfunction and reduced libido, infertility, breast growth, decreased body hair and muscle mass, and headaches. (Not all of these may be undesirable for trans women, of course.)  It is not otherwise dangerous, and can be treated with dopamine agonists such as bromocriptine.

In a total of 1109 trans women across six studies, there were elevated prolactin levels in 19.5%. [5]  Trans women on hormone therapy have much higher rates of migraine than the baseline population: 26% out of 50, as opposed to a baseline rate of 6%.  This may be due to higher prolactin levels.[6] 14/47, or 30% of trans women reported new sources of pain after going on hormones, in particular headaches, breast pain, and musculoskeletal pain.[7] This may also be a result of hyperprolactinemia, or it may be related to other hormonal-balance issues (women generally are more pain-sensitive than men.)

Cyproterone acetate increases prolactin levels; spironolactone does not. (p = 0.0002).[8]  Avoiding cyproterone acetate seems likely to reduce the risk of hyperprolactinemia.

Risks of Hormone Therapy: Infertility

Estrogen therapy usually eliminates the production of sperm.  In 7 out of 10 trans women on estrogen, there was no spermatogenesis.[53] A single male given estrogen had a pronounced drop in sperm motility and density by 4 weeks of estrogen treatment, though it did recover after discontinuation of treatment.[54] As of 2009, there have been no studies of restoration of spermatogenesis after prolonged treatment with estrogen. [52]

Benefits of Hormone Therapy: Improved Mood

Hormone treatment (transdermal estradiol + cyproterone acetate) reduced anxiety and depression scores (p < 0.001) in a cohort study of 107 trans women.[16]

Estrogen has a complex relationship to mood even in cis women.  One credible model is that estrogen fluctuations (for example, around the menstrual cycle, or around the start of menopause) cause mood disorders.  Increased vulnerability to depression in women begins with puberty and ends with menopause, though the perimenopause period is associated both with new onset of depression and increased depression symptoms. [17]  For this reason, estrogen supplementation in cis women is sometimes an effective treatment for mood disorders associated with hormone fluctuations. Estrogen has been consistently shown to be effective as a treatment for PMS, for postpartum depression, and for the milder mood problems associated with menopause, but not with severe menopausal depression or non-reproductive-related major depressive disorder.[18]

Higher doses of estrogen, on the other hand, tend to make mood problems in cis women worse. 3 mg estradiol vs. 2 mg estradiol in HRT for perimenopausal women significantly (p < 0.001) increased tension, irritability, and depressed mood, and decreased friendliness. [19] In postmenopausal women treated with 2 mg/day estrogen or placebo for three months, there was no difference in baseline mood, but the estrogen-treated group had stronger negative emotion responses to a social stress test.[20]  Chronic administration of E2 to ovariectomized female rats and mice at much higher than physiologic doses increases anxious and depressive behaviors.[21]  It’s not clear how this translates to trans women, but it may be preferable to err on the side of lower estrogen doses when possible.

The anti-androgen spironolactone is used to treat symptoms of PMS in cis women, such as irritability, depression, feeling of swelling, breast tenderness, and food craving. Unlike other anti-androgens such as cyproterone acetate or finasteride, it has not been connected with negative effects on mood or cognition.[22]

Benefits of Hormone Therapy: Reduced Gender Dysphoria

Cross-hormone therapy resulted in less body uneasiness in trans women, in a study of 125 subjects.[23]  Adolescents (mean age 17) treated vs. rejected for cross-sex hormone therapy had less gender dysphoria at follow-up in both groups, but significantly less in the treated group.  The treated group were more satisfied with their bodies.[24]

Benefits of Hormone Therapy: Higher Agreeableness

Androgen deprivation and estrogen supplementation in males (e.g. treated for prostate cancer) correlates with higher agreeableness on the Big Five personality test.[25]

Benefits of Hormone Therapy: Altered Sexual Patterns

Estrogen treatment inhibits sexual activity, spontaneous erections, and nocturnal penile tumescence.[4]   Androgen deprivation therapy in cis men (as part of treatment for prostate cancer) consistently causes reduced libido and lower frequency of early morning erections, p < 0.0001.[51] However, trans women have no higher rates of hypoactive sexual desire syndrome than cis women[47]; it may simply be that estrogen causes a more female-typical sex pattern.

Benefits of Hormone Therapy: Physical Appearance Changes

Estrogen and anti-androgens reduce hair on the trunk and limbs, but don’t completely remove it on the face; electrolysis or shaving is still usually necessary.[26]

Breast growth is usually present, with a mean hemicircumference of 18 cm after a year of hormone therapy — this is still a few centimeters less than the mean for cis women.[26]  Most trans women are dissatisfied with the final size of their breast development.[30]

Hormone therapy significantly (p < 0.01, Cohen’s d = 1) improved the “physical appearance score” for gender compatibility of transgender people, a composite made of hair, facial hair, larynx, voice, figure, height, skin, hands/feet, muscularity, chin, nose, jaw, speech, and gestures/movement.[27]

Breast growth, redistribution of body fat, and decrease in muscle mass begin at 3-6 months and peak at 2 years; decreased hair growth begins at 6-12 months and peaks at >3 years.[28]

Trans women, compared to cis men, had similar BMI but higher body fat percentage: 29% vs. 21%, p < 0.001. They also had lower grip, biceps, and quadriceps strength (p < 0.001).[29]

Non-Effects of Hormone Therapy: Cognitive Ability

A study of 35 trans men and 15 trans women at the beginning of hormone treatment, as well as 20 control (cis) men and 20 cis women, found that the trans men’s spatial rotation ability increased during 12 weeks of hormone treatment, while the trans women’s spatial rotation ability slightly declined (p < 0.01), from an average score of 101.9 to 98.5, or a 3% drop.  In this study, trans women were treated with with 100 ug/day of ethinyl estradiol and 100 ug/day of cyproterone acetate.[31]

A study of 51 trans people given hormone therapy and 29 cis controls found no effect on cognitive abilities of hormone treatment over the course of a year. Trans women were given 100 ug/day of oral ethinyl estradiol.[32]

A study of 103 trans women, treated with conjugated equine estrogens or ethinyl estradiol, and in some cases cyproterone acetate and/or medroxyprogesterone acetate, found a slight improvement in digit span after going on estrogen (6.70 on estrogen, 6.00 off estrogen), and a slight improvement in a visual recall test after going off estrogen, but mostly found no effect on a large battery of cognitive tests.[34]

The anti-androgens leuprorelin, goserelin, and cyproterone acetate, when given to men with prostate cancer, caused a drop in one or more cognitive tests in 24/50 men randomized to active treatment, compared to none of the men randomized to placebo.[33]  However, when men treated with anti-androgens were subsequently given estrogen, their memory performance improved.[50]

It seems likely that estrogen has little or no effect on cognitive abilities. Cyproterone acetate taken alone has a negative effect on cognition in cis men, and may contribute to a slight drop in spatial rotation ability in the context of hormone therapy for trans women.

Non-Effects of Hormone Therapy: All-Cause Mortality

In a retrospective study of 816 trans women and 293 trans men, all-cause mortality was not different than in the general population.[47]  In a long-term follow-up study of 2236 trans women and 876 trans men, there was no elevated mortality compared to the general population.[49] In a cohort study of 966 trans women and 365 trans men, the trans women group had 51% higher mortality than the general population, due mostly to suicide, cardiovascular disease, AIDS, and drug abuse; but the use of estrogen among trans women was not an independent predictor of mortality generally or of any cause of mortality except for cardiovascular disease. In other words, trans women are an at-risk population for problems like suicide, drug abuse, and AIDS, but hormone users are at no higher risk than non-users.[48]

Neutral Effects of Hormone Therapy: Brain Morphology

Men and women have structural brain differences. Men have larger brain volumes (and smaller ventricles) than women; they have larger hypothalamuses; and they have a higher fraction of white matter relative to gray matter.

In a study of eight trans women and six trans men, receiving estrogen and cyproterone acetate, and testosterone, respectively, as well as 9 cis male and 6 cis female controls, the trans women had significantly reduced brain and hypothalamus volume, while the trans men had significantly increased brain volume.  Brain volume decreased by a mean of 25 mL in trans women, from 1300 mL to 1275 mL, or about a 2% drop, leaving brain volume somewhere between that of cis men and cis women.[35]  Another study, of 15 trans men on testosterone and 14 trans women on estrogen and an anti-androgen, found that testosterone increased cortical thickness while estrogen and anti-androgens decreased it and increased ventricle size.[36]

While brain volume correlates with IQ,[37] and while some studies find slightly higher mean IQ in men than women (about 3.63 IQ points, extrapolated from the differences in SAT scores in a sample of 100,000)[38], the more common position among IQ researchers is that there are no significant sex differences in mean IQ.[39]  It’s not at all clear that hormone therapy’s effect on shrinking brain volume significantly impairs cognition.

Nonstandard Cases of Cross-Gender Hormone Use

Anti-Androgens May Not Be Necessary

Lower estrogen doses (0.625 mg conjugated estrogen daily) without cyproterone acetate, given to trans women, are sufficient to keep estrogen levels in the normal range for premenopausal women.[9]  7/10 trans women on estrogen alone, without anti-androgens, had testosterone levels drop into the normal female range.[10]  Given that anti-androgens, particularly cyproterone acetate, are responsible for many of the negative side effects of hormone therapy, taking estrogen alone may be a lower-risk approach to hormone therapy.

Risks of Anti-Androgens Without Estrogen: Depression and Cognitive Impairment

Men being treated for prostate cancer are regularly given anti-androgens to suppress the tumor. These men experience significantly elevated rates of anxiety and depression. (This is in contrast to trans women given anti-androgens along with estrogen, who generally experience significant psychological benefit.)

Chemical castration in men significantly reduces estrogen and testosterone levels, and causes significant increases in depression and anxiety scores (though generally subclinical.)[11]  Compared to controls, prostate cancer patients treated with anti-androgens had significant drops in spatial reasoning and executive function, more depressed mood and irritability, less energy and vigor.[12]

The anti-androgen finasteride, given to men as a treatment for hair loss, produced depressive symptoms in 64% of users and 0% of controls in responses to an internet survey (though there may be significant response bias in who chooses to take the survey); finasteride users reported sexual dysfunction, problems with attention and memory, anxiety, depression, and suicidality.[13]  An Iranian prospective study on finasteride found that it increased scores on the Beck depression inventory (p < 0.001) and HADS depression scores (p = 0.005)[14]  A meta-analysis of randomized trials found that finasteride increased the rate of erectile dysfunction, with a relative risk of 2.22 compared to placebo.[55]

Cyproterone acetate in men treated for prostate cancer is associated with declines (compared to placebo) in attention and memory.[15]


Tamoxifen is an selective estrogen-receptor modulator; its primary use is as a breast cancer drug, but it also prevents gynecomastia related to estrogen or anti-androgen use.[40]  It might in principle be possible that if one combines tamoxifen with estrogen, one can get some of estrogen’s feminizing effects without growing breasts, but I couldn’t find any case studies of this being done successfully.

Tamoxifen taken alone does not have feminizing effects on men.  It increases both serum estrogen and testosterone levels in men, and increases sperm count.[41]

Female Hormone Use in Men

Male cross-dressers do sometimes use female hormones, and in past decades the social concept of “transgender” was less sharp than it is today. In early-1990’s radical contexts, “transgender” was considered an umbrella term that would include transvestites, drag queens, feminine gay men, butch lesbians, and other gender-nonconforming people who would not usually be considered “trans” today.[43]

In a 1992 sample of 1032 male cross-dressers, 43% said they “would like to use” hormones and 9% had used or were using hormones; in a 1972 sample of of 504 male cross-dressers, 50% said they “would like to use” hormones and 9% had used or were using hormones. However, the majority of these people viewed themselves as “a man with a feminine side” rather than “a woman trapped in a man’s body,” and did not plan to live full-time as women.[42]

From a biological standpoint, there’s no strong reason to believe that hormones would have different effects depending on whether they’re taken by a person who identifies as trans or not.  Men given estrogen for medical reasons (coronary heart disease) had similar side effects as trans women do, including breast tenderness and growth, testicular shrinkage, sexual dysfunction, and depression upon discontinuing estrogen,[44] but there was no evidence of psychological disturbance as a result of taking estrogen.[45]




[2]Weinand, Jamie D., and Joshua D. Safer. “Hormone therapy in transgender adults is safe with provider supervision; A review of hormone therapy sequelae for transgender individuals.” Journal of Clinical & Translational Endocrinology 2.2 (2015): 55-60.

[3]Kwan, Marie, Judly VanMaasdam, and Julian M. Davidson. “Effects of estrogen treatment on sexual behavior in male-to-female transsexuals: experimental and clinical observations.” Archives of sexual behavior 14.1 (1985): 29-40.

[4]Lidegaard, Øjvind, et al. “Hormonal contraception and risk of venous thromboembolism: national follow-up study.” Bmj 339 (2009): b2890.

[5]Bourgeois, Anne Laure, et al. “Risk of hormonotherapy in transgender people: Literature review and data from the French Database of Pharmacovigilance.” Annales d’endocrinologie. Vol. 77. No. 1. Elsevier Masson, 2016.

[6]Pringsheim, Tamara, and Louis Gooren. “Migraine prevalence in male to female transsexuals on hormone therapy.” Neurology 63.3 (2004): 593-594.

[7]Aloisi, Anna Maria, et al. “Cross-sex hormone administration changes pain in transsexual women and men.” Pain 132 (2007): S60-S67.

[8]Sofer, Yael, et al. “SAT-0111: High Prolactin Levels in Transsexual Women Are Related to the Anti-Androgen Treatment Modality.”

[9]Cunha, Flávia Siqueira, et al. “MON-595: Low estrogen doses are effective to keep estradiol and testosterone serum levels at normal premenopausal women in male-to-female transsexuals.” (2013).

[10]Spratt, Lindsey V., et al. “OR42-2: Efficacy of Testosterone (T) or Estradiol (E2) Therapy without a GnRH Agonist or Progestin to Suppress Endogenous Gonadal Activity in Transsexual Patients.” (2014).

[11]Almeida, Osvaldo P., et al. “One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men.” Psychoneuroendocrinology 29.8 (2004): 1071-1081.

[12]Cherrier, M. M., S. Aubin, and C. S. Higano. “Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non‐metastatic prostate cancer.” Psycho‐Oncology 18.3 (2009): 237-247.

[13]Ganzer, Christine Anne, Alan Roy Jacobs, and Farin Iqbal. “Persistent Sexual, Emotional, and Cognitive Impairment Post-Finasteride A Survey of Men Reporting Symptoms.” American journal of men’s health 9.3 (2015): 222-228.

[14]Rahimi-Ardabili, Babak, et al. “Finasteride induced depression: a prospective study.” BMC Pharmacology and Toxicology 6.1 (2006): 7.

[15]Green, Heather J., et al. “Altered cognitive function in men treated for prostate cancer with luteinizing hormone‐releasing hormone analogues and cyproterone acetate: A randomized controlled trial.” BJU international 90.4 (2002): 427-432.

[16]Colizzi, Marco, Rosalia Costa, and Orlando Todarello. “Transsexual patients’ psychiatric comorbidity and positive effect of cross-sex hormonal treatment on mental health: results from a longitudinal study.”Psychoneuroendocrinology 39 (2014): 65-73.

[17]Newhouse, Paul A., et al. “Estrogen administration negatively alters mood following monoaminergic depletion and psychosocial stress in postmenopausal women.” Neuropsychopharmacology 33.7 (2008): 1514-1527.

[18]Epperson, C. Neill, Katherine L. Wisner, and Bryan Yamamoto. “Gonadal steroids in the treatment of mood disorders.” Psychosomatic Medicine 61.5 (1999): 676-697.

[19]Björn, Inger, et al. “Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy.” The Journal of Clinical Endocrinology & Metabolism 88.5 (2003): 2026-2030.

[20]Newhouse, Paul A., et al. “Estrogen administration negatively alters mood following monoaminergic depletion and psychosocial stress in postmenopausal women.” Neuropsychopharmacology 33.7 (2008): 1514-1527.

[21]Wharton, Whitney, et al. “Neurobiological underpinnings of the estrogen-mood relationship.” Current psychiatry reviews 8.3 (2012): 247-256.

[22]Wang, Mingde, et al. “Treatment of premenstrual syndrome by spironolactone: A double‐blind, placebo‐controlled study.” Acta obstetricia et gynecologica Scandinavica 74.10 (1995): 803-808.

[23]Fisher, Alessandra D., et al. “Cross‐sex hormonal treatment and body uneasiness in individuals with gender dysphoria.” The journal of sexual medicine 11.3 (2014): 709-719.

[24]Smith, Yolanda LS, Stephanie HM van Goozen, and Peggy T. Cohen-Kettenis. “Adolescents with gender identity disorder who were accepted or rejected for sex reassignment surgery: a prospective follow-up study.” Journal of the American Academy of Child & Adolescent Psychiatry 40.4 (2001): 472-481.

[25]Treleaven, Michelle MM, et al. “Castration and personality: Correlation of androgen deprivation and estrogen supplementation with the Big Five factor personality traits of adult males.” Journal of Research in Personality 47.4 (2013): 376-379.

[26]Asscheman, Henk, and Louis JG Gooren. “Hormone treatment in transsexuals.” Journal of Psychology & Human Sexuality 5.4 (1993): 39-54.

[27]Smith, Yolanda LS, et al. “Sex reassignment: Outcomes and predictors of treatment for adolescent and adult transsexuals.” Psychological medicine35.01 (2005): 89-99.

[28]Hembree, Wylie C., et al. “Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline.” The Journal of Clinical Endocrinology & Metabolism 94.9 (2009): 3132-3154.

[29]Lapauw, Bruno, et al. “Body composition, volumetric and areal bone parameters in male-to-female transsexual persons.” Bone 43.6 (2008): 1016-1021.

[30]Wierckx, Katrien, Louis Gooren, and Guy T’Sjoen. “Clinical review: Breast development in trans women receiving cross‐sex hormones.” The journal of sexual medicine 11.5 (2014): 1240-1247.

[31]Van Goozen, Stephanie HM, et al. “Gender differences in behaviour: Activating effects of cross-sex hormones.” Psychoneuroendocrinology 20.4 (1995): 343-363.

[32]Haraldsen, Ira R., et al. “Cross-sex hormone treatment does not change sex-sensitive cognitive performance in gender identity disorder patients.”Psychiatry research 137.3 (2005): 161-174.

[33]Green, Heather J., et al. “Altered cognitive function in men treated for prostate cancer with luteinizing hormone‐releasing hormone analogues and cyproterone acetate: A randomized controlled trial.” BJU international 90.4 (2002): 427-432.

[34]Miles, Clare, Richard Green, and Melissa Hines. “Estrogen treatment effects on cognition, memory and mood in male-to-female transsexuals.” Hormones and Behavior 50.5 (2006): 708-717.

[35]Pol, Hilleke E. Hulshoff, et al. “Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure.”European Journal of Endocrinology 155.suppl 1 (2006): S107-S114.

[36]Zubiaurre‐Elorza, Leire, et al. “Effects of Cross‐Sex Hormone Treatment on Cortical Thickness in Transsexual Individuals.” The journal of sexual medicine 11.5 (2014): 1248-1261.

[37]Posthuma, Daniëlle, et al. “The association between brain volume and intelligence is of genetic origin.” Nature neuroscience 5.2 (2002): 83-84.

[38]Jackson, Douglas N., and J. Philippe Rushton. “Males have greater g: Sex differences in general mental ability from 100,000 17-to 18-year-olds on the Scholastic Assessment Test.” Intelligence 34.5 (2006): 479-486.

[39]Halpern, Diane F., and Mary L. LaMay. “The smarter sex: A critical review of sex differences in intelligence.” Educational Psychology Review 12.2 (2000): 229-246.

[40]Parker, Lawrence N., et al. “Treatment of gynecomastia with tamoxifen: a double-blind crossover study.” Metabolism 35.8 (1986): 705-708.

[41]Vermeulen, Alex, and Frank Comhaire. “Hormonal effects of an antiestrogen, tamoxifen, in normal and oligospermic men.” Fertility and sterility 29.3 (1978): 320-327.

[42]Docter, Richard F., and Virginia Prince. “Transvestism: A survey of 1032 cross-dressers.” Archives of Sexual Behavior 26.6 (1997): 589-605.

[43]Valentine, David. Imagining transgender: An ethnography of a category. Duke University Press, 2007.

[44]Robinson, Roger W., Norio Higano, and William D. Cohen. “Long-term effects of high-dosage estrogen therapy in men with coronary heart disease.”Journal of chronic diseases 16.2 (1963): 155-161.

[45]Kaplan, Benjamin M., and Jerome Grunes. “Emotional aspects of estrogen therapy in men with coronary atherosclerosis.” JAMA 183.9 (1963): 734-736.

[46]Klein, Carolin, and Boris B. Gorzalka. “Continuing Medical Education: Sexual Functioning in Transsexuals Following Hormone Therapy and Genital Surgery: A Review (CME).” The Journal of Sexual Medicine 6.11 (2009): 2922-2939.

[47]Van Kesteren, Paul JM, et al. “Mortality and morbidity in transsexual subjects treated with cross‐sex hormones.” Clinical endocrinology 47.3 (1997): 337-343.

[48]Asscheman, Henk, et al. “A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones.” European Journal of Endocrinology 164.4 (2011): 635-642.

[49]Gooren, Louis J., Erik J. Giltay, and Mathijs C. Bunck. “Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience.”The Journal of Clinical Endocrinology & Metabolism 93.1 (2008): 19-25.

[50]Beer, Tomasz M., et al. “Testosterone loss and estradiol administration modify memory in men.” The Journal of urology 175.1 (2006): 130-135.

[51]Basaria, Shehzad, et al. “Long‐term effects of androgen deprivation therapy in prostate cancer patients.” Clinical endocrinology 56.6 (2002): 779-786.

[52]Hembree, Wylie C., et al. “Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline.” The Journal of Clinical Endocrinology & Metabolism 94.9 (2009): 3132-3154.

[53]Thiagaraj, D., et al. “Histopathology of the testes from male transsexuals on oestrogen therapy.” Annals of the Academy of Medicine, Singapore 16.2 (1987): 347-348.

[54]Lübbert, Horst, Inka Leo-Roßberg, and Jürgen Hammerstein. “Effects of ethinyl estradiol on semen quality and various hormonal parameters in a eugonadal male.” Fertility and sterility 58.3 (1992): 603-608.

[55]Mella, José Manuel, et al. “Efficacy and safety of finasteride therapy for androgenetic alopecia: a systematic review.” Archives of dermatology 146.10 (2010): 1141-1150.


Epistemic status: medium

There are a lot of drugs and supplements reputed to improve cognitive function.  I was sick of relying on hearsay and anecdote, so I did my best attempt at a systematic overview of what works and what doesn’t.


Caffeine, modafinil, amphetamine, methylphenidate, and maybe a discontinued nicotinic-receptor agonist drug called ispronicline, have really big effects on cognitive function in healthy people.

Caffeine and modafinil work significantly better in sleep-deprived than non-sleep-deprived people.

Caffeine, nicotine, and amphetamine, in contrast to methylphenidate and modafinil, do not improve memory performance or accuracy on cognitive tasks in healthy people, but only reaction time.  In other words: caffeine, nicotine, and amphetamine make you more alert but not smarter; methylphenidate and modafinil also seem to improve memory.

Amphetamine and modafinil work better on people with the COMT val/val phenotype (who tend to be less intelligent) and may be ineffective or counterproductive on COMT met/met phenotype people.

All of the above (caffeine, nicotine, modafinil, amphetamine, and methylphenidate) cause some tolerance.

Cerebrolysin, a mixture of neural growth factors, apparently works really well on Alzheimer’s patients, though there’s fewer studies of it than more common Alzheimer’s drugs.  It might extrapolate to people with other kinds of neurodegenerative problems, or to slow the effects of aging.

Cognitive training (memorization practice including spaced repetition) works moderately well on Alzheimer’s patients and schizophrenics.  It’s quite plausible that it’s also good for healthy people.

Healthy people can get small positive effects from nicotine, possibly the herb Bacopa monniera, and from transcranial magnetic stimulation.

Alzheimer’s patients can get small effects from cholinesterase inhibitors (which are standard Alzheimer’s drugs); from a mixture of vitamins, fatty acids, choline, and uridine; from melatonin, the hormone which regulates sleep; and from the amino acid derivative acetyl-l-carnitine. Apart from the cholinesterase inhibitors (which have GI side effects) these are safe for healthy people to take, but it’s not known whether they affect cognitive function in healthy people.


only looked at published studies on cognitive outcomes in humans: tests of memory, reaction time, and the like.  No animal studies. No measurements of neural correlates or biomarkers. To show up in my list, it has to make humans perform better.  I didn’t restrict attention to healthy humans, however; a lot of the studies on cognitive enhancement are performed on subjects with diseases like Alzheimer’s or schizophrenia, so I included some of those, under the suspicion that they might generalize to healthy people.

I ranked nootropics by effect size. That is, Cohen’s d, the difference in mean outcome between treatment and control groups divided by the pooled standard error.

Assume that a trait, like your score on an exam, has a Gaussian distribution. Suppose you have some treatment that increases the mean score in the treatment vs. the control group. Then you can divide by the (pooled) standard deviation of the score to get an estimate of how big a difference the treatment makes, compared to the population variation in the trait. Does it increase your score by one standard deviation? That’s an effect size of one.  Does it increase your score by half a standard deviation? That’s an effect size of 0.5.

This allows us to compare “how big an effect” different interventions have, along one scale, even if they’re acting on different traits. If drug A improves your reaction times by two standard deviations, and drug B improves your memory by half a standard deviation, you can still say that drug A has a larger effect than drug B, even though the effect isn’t on the same thing.

Conventionally, an effect size of 0.2-0.3 is a “small” effect, around 0.5 is a “medium” effect, and anything greater than 0.8 is a “large” effect. Most drugs used in psychiatry have effect sizes around 0.5.  Intuitively, effect sizes of about 0.5 look like “sorta works” to the naked eye. Effect sizes greater than 1 look like “holy shit, that’s an unmistakable effect” to the naked eye.

Anything with a p-value of <0.05 (but not <0.01) I didn’t include in the table of best nootropics, because the vast majority of studies with such high p-values don’t replicate.  I also didn’t include things in the table if they were shown to not work on healthy subjects (even if they did work on ill subjects).  When there was conflict between studies, I erred on the conservative side and chose smaller effect sizes.


Drug Effect Size Trait
Modafinil, Caffeine 2-3 Executive function in sleep deprived people
Modafinil, Caffeine 2-3 Wakefulness in sleep deprived people
Ispronicline 2.5 Attention and episodic memory in healthy people
Amphetamine 2.3 Reaction time in healthy people
Cerebrolysin 1.8-2.2 ADAS-cognitive test in Alzheimer’s patients
Methylphenidate 1.4 Memory in healthy non-sleep-deprived people
Modafinil 1.22 Working memory in sleep deprived people
Caffeine 0.7 Reaction time in non-sleep-deprived healthy people
Nicotine 0.7 Attention in schizophrenics
Modafinil 0.56 Attention in non-sleep-deprived healthy people
Melatonin 0.56 ADL’s for Alzheimer’s patients
Cognitive training (including spaced repetition) 0.43-0.47 Various cognitive tests and ADL’s for Alzheimer’s patients and schizophrenic patients
Bacopa monniera 0.32 Learning rate in healthy people
Nicotine 0.3 Reaction times in smokers and nonsmokers
Cholinesterase inhibitors 0.2-0.5 ADAS-cognitive test in Alzheimer’s patients
rTMS 0.2-0.3 Working memory and reaction time in healthy subjects
Souvenaid 0.23 Memory in Alzheimer’s patients
Acetyl-L-carnitine 0.2 Various cognitive tests in Alzheimer’s patients



ALCAR, or acetylcarnitine, is an amino acid derivative used in the metabolism of fatty acids.

A meta-study of 21 studies of Alzheimer’s patients found a median effect size of 0.2, with a total of 499 patients, across various cognitive tests.


Amphetamine is a dopaminergic stimulant drug.

Amphetamine improved working-memory performance in healthy subjects only if they had low performance at baseline, and worsened it in those who had high performance at baseline.[4]

Improves working memory on healthy val/val COMT subjects, doesn’t, or deteriorates it, on met/met subjects. (“Warriors” benefit, “worriers” do not.)[38]

Improves reaction time on a movement estimation task (effect size: 2.3) but not digit span.[39]

Bacopa monniera

Bacopa monniera is a plant traditionally supposed to improve memory. The active ingredient is bacoside, a triterpenoid saponin.

Randomized study of 46 healthy adults, AVLT learning rate after 12 weeks is better, effect size 0.32, a significant effect at p < 0.01.  State anxiety also lower, p < 0.001. No effect on digit span.[33] No effects on memory.[34]


Caffeine is the most commonly used psychoactive chemical worldwide, and is a stimulant that works by adenosine receptor antagonism.

Cross-sectional study of 9003 adults finds that higher habitual coffee and tea consumption has a significant dose-response relationship (p < 0.001) with performance tests of memory, visuospatial reasoning, and reaction time, suggesting that tolerance to caffeine is incomplete and caffeine does cause higher absolute levels of cognitive performance.[1]

Metastudy found that caffeine had no effect on free recall in most short-term memory studies. It does reliably improve reaction time.  Reduces the risk of sleep-deprivation-related work accidents by about two-fold.  Generally improves cognitive performance more in sleep-deprived than in non-sleep-deprived subjects. Caffeine improves cognitive function in elderly subjects more than in young (20-60) subjects, and regular caffeine consumers have less (half as much) age-related cognitive decline.[20]

Caffeine improves reaction time over placebo with an effect size of 0.7[21]


Cerebrolysin is a mixture of neurotrophic peptides derived from pig brains, including BDNF, GDNF, NGF, and CNTF. It may have a neuroprotective or neurorestorative effect.

Randomized study of 279 Alzheimer patients found scores on the cognitive subscale of the ADAS improved by 4 points on Cere vs. placebo, effect size of 1.86, p = 0.03.  Global clinical outcome significantly better than placebo (p < 0.001).[27]  A randomized trial of 149 Alzheimer patients found an effect size of 2.22, improvement of 3.2 on the ADAS-cog on Cerebrolysin vs. placebo, p < 0.001.[28]  Effect size of 2 on elderly controls on the ADAS-cog.[67]

Cholinesterase inhibitors

This is a class of drugs used for Alzheimer’s disease, including donepezil and galantamine.  A meta-study found they had median effect size 0.28 on the ADAS-Cog for high-dose studies, 0.15 for low dose.[48]  Another meta-study found they had mean effect size 0.1 for ADLs in Alzheimer’s and there’s no difference between cholinesterase inhibitors.

Cognitive Training

For Alzheimer’s disease. Mostly these are memory practice games or drills, many of which are spaced repetition. Across various measurements of outcome (CPT, memory tests, IADLs, etc) median effect size was 0.47.[50] A metastudy of cognitive remediation for schizophrenia found a median effect size of 0.43 across various cognitive tests.[56]


Donepezil is an acetylcholinesterase inhibitor used in Alzheimer’s.

Effect size of 1.25 on ADAS-Cog in Alzheimer’s patients (p < 0.001).[51]  Odd that it is so much better than “cholinesterase inhibitors” as a class.  Doesn’t affect progression to Alzheimer’s in mild cognitive impairment.[53] Effect size of 0.6 on the MMSE in Parkinson’s patients, p = 0.0013.[54]  One study showed that donepezil did not have an effect in mild cognitive impairment.[55] Doesn’t work on schizophrenics either. [58]  Did not have an effect on healthy elderly volunteers on cognitive tasks.[66]  I’m going to take the conservative, lower estimates that effect sizes are around 0.2 or 0.5.


Erythropoietin is a hormone that increases red blood cell production.

It improves working memory, verbal processing, and Wisconsin Card Sorting scores significantly over placebo in schizophrenic patients.[8]  Significantly improves (p < 0.01) sustained attention and information processing speed in bipolar patients.[72] “EPO acts in an antiapoptotic, anti-inflammatory, antioxidant, neurotrophic, angiogenetic, stem cell–modulatory fashion” so it’s investigated as a neuroprotective for stroke and neurodegenerative diseases, but so far mostly in animals.[42]


Galantamine is an acetylcholinesterase inhibitor used in Alzheimer’s.

Effect size of 8.18 (?!) in Alzheimer’s patients after 6 months; slows cognitive decline.[59] After 3 months, effect size of 2.4 in Alzheimer’s patients, p = 0.002.[63] Galantamine is better than donepezil for Alzheimer’s ADAS-Cog and MMSE.[64] On schizophrenics, effect size of 0.89 in schizophrenic patients on RBANS test, one standard deviation up on the memory subscale, effectively normalizing performance.[60] A much larger randomized study on schizophrenics, however, found no overall effect. [61]  Metastudy on galantamine vs. donezepil for Alzheimers found much weaker effects: 0.48 effect size for donepezil and 0.52 for galantamine.[65]


Panax ginseng is a plant traditionally used as an “adaptogen” to increase alertness and endurance; the active ingredients are triterpinoid saponins called ginenosides.

In a controlled trial of Alzheimer’s, ginseng improves performance on MMSE and ADAS scales after 12 weeks (p = 0.009 and 0.029 respectively) and declined to baseline after discontinuation.[6] Reduces blood glucose acutely (p < 0.001) in 30 healthy volunteers [40] and improves performance at p < 0.05 at “repeated sevens” task. Effect size of 1-2, but since effects were only slightly significant here and were not in other tasks, there’s some reason for skepticism.  This study found that it didn’t improve working memory or reaction time but did improve the “quality of memory” subscore.[41]


Ispronicline is a nicotinic receptor agonist.  The company that produced it, Targacept, appears to have gone out of business, and the drug was discontinued after it failed to make progress on Alzheimer’s.

It significantly improves measures of attention & episodic memory on healthy male volunteers vs. placebo. Also increases upper alpha peak on EEGs.[44]  2.5 effect size, p < 0.01 for 50 mg AZD vs. placebo for elderly patients on attention, episodic memory, and SDI-cog.[46]   Not statistically significantly effective on Alzheimer’s.[45] 


This is a precursor to dopamine, used as a treatment for Parkinson’s disease.

Slightly reduces reaction time in healthy subjects, p < 0.05.[74]  Some healthy subjects develop side effects of nausea and excitation under L-Dopa, and these have slower reaction time than placebo; those who don’t have adverse effects have faster reaction times, p = 0.02.[75]


Melatonin is the hormone that regulates sleep cycles, often taken as a sleep aid.

Significant (p = 0.004) improvement in IADL score (activities of daily living, effect size 0.56) on 80 Alzheimer’s patients.[25]


Methylphenidate is a stimulant that works by dopamine reuptake inhibition and is used as a treatment for ADD.

Meta-analysis finds a large effect size (1.4) in memory on healthy non-sleep-deprived subjects, but no other improvements on executive function, attention, or mood.  Does not reduce sleepiness after sleep deprivation.[17]


Modafinil is a stimulant that works primarily by histamine agonism.

Significantly improves digit span (by 1-2 digits) and improved pattern recognition (by 8 percentage points), fewer stop errors & lower stop signal reaction time, better spatial planning.[11]

Significant effects (in a meta-study) on working memory, digit span, reaction time, in most studies; no effect on Stroop, spatial planning, verbal fluency; no effect at all on high-IQ population.[14]

Does not cause overconfidence vs. placebo.[15]

Improves performance in a mean 100 IQ group, but not a mean 115 IQ group.[16]

Meta-study founds a moderate improvement on attention (0.56) in healthy non-sleep-deprived individuals. No changes in mood, memory, or motivation.  In sleep-deprived individuals, has a large (2-3) effect size on executive function, a large effect size (1.22) on memory, and a large effect size on wakefulness (2-3).[17]

Comparable alertness and performance effects for 200 or 400 mg modafinil vs. 600 mg caffeine (6 cups of coffee) in sleep-deprived patients.[18]  Caffeine, amphetamine, and modafinil are comparably effective in increasing alertness & reaction time in sleep-deprived patients.[9]


Nicotine is a stimulant and nicotinic acetylcholine receptor agonist.

4-week nicotine skin patch improves performance on continuous performance test vs. placebo in 8-person trials of Alzheimer’s.[3]

In abstinent smokers, nicotine improves performance on all tests; in never-smokers, produces faster reaction times but more errors.

6-month trial on schizophrenics improves performance on the CPT with an effect size of 0.7.[22]

A meta-analysis found that nicotine improved working memory reaction time in both smokers and nonsmokers, effect size 0.34, but did not improve accuracy; also improved reaction time in orienting attention, effect size 0.34, and alerting attention, 0.3


Breathing high-oxygen air increases blood oxygen concentration.

It improves word recall vs. placebo in healthy subjects, but only at a p < 0.05 level.  Reaction time lowered, p < 0.0005.  No effect on working memory.[10]  Effect size on word recall and reaction time in another study on healthy subjects was ~2.5, p < 0.05.[43]


Piracetam has an unknown mechanism of action but is sometimes used as a nootropic.

In a metastudy of piracetam for cognitive impairment (mostly age-related), 63.9% were improved on piracetam vs. 34.1% on placebo. Fixed-effects model OR is 3.35.[29]  Doesn’t work on Alzheimer’s.[69]


PRL-8-53 is an experimental compound with some cholinergic properties.

Significant (p < 0.01) improvement in word retention over placebo; 30-45% improvements in # of words retained.[26]


Repetitive transcranial magnetic stimulation involves placing a magnetic coil near the head of the subject and produces small electric currents in the brain.

A meta-study found improvements with effect size of 0.2-0.3 in working memory and response times on healthy subjects on n-back tasks.[12]


Semax is a Russian nootropic that seems to work by stimulate nerve growth factors.

Significant 74% improvement over placebo on memorization exam in power plant operators.[24]  Most of the other evidence about Semax is from Russian rat studies.


Souvenaid is a cocktail containing essential fatty acids, vitamins, uridine, and choline, used to treat Alzheimer’s.  

A randomized 24-week trial on Alzheimer’s patients found that it improved the memory subscore on the NTB with an effect size of 0.23.[68]


Tandospirone is a serotonin partial agonist, similar to buspirone, used for anxiety and depression.

In schizophrenic patients, improves performance on Wechsler Memory Scale and Wisconsin Card Sorting, p < 0.001 and 0.0001 respectively, effect sizes of 0.63 and 0.7.[4]  However, tandospirone impaired memory in healthy subjects.[71]


Tianeptine is an antidepressant that seems to work by enhancing dopamine release, enhancing BDNF, and/or targeting opioid receptors.

In an uncontrolled trial of depressed patients, tianeptine improved working memory and reaction time.[23]  Did not affect memory, attention, or psychomotor performance on young healthy volunteers.


Tolcapone is a COMT inhibitor used in the treatment of Parkinson’s.

Tolcapone improves memory for val/val COMT healthy subjects, but worsens it for met/met. (“Warriors” benefit, “worriers” don’t.)  Effect size of about 0.8, p < 0.05 on the val/val’s.[73]

B vitamins

No effect on elderly subjects. [7]


Creatine is a compound that occurs naturally in vertebrates and supplies ATP to muscles.

No effect on cognitive function on healthy young adults.[35]  Does have effects on memory in the elderly [36] (d = 1.5, p < 0.001 for backward digit span) and vegetarians [37]


D-cycloserine is an amino acid derivative and antibiotic.

Doesn’t improve cognitive function/digit span in schizophrenics.[57]


DHEA is a steroid hormone and precursor to estrogen and testosterone.

No effect on elderly subjects.[5]

Dual N-Back

Dual N-back is a memory practice game.

Metastudy shows that, while performance on the N-back task improves, no crossover improvement on IQ tests occurs.[13]

Gingko Biloba

Fails to find effect on cognitive performance on Stroop test in MS patients.[2]  Also fails to prevent cognitive decline in older adults.[76]g


Oxiracetam is in the racetam class of drugs, unknown mechanism of action.

Doesn’t work on Alzheimer’s. [32]


Selegiline is an MAOB inhibitor used in Parkinson’s and depression.

Not effective on cognitive performance in Alzheimer’s.[30]  Doesn’t help in Parkinson’s either.[31]


Tarenflurbil is a discontinued putative Alzheimer’s drug that destroys amyloid plaques.

Doesn’t slow cognitive decline in Alzheimer’s.[49]


Unsurprisingly, the classic stimulants do quite well. (Caffeine, nicotine, amphetamine, methylphenidate, modafinil.)  Ispronicline is less well known and its evidence base is much smaller, but since it’s also a nicotinic receptor agonist, it’s possible that it also belongs in this category.

Cerebrolysin is interesting. It’s a legal anti-Alzheimer’s drug in Europe, and one of the few drugs that directly focuses on neural growth factors. These are known (mostly in animal studies) to be protective against brain damage, as from stroke or Parkinson’s.  Deficiency in BDNF is also one of the current hypotheses for what’s going wrong in depression.  “Just give people some growth factors” might be one of these simple obvious-in-retrospect things that could pan out to be widely effective.  In animal studies, growth factor gene therapy often has neuroprotective effects, and Nobel Prize-winning neuroscientist Rita Levi-Montalcini took daily NGF eyedrops.

There’s a common pattern in anything dopaminergic (such as: amphetamines, tolcapone, L-dopa, etc) that they improve cognitive performance in people who have “too little dopamine” (Parkinson’s patients, ADHD patients, val/val COMT genotypes) but are useless or worse in those who have “too much dopamine” (met/met COMT genotypes.)  This seems like a fairly robust finding, across many drugs as well as a lot of fMRI studies about dorsolateral prefrontal cortex activation.  How good dopaminergics are for your mental performance may depend a lot on who you are.



[1]Jarvis, Martin J. “Does caffeine intake enhance absolute levels of cognitive performance?.” Psychopharmacology 110.1-2 (1993): 45-52.

[2]Lovera, Jesus, et al. “Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial.”Multiple Sclerosis (2007).

[3]White, Heidi K., and Edward D. Levin. “Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease.”Psychopharmacology 143.2 (1999): 158-165.

[4]Mattay, Venkata S., et al. “Effects of dextroamphetamine on cognitive performance and cortical activation.” Neuroimage 12.3 (2000): 268-275.

[5]Wolf, Oliver T., et al. “Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men 1.” The Journal of Clinical Endocrinology & Metabolism 82.7 (1997): 2363-2367.

[6]Lee, Soon-Tae, et al. “Panax ginseng enhances cognitive performance in Alzheimer disease.” Alzheimer Disease & Associated Disorders 22.3 (2008): 222-226.

[7]McMahon, Jennifer A., et al. “A controlled trial of homocysteine lowering and cognitive performance.” New England Journal of Medicine 354.26 (2006): 2764-2772.

[8]Ehrenreich, H., et al. “Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin.” Molecular psychiatry 12.2 (2007): 206-220.

[9]Dunbar, G., et al. “Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers.” Psychopharmacology 191.4 (2007): 919-929.

[10]Moss, Mark C., Andrew B. Scholey, and Keith Wesnes. “Oxygen administration selectively enhances cognitive performance in healthy young adults: a placebo-controlled double-blind crossover study.”Psychopharmacology 138.1 (1998): 27-33.

[11]Turner, Danielle C., et al. “Cognitive enhancing effects of modafinil in healthy volunteers.” Psychopharmacology 165.3 (2003): 260-269.

[12]Brunoni, André Russowsky, and Marie-Anne Vanderhasselt. “Working memory improvement with non-invasive brain stimulation of the dorsolateral prefrontal cortex: a systematic review and meta-analysis.” Brain and cognition 86 (2014): 1-9.

[13]Redick, Thomas S., et al. “No evidence of intelligence improvement after working memory training: a randomized, placebo-controlled study.” Journal of Experimental Psychology: General 142.2 (2013): 359.

[14]Minzenberg, Michael J., and Cameron S. Carter. “Modafinil: a review of neurochemical actions and effects on cognition.” Neuropsychopharmacology33.7 (2008): 1477-1502.

[15]Baranski, Joseph V., et al. “Effects of modafinil on cognitive and meta‐cognitive performance.” Human Psychopharmacology: Clinical and Experimental 19.5 (2004): 323-332.

[16]Randall, Delia C., John M. Shneerson, and Sandra E. File. “Cognitive effects of modafinil in student volunteers may depend on IQ.” Pharmacology Biochemistry and Behavior 82.1 (2005): 133-139.

[17]Repantis, Dimitris, et al. “Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review.”Pharmacological Research 62.3 (2010): 187-206.

[18]Wesensten, Nancy, et al. “Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine.” Psychopharmacology 159.3 (2002): 238-247.

[19]Wesensten, Nancy J., William DS Killgore, and Thomas J. Balkin. “Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation.” Journal of sleep research 14.3 (2005): 255-266.

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Contra Science-Based Medicine

Epistemic status: hand-wavy, but making a serious point

TW: diets.

I recently did some reading about ketogenic diets for cancer, and I’d like to compare and contrast my approach with the explanation on the blog Science-Based Medicine, which consistently presents the “skeptical” perspective on alt-med questions.

David Gorski is a cancer biologist himself, as I am not; his posts are always informative, and I have no quarrel with his facts. I read the studies mentioned in the post, so we’re using pretty much the same set of data points. And I agree with the broad outlines of his claims: ketogenic diets have some promising but by no means conclusive preclinical evidence for brain cancers; they’re definitely not a substitute for chemotherapy in general; and Dr. Seyfried has been overselling his research as a cure for cancer in disreputable alt-med venues.

But I want to pick apart some points of perspective and interpretation.

The first part of the post is all about painting Seyfried as disreputable because of his associations with alt-med institutions. Gorski says of the American College for Advancement in Medicine, “this is not an organization with which a scientist who wishes to be taken seriously by oncologists associates himself.”

Now, I’m not defending the cancer quacks mentioned; these are people who pitch chelation and coffee enemas, things that are pretty clearly scientifically disproven.  However, I’m suspicious of the rhetorical trick of guilt by association and argument from consensus.  Surely we care about whether Seyfried is correct, not whether he is “taken seriously”, “reputable”, or “legitimate.”  These are all social words, not scientific ones, and constitute an emotional appeal to social conformity and authority.

To his credit,  Gorski doesn’t stop there; he does make substantive criticisms of Seyfried’s work.  But I think it’s worth pointing out when, as happens so often in the biomedical world, a social argument is conflated with a scientific one.

Gorski goes on to criticize Seyfried for “exaggerating how hostile the cancer research community is towards metabolism as an important, possibly critical, driver of cancer” when cancer metabolism is, in fact, an active area of current cancer research.  He goes on to say, “Dr. Seyfried, in my readings, appears all too often to speak of “cancer” as if it were a monolithic single disease. As I’ve pointed out many times before, it’s not. Indeed, only approximately 60-90% of cancers demonstrate the Warburg effect.”

None of these facts are wrong, but the interpretation is misleading. Cancer metabolism and metabolic mechanisms for cancer treatments are, in fact, common topics of cancer research; but this ought to be evidence in favor of Seyfried’s hypothesis, that it’s within the range of mainstream science and is supported by many cancer biologists, rather than being pure invention like most alt-med “cancer cures.”

I’d also argue with the statement that “cancer isn’t one disease.”  It’s true that not all cancers demonstrate the Warburg effect, but 60-90% is a lot of cancers; a drug that was effective in 60-90% of cancers would be as revolutionary an advance as chemotherapy.  An antibiotic that killed 60-90% of bacteria could fairly be said to “kill bacteria.” When most (if not all) cancers have structural features in common, that indicates that talking generally about “cancer” is meaningful, and that it doesn’t make sense to treat every sub-sub-type as though it is a completely different disease.  Cancer has both unity and diversity.  Saying “cancer isn’t one disease” is a rhetorically loaded move that means “don’t generalize from one type of cancer to another.”  But it’s not correct to never generalize; that would utterly paralyze research.  How much it’s safe to generalize depends on how common the relevant feature is across cancers; in the case of the Warburg effect, that’s a matter of current debate, but it’s fair to call it pervasive.

I don’t have much criticism of the way Gorski handles the ketogenic diet studies. He’s on the skeptical side, but skepticism is warranted. Mouse studies very frequently don’t generalize to humans; they’re suggestive, but only weak evidence. And while there were two case studies of patients who did notably better than typical glioblastoma patients on ketogenic diets, we don’t have enough patients to be confident that the improvements were a result of the diet.

But then Gorski says, “Clearly, ketogenic diets are not ready for prime time as a treatment for cancer.”

Now, wait a minute. What does that even mean?

As a cancer patient, does it make sense for you to try a ketogenic diet?  Well, there’s a plausible mechanism for it to work (particularly in brain cancer), there’s some suggestive evidence in mice and a few humans with brain cancers, and — crucially — it’s just a diet.  People go on ketogenic diets all the time, for no other reason than wanting to lose weight. It’s even been shown medically safe (though apparently hard to comply with) in cancer patients. Trying a special diet is pretty low risk, and a reasonable person aware of the evidence might very well choose to try it.

It doesn’t make sense to use a ketogenic diet as a replacement for chemotherapy or radiotherapy in cancers where those treatments work. That would be very unsafe.  But for certain advanced brain cancers, chemo barely extends life if at all, and is very unpleasant. If there’s anyone who has a good reason to refuse chemotherapy, it’s someone who’s almost certain to die soon and doesn’t want their last few months to be agonizing.

Is a ketogenic diet for cancer something that every oncologist in the world should be prescribing for his patients? No way. Should it be the “standard of care”? No; there isn’t enough evidence that it helps.  But is it worth trying for an individual who wants to? Quite possibly.

The distinction here is about where you put the reader’s locus of identity. Is a reader supposed to imagine herself as a potential cancer patient, considering whether or not to try the diet? Or as a potential administrator, considering whether or not to make the diet a policy for everyone?  The rhetorical trick Gorski’s using here is in identifying the reader with a nebulous “we”, as in “should we put cancer patients on ketogenic diets?”  You are meant to imagine a consensus, or an authoritative body.  The medical profession, the government, something like that.  This imagined “we” is the mirror image of the nebulous “they” that conspiracy theorists believe in, the “they” who doesn’t want you to know about cancer cures.

The overall effect of believing in an imagined “we” or an imagined “they” is to make social reality the primary reality.  “We” or “they” represents a vague model of “society” — the “respectable” people, the “legitimate” and “reputable” people, the “consensus”. In other words, the tribal elders. If you have a positive association with “the consensus”, as Gorski clearly does, then you want to expel the “disreputable” from the consensus.  If you have a negative association with “the consensus”, then you mistrust anything that sounds official and look for fellow mavericks and outsiders.  In neither case are you primarily evaluating claims of fact; you are evaluating people.

For instance, the existence of Phase I/II trials of the ketogenic diet on glioblastoma ought to be good news for ketogenic diets.  More evidence will soon come in; and the fact that the studies exist at all is further evidence that ketogenic diets are taken seriously by mainstream cancer researchers.  However, Gorski treats this as an indictment of Seyfried, because he wanted to do an (uncontrolled) case series of ketogenic diets rather than the more thorough controlled studies.  The overall intent of the blog post is to communicate Seyfried is disreputable, cancer is complicated, people who believe in cancer cures are beyond the pale, when one could have used exactly the same facts to make the point ketogenic diets are an exciting possibility for glioblastoma and the preliminary evidence is encouraging.

My own perspective can perhaps be summarized as “a contrarian worldview from mainstream sources.”  Looking at ordinary sources like journal articles and historical primary sources, looking at uncontroversial claims of fact, often gives me a view of the world that is quite different from the “we”-based view where “society” is more or less getting things right.  My object-level beliefs are rarely that unusual; the connotation of those beliefs is where I differ from most people.  I don’t feel myself to be safely nestled in the lamplit circle of “we”; I feel like I’m outside, tumbling in the abyss, with only the frail spark of my mind to illuminate a small patch around me.  And I think that, ultimately, the abyss is real, and the lamplit circle is imaginary.

Regulatory Problems with Cancer Research

Epistemic status: more argumentative than the other posts in this sequence. This is obviously informed by my own political views, but my intent is to be convincing to a range of audiences.

In this sequence I’ve been arguing that, while most cancer drugs developed over the past several decades are not very effective, there are potentially exciting avenues of research that haven’t gotten much attention or funding yet.

Why is this the case?  Cancer research is a huge field full of intelligent people. Cancer is a very common disease and there’s a lot of money to be made in treating it. “Curing cancer” is a byword for a lofty goal.  Why should there be any 20-dollar bills lying on the sidewalk at all?

In particular, why would there be less progress since the War on Cancer, which allocated much more federal funding to cancer research than was available before?

The conventional story is that cancer is simply hard. We already gathered the low-hanging fruit of radiotherapy and cytotoxic chemotherapy; now we’re trying to cure the tougher cancers, and it just takes more money and time.

I’ve been arguing that the “cancer is hard” story is incorrect. Targeted chemotherapy, the most popular approach for the past two decades, tends to fail because of the incredible diversity and mutability of cancer.  Approaches that focus on what cancers have in common, like their high glucose requirements or susceptibility to immune defenses, might turn out to work much better.

But, if I’m correct, why hasn’t some enterprising cancer researcher already come to the same conclusions? Even if I’m wrong, I’m not unique; a lot of my argument is just echoing James Watson’s views. Why haven’t any investors and funders decided it might be a good idea to try cancer research the way the discoverer of the double helix thinks we should do it?

This can be explained by an increase in the regulatory burden of cancer research in the past several decades. Clinical trials have become more expensive, require more paperwork, and allow less freedom of judgment from clinicians and researchers.  Only a large pharmaceutical company can afford to run Phase II and III clinical trials these days.  There’s more money in cancer research than ever, but it’s harder to try new things on sick people.  This tends to narrow cancer research to established players and drug classes.

In the world of early-stage tech startups, success follows a power-law distribution. Investors gain more money by funding a handful of huge successes than they lose by giving small investments to a lot of things that don’t work out. So it makes sense that, for instance, YCombinator keeps casting a wider net, accepting startups at earlier stages, and actively seeking outliers and mavericks. They want to make sure they don’t miss the next AirBnB.

It would seem to make sense that investing in drug candidates would work similarly; you don’t want to miss the next Gleevec either.  But if the cost of testing is too high, casting a wide net becomes much more expensive. You can’t just give the founders of an early-stage biotech company a little funding to see if they can do something awesome with it.  And so, medical research becomes much more conservative.

Regulation Has Increased Costs and Slowed Drug Development

90% or more of a typical drug’s costs come from Phase III clinical trials. So it makes sense to focus on the costs and barriers associated with clinical trials, to see if they’ve gone up over time and what the consequences have been.

As of 2005, the R&D cost of the average drug was $1.3 billion. In 1975, that figure was $100 million. (That is, drug trials have gotten on average more than 13 times more expensive over the past forty years.)  Phase III trials are becoming longer, involving more procedures and more hours of work, and have lower enrollment and retention due to more stringent enrollment criteria and trial protocols.  

Protocols for clinical trials are now over 200 pages long on average. The combined costs are $26,000 per patient.  The annual rate of cost increase is itself increasing, from an annual increase of 7.3% in 1970-1980 to 12.2% from 1980-1990 (inflation-adjusted.)  The estimated cost per life-year saved from current clinical cancer trials is approximately $2.7 million.

It now takes an average of 12-15 years from drug discovery to marketing, compared to an average of 8 years in the 1960’s.  Before the 1962 Kefauver-Harris amendment that vastly increased FDA powers, it took only 7 months. For oncology drugs, just the preclinical work takes 6 years; once early clinical trial data are in, it takes 26-27 months to proceed to Phase II or III; and it takes an average of 14.7 clinical trials (Phase I, II, or III) to get a drug approved.

Running a clinical trial requires protocols to be approved by the FDA, the NCI (National Cancer Institute, the primary funder of cancer research in the US), and various IRBs (institutional review boards, administered by the OHRP, or Office of Human Research Protections.)  On average, “16.8% of the total costs of an observational protocol are devoted to IRB interactions, with exchanges of more than 15,000 pages of material, but with minimal or no impact on human subject protection or on study procedures.”  Adverse events during trials require a time-consuming reporting and re-consent process. While protocols used to be guidelines for investigators to follow, they are now considered legally binding documents; so that, for instance, if a patient changes the dates of chemotherapy to schedule around family or work responsibilities, that is considered to be a violation of protocol that can void the whole trial.

To handle this regulatory burden, an entire industry of CROs (contract research organizations) has grown up, administering trials and handling paperwork to make the experimental drug look good to federal regulators. Like tax preparers, CROs have an incentive to keep the regulatory process complex and expensive.

The result of all this added cost is that fewer drugs get developed than otherwise would.  Sam Peltzman’s 1973 study of drug availability and safety before and after the 1962 Kefauver-Harris amendment (which significantly enhanced FDA powers) found that a model of drug development predicted a post-1962 average of 41 new drugs approved per year, while the actual average was 16 new drugs approved per year. The pre-1962 average number of drugs approved per year was 40.


Screen Shot 2015-12-06 at 10.57.51 AM

This is a graph of the number of new drug applications approved by the FDA every year from 1944 to the present. Note that the number of drugs approved has been largely flat since the 1962 Kefauver-Harris amendment, though the decline in drug approvals appears to precede the law by several years.

Increased Drug Regulation Has Not Meaningfully Decreased Risk

Peltzman’s study on the Kefauver-Harris amendment found that there was little evidence suggesting that more ineffective drugs reached the market pre-1962 compared to post-1962.

Comparing the US to Great Britain and Spain, each of which approve more drugs per year than the US, the other countries have no higher rates of postmarket withdrawals of drugs, suggesting that the extra regulatory scrutiny is not providing us with safer drugs.

Toxic death rates haven’t dropped much in Phase I trials. In 6639 patients, comprising 211 trials, between 1972 and 1987, the toxic death rate was 0.5%. In 11,935 patients, comprising 460 studies, between 1991 and 2002, the toxic death rate was also 0.5%.  

Between 1999 and 2006, the number of adverse drug reactions recorded in the US has actually been increasing, particularly  as the proportion of elderly patients taking many drugs has increased.

The most common severe drug interactions are often from old, well-known drugs, like insulin, warfarin, and digoxin.  “Antibiotics, anticoagulants, digoxin, diuretics, hypoglycaemic agents, antineoplastic agents and nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for 60% of ADRs leading to hospital admission and 70% of ADRs occurring in hospital.”  Increasing regulation on new drugs isn’t going to stop the problem of increasing adverse drug reactions, because most of those come from old drugs.

Cost-Benefit Tradeoffs Support Looser Regulations On Drugs

Gieringer’s 1985 study estimated the loss of life from FDA-related delay of drugs since 1962 to be in the hundreds of thousands.  This only includes the delay of drugs that were eventually approved, not the potentially beneficial drugs that were never approved or never developed, so it’s probably a vast underestimate.

In a recent paper, “Is the FDA Too Conservative Or Too Aggressive?“, the authors apply a Bayesian decision analysis to evaluate the overall cost of a trial based on the disease burden of Type I vs. Type II errors.

The classical approach used by the FDA is to constrain experiments to a maximum 2.5% risk of Type I error for all tests, and then choose a power for the alternative hypothesis by making the sample size large enough.  That is, no drug can be approved if there is a greater than 2.5% chance that it is ineffective.

This doesn’t make sense from a disease risk standpoint, because for very severe diseases, the risk of not trying a drug that might work is higher than the risk of trying a drug that doesn’t work.  The authors use data from the U.S. Burden of Disease study, which measures Years Lived with Disability to compute the “optimal” level of acceptable risk of inefficacy for drugs for different diseases. For instance, in pancreatic cancer, the BDA-optimal risk of Type 1 error is 27.9%, since the disease is so deadly.

Cancer in general, being both common and deadly, is an especially good area for looser drug regulation.  If a new therapy increased the cure rate of lung cancer by just 1% (through improved adjuvant therapy) and increased the average life expectancy of uncured patients by just 3 months, the [five-year] regulation-induced delay would cost more than 2,000,000 life-years worldwide.

Even this cost-benefit framing may be understating the case for FDA and OHRP reform, though. The problem seems to be less that the standards for efficacy are too high, than that the costs of compliance are too high because of redundant and excessive required documentation.  It would in principle be possible to streamline the process of conducting clinical trials without reducing its rigor.

We Think About Risk Wrong

In medical contexts, people often talk about the unknown as disrespectable. An “unapproved” drug, an “untested” drug, an “unproven” drug, a treatment that is “not indicated”, all sound unsettling.  Nobody wants to play cowboy in life-and-death situations.

But this kind of language is not actually about reducing risk.  Reality is probabilistic; all choices have potential risks and potential benefits. There’s no real wall, out in the universe, between the “safe/known” and the “unsafe/unknown”; that’s a human framing, akin to the Ellsberg paradox or the bias of ambiguity aversion. People prefer known risks to unknown risks.

In other words: death and disease are scary, and rightly so, but people will tend to be less frightened of risks that seem normal and natural (people have always died of cancer) than of risks that seem outlandish or like somebody’s fault (taking an experimental drug that might or might not work).  Chosen risk, conscious risk, stepping into the unknown, is viewed as worse than the risk of passively allowing harm to occur.  Even if the objective risk-benefit calculations actually work out the other way.

This is an instinct worth fighting.  Cancer is a common disease, yes; but the “normalcy” of it can blind us to the horrifying death toll.  As Bertrand Russell said, the mark of a civilized man is the capacity to read a column of numbers and weep.

Fear of action isn’t actually about making people safer. It’s about making people feel safer, because they aren’t looking at the whole picture.  It’s about making people feel like they can’t be blamed.

It’s Too Hard to Do Transformative Biomedical Research Today

Derek Lowe, an always insightful observer of the pharmaceutical scene,  comments on the VC firm Andreessen Horowitz’s first foray into biotech, “In this business, you work for years before you can have the tiniest hope of ever selling anything to anyone. And before you can do that, you have to (by Silicon Valley standards) abjectly crawl before the regulatory agencies in the US and every other part of the world you want to sell in. Even to get the chance to abase yourself in this fashion, you have to generate a mountain of carefully gathered and curated data, in which every part of every step must be done just so or the whole thing’s invalid, go back and start again and do it right this time. The legal and regulatory pressure is, by Valley standards, otherworldly.”

It shouldn’t be.

I am not a policy expert, so I don’t know what the appropriate next steps are.  What kinds of reforms in FDA and OHRP rules have a reasonable chance of being passed?  I don’t know at this point, and I hope some of my readers do.

I do know that committed activists can change things. In 1992, after a decade of heroic advocacy by AIDS patients, the FDA created the “accelerated approval” process, which can approve drugs for life-threatening diseases after Phase II studies.

We have to find a way to continue that legacy.


Epistemic status: fairly confident

Most cancer cells, instead of using cellular respiration, get ATP  from glycolysis. This is called the “Warburg Effect.”

Glycolysis is less efficient than cellular respiration, which is why cancer cells have higher glucose requirements and why interventions that improve insulin sensitivity (like metformin) have anti-cancer effects.  The high glucose consumption of cancer cells is so reliable an indicator of cancer that it is the basis of detecting metastases in PET scans.

Tumor progression is associated with the emergence of the Warburg effect.  One hypothesis for why is that cancer cells lose mitochondrial function (and thus the capacity for cellular respiration) as they mutate; another is that the hypoxic environment of a tumor makes cellular respiration impossible.

Because  reliance on glycolysis is such a general feature of cancer, a natural type of drug to try on cancers is a glycolysis inhibitor, which would cut off tumors’ energy supply.  To the extent that the Warburg effect is a result of the inability to engage in cellular respiration, glycolysis inhibitors should not fail as cancers continue to advance, but should, if anything, become more effective; cancer cells which have lost mitochondrial function are unlikely to regain it, while cancer cells which have some distinctive surface marker targeted by a drug are likely to lose it over time.

An early-stage drug called 3-bromopyruvate is a glycolysis inhibitor which has shown promising animal results.

3-BP is a strong alkylating agent that inhibits the glycolysis enzyme GAPDH.

In a rat model of hepatocellular carcinoma [1], rats were treated with 2.0 mM of 3-BP; all treated rats survived more than seven months, while all control rats died within days.  The 3-BP eradicated large bulging tumors in the treated rats. The cellular ATP level of healthy cells stayed constant while the cellular ATP level of cancer cells dropped to 10% of its former level.

In a study of rabbits with liver tumors [2], mean survival in the control group was 18 days while mean survival in the treated group (with intraarterial 3-BP) was 55 days.  The tumors in treated animals had not grown and were mostly necrotic; the livers in control animals was almost completely replaced by tumor, with extension into the diaphragm and lungs.  Death in the treated animals was believed to be due to extrahepatic disease (by the time of treatment, the tumors were already metastatic, both in control and treated animals.)  Three animals were treated “earlier” (one week after implantation): one survived, the other two survived 80 days and died of lung metastases.  Intravenous administration, by contrast, was not effective.

Another rabbit study [3] found that intravenous 3-BP doesn’t kill liver tumors but does eliminate their lung metastases.

3-BP  also enhances survival of nude mice injected with human mesothelioma.[4]  There was a control group, a 3-BP treated group, a cisplatin-treated group, and a combined 3-BP and cisplatin group.   In the control group, 3-BP only group, and cisplatin only group, all mice died before day 45. In the combined group, survival was better than control (p = 0.0021), 3-BP alone (p = 0.0024), and cisplatin alone (p = 0.0161).  

In a study of 3-BP on mice with lymphoma[5], a significant reduction in tumor activity was found among those given repeated treatments (p = 0.0043 at day 7) but in those given only a single treatment, the effect was only significant at the second day (p = 0.0152 at day 2) and afterwards the tumors returned to normal.  The only manifestation of toxicity was lower body weight in the 3-BP-treated groups.

Microencapsulated 3-BP, delivered systemically, into a mouse model of pancreatic ductal carcinoma[6], causes minimal to no tumor progression, compared to animals treated with gemcitabine, which had a 60-fold increase in BLI, a measure of tumor activity.

Glioma cells are refractory to most treatment. D-amino acid oxidase combined with 3-bromopyruvate [7] decreased proliferation and viability in rats.

Aerosolized 3-BP also prevents the development of lung cancer in carcinogen-treated mice, without causing liver toxicity.[11]

There has been one human case study of 3-bromopyruvate, [8] on a young man with terminal fibrolamellar carcinoma. At the time of treatment, he was on a feeding tube, he had ascites, and his spleen was swollen due to complete blockage of the renal artery. He had already been treated with chemotherapy.  The University of Frankfurt’s ethics committee permitted him to be treated with a 3-BP, through the TACE delivery method (transcatheter arterial chemoembolism). He began having symptoms of tumor lysis syndrome, a dangerous condition associated with tumor necrosis.  CT scans showed that the tumors were necrotic after administering 3-BP, and the tumor areas were encapsulated and showed fibrosis.   His mobility was limited due to pre-existing ascites and edema, but he began to go out in his wheelchair. He died of liver failure 2 years after his initial diagnosis.   A fluid sample from his ascites found some mesothelial cells, but detected no tumor cells.

There are also a few negative results about 3-BP, but these are explainable by differences in protocols from the successful studies. One study of rabbits with liver cancer found 3-BP didn’t significantly increase tumor necrosis relative to controls, but it only used a single administration rather than repeated administration.[9]  One study of rabbits with liver cancer found that 3-BP killed them, but that was with a dose of 12x the dose in the successful studies.[10]  

This is fairly strong animal evidence, across a variety of cancers, of the most confident kind (tumor eradication and prolonged survival, not just inhibition of growth).  The single human study is not strongly conclusive but leans towards a positive effect.

One major issue is that intra-arterial administration for liver cancer seems to work while systemic administration doesn’t, though other types of cancer do seem to respond to systemic, microencapsulated, or aerosolized delivery. Clearly, attention needs to be paid to optimizing dosage, administration schedule, and delivery method.

As well as being a glycolysis inhibitor, 3-BP is also an alkylating agent, like most cytotoxic chemotherapies; this suggests it may work along multiple pathways. It also suggests we might see similar side effects to cytotoxic chemotherapy in humans.

3-BP is not the only glycolysis-inhibiting drug that has been tried.

Imatinib, which is by far the most successful targeted cancer therapy, is, among other things, a glycolysis inhibitor.

Dichloroacetic acid had some promising animal studies and stabilized five patients with recurrent glioblastoma on palliative care[12] for fifteen months (note that median survival time after the first round of radiation + chemo is only 15 months itself). But DCA has carcinogenic effects in animals, so research was halted. It also lost credibility due to alt-med practitioners selling DCA without FDA approval.

Lonidamine, another glycolysis inhibitor, is currently in clinical trials for brain cancer, but its past clinical results have been unspectacular.  I would have to look in more detail to understand whether there’s any mechanistic reason why 3-BP could be expected to do better than lonidamine in human trials; but for now, the failure of an earlier glycolysis inhibitor is admittedly an argument against 3-BP.

The case for 3-BP may be somewhat weakened but not wholly dismantled by alternate hypotheses about what causes the increased rate of glycolysis in cancer.

The “Reverse Warburg Effect” is a theory that argues that in some epithelial cancers (such as types of breast cancer), it is not the cancer cells but a type of neighboring healthy cells called fibroblasts that have elevated levels of glycolysis.  Glycolysis inhibitors still work on such cancers, however; DCA blocks cancer growth in vitro in fibroblast-induced breast cancer tumor growth.[13]

The Crabtree effect[14] is the phenomenon that some tumor cells have a reversible, short-term shift to glycolysis in the presence of glucose; in such cells, glycolysis inhibitors might not work because the cells could switch back to cellular respiration.  The overall effectiveness of glycolysis inhibitors on cancer will depend on whether the shift to glycolysis is mostly a facultative or an obligate phenomenon.  We can expect glycolysis inhibition to slow growth even if it doesn’t kill tumors, because glycolysis allows for faster cell growth than respiration; but if tumor cells can switch back and forth from glycolysis to respiration, then glycolysis inhibitors wouldn’t be likely to eradicate late-stage tumors, but only to stall early ones.

Overall, 3-BP looks like an unusually strong early-stage cancer drug. It appears likely to be broadly effective among many types of cancer. It is simple, has dramatic results (in animals), and is upstream.

Mechanistically, glycolysis inhibitors seem to be a strategy that is robust to different hypotheses about the cause of the high rate of glycolysis in cancer, and glycolysis inhibitors that are also generally cytotoxic would be even more robust to mechanistic uncertainty.

While there are many preclinical drugs that never succeed in humans, 3-BP is fairly novel in mechanism and seems likelier to pan out than the average new targeted therapy, precisely because it relies on a strategy of attacking cancer that is quite simple, should be broadly applicable across cancers and shouldn’t change over time as tumors evolve.  In order for a tumor to “work around” 3-BP, it would have to create an alternate enzyme to catalyze the 6th step of glycolysis, which seems unlikely; while in order for a tumor to work around an angiogenesis inhibitor, for instance, it would only have to find a different way to stimulate blood vessel growth, which, given the wide variety of growth factors in the human body, is not too unlikely.


[1]Ko, Young H., et al. “Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP.” Biochemical and biophysical research communications 324.1 (2004): 269-275.

[2]Vali, Mustafa, et al. “Targeting of VX2 rabbit liver tumor by selective delivery of 3-bromopyruvate: a biodistribution and survival study.” Journal of Pharmacology and Experimental Therapeutics 327.1 (2008): 32-37.

[3]Geschwind, Jean-Francois H., et al. “Novel Therapy for Liver Cancer Direct Intraarterial Injection of a Potent Inhibitor of ATP Production.” Cancer research62.14 (2002): 3909-3913.

[4]Zhang, Xiaodong, et al. “Novel therapy for malignant pleural mesothelioma based on anti-energetic effect: an experimental study using 3-Bromopyruvate on nude mice.” Anticancer research 29.4 (2009): 1443-1448.

[5]Schaefer, Niklaus G., et al. “Systemic administration of 3-bromopyruvate in treating disseminated aggressive lymphoma.” Translational Research 159.1 (2012): 51-57.

[6]Chapiro, Julius, et al. “Systemic Delivery of Microencapsulated 3-Bromopyruvate for the Therapy of Pancreatic Cancer.” Clinical Cancer Research (2014): clincanres-1271.

[7]El Sayed, S. M., et al. “D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate.” Cancer gene therapy 19.1 (2011): 1-18.

[8]Ko, Y. H., et al. “A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside.” Journal of bioenergetics and biomembranes 44.1 (2012): 163-170.

[9]Shin, S. W., et al. “Hepatic intra-arterial injection of 3-bromopyruvate in rabbit VX2 tumor.” Acta Radiologica 47.10 (2006): 1036-1041.

[10]Chang, Jung Min, et al. “Local toxicity of hepatic arterial infusion of hexokinase II inhibitor, 3-bromopyruvate: in vivo investigation in normal rabbit model.”Academic radiology 14.1 (2007): 85-92.

[11]Zhang, Qi, et al. “Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity.” Cancer Prevention Research 5.5 (2012): 717-725.

[12]Michelakis, E. D., et al. “Metabolic modulation of glioblastoma with dichloroacetate.” Science translational medicine 2.31 (2010): 31ra34-31ra34.

[13]Bonuccelli, Gloria, et al. “The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts.” Cell cycle 9.10 (2010): 1960-1971.

[14]Diaz-Ruiz, Rodrigo, Michel Rigoulet, and Anne Devin. “The Warburg and Crabtree effects: On the origin of cancer cell energy metabolism and of yeast glucose repression.” Biochimica et Biophysica Acta (BBA)-Bioenergetics 1807.6 (2011): 568-576.