Do Allergy-Induced Endogenous Blood Histamine Fluctuations in Humans Modulate Blood-Brain Barrier Permeability and Psychotropic Drug Efficacy?
[Draft of December 10, 2015]
Simple seasonal allergies, or other allergies, may impact the efficacy of psychotropic drugs in some people, because:
- Histamine modulates blood-brain barrier permeability (BBBp) ( and refs., ).
- Psychotropic drug efficacy is determined in part by BBBp.
- Human blood-histamine levels vary idiosyncratically as part of the allergic response.
- A normal human allergic response can elevate blood histamine levels to 10(-8) M.
- Histamine levels of 10(-9) M are sufficient to open the BBB significantly in cats.
That is, allergies cause histamine level fluctuations, which cause BBBp fluctuations, so constant extracranial drug levels may correspond to varying intercranial levels, with widespread clinical implications.
Wide agreement in the literature, going back to the 1990s, supports the observation that endogenous histamine mediates BBBp — e.g.,  from 1992,  from 2000 (authorship overlapping with ), and , also from 1992.
Schilling and Wahl  show that an in vivo blood histamine concentration in cats of 10(-9) M is sufficient to let Na(+)-fluorescein (mw 376 g/mol) through the BBB.
The molecular weights of common psychotropics fall within the range that may be impacted by histamine-induced changes in the BBBp: Diazepam (Valium) [285 g/mol], Fluoxetine (Prozac) [309 g/mol], Lorazepam (Ativan) [321 g/mol], Quetiapine (Seroquel) [384 g/mol], Haloperidol (Haldol) [376 g/mol], Sertraline (Zoloft) [306 g/mol], Carbamazepine (Tegretol) [236 g/mol], Paroxetine (Paxil) [329 g/mol], etc.
Patient S, suffering from intractable epilepsy and seasonal allergies, was hospitalized 31 times before age 25 for either uncontrolled seizures or intolerable adverse reactions to various AEDs. None of her hospitalizations occurred in May, June, July, or August. (The statistical likelihood of 31 events occurring at random during the same 2/3 of the year is about 5 in a million.)
My hypothesis is that seasonal allergies give S constant histamine levels during the summer but, during the rest of the year, varying histamine levels, and thus varying intercranial AED levels.
Therapeutic dosing for psychotropics may depend on the presence of serum histamine, and may be impacted by allergies, including seasonal allergies.
Therapeutic AED levels, in particular, are often expressed in extracranial blood concentrations. This approach may need to be modified.
- Retroactive patient intake review: Do other epileptics demonstrate seasonal hospital admission patterns?
- Retroactive patient intake review: Do other patients taking psychotropic drugs demonstrate seasonal hospital admission patterns?
- Patient study: Measure histamine levels as part of routine AED monitoring.
- Patient study: Measure histamine levels as part of other psychotropic-drug efficacy monitoring.
- Basic research: Study BBBp with regard to AEDs/other psychotropics in other mammals, to see if Schilling and Wahl’s results hold for these compounds.
 Lin RY, Schwartz LB, Curry A, Pesola GR, Knight RJ, Lee HS, Bakalchuk L, Tenenbaum C, Westfal RE. Histamine and tryptase levels in patients with acute allergic reactions: An emergency department-based study. J Allergy Clin Immunol. 2000 Jul;106(1 Pt 1):65-71.
 De Marchi, Sergio M.D., Emanuela Cecchin, M.D., Danilo Villalta, M.D., Grazia Sepiacci, M.D., Gianfranco Santini, M.D., and Ettore Bartoli, M.D. Relief of Pruritus and Decreases in Plasma Histamine Concentrations during Erythropoietin Therapy in Patients with Uremia. N Engl J Med 1992; 326:969-974 April 9, 1992.
 Patnaik R, Mohanty S, Sharma HS. Blockade of histamine H2 receptors attenuate blood-brain barrier permeability, cerebral blood flow disturbances, edema formation and cell reactions following hyperthermic brain injury in the rat. Acta Neurochir Suppl. 2000;76:535-9.
 Sharma HS, Nyberg F, Cervos-Navarro J, Dey PK. Histamine modulates heat stress-induced changes in blood-brain barrier permeability, cerebral blood flow, brain oedema and serotonin levels: an experimental study in conscious young rats. Neuroscience. 1992 Sep;50(2):445-54.
I managed to squeeze in time with good friends and colleagues, dinner with my father, a book signing, a panel presentation, and a pre-announcement announcement. (Look for more on that here soon.)
The Jewish Book Council had brought me down, as part of their partnership with the URJ, for a panel discussion along with Aviya Kushner and Michal Lemberger on “Rereading the Bible: Text, Subtext, and Filling in the Gaps in Between.”Joe Biden was scheduled for Saturday evening, by which time I was already en route back to New York. At first I didn’t care that I was missing his address and the inconvenient security that it necessitated. But apparently it was quite an event, with the vice president praising the Jewish commitment to social justice and thanking the Jews for never remaining silent.
We got the idea, of course, from the prophets of the first millennium BCE, whose vision for a better world lives on a hundred generations later.
Fittingly, the taxi driver to the airport had foreshadowed the acknowledgment of that achievement. A woman from Haiti, she heard us talking about this and that, and in response told us how much she admired the Jews and the way they kept their heritage alive.
What a thing to be a part of.
There are two parts to understanding what’s going on.
The first part is how computer memory works.
Computer memory is like a book of pages made from magic slates or mini whiteboards. Anything can be written on any page, and every page can be erased and overwritten with something new. The pages go in order, but the information doesn’t have to, which is why the computer constantly updates a changing table of contents to keep things straight.
For example, when you connect to, say, one of your bank’s computers to pay your bills online, that computer has to keep track of your name, your account number, your password, etc. So it puts all of that on whichever page is convenient — call it page 99 — and also makes a note in the table of contents so it knows where your information is.
The second part of understanding the heartbleed bug is knowing about an obscure part of the way computer connections work.
When your computer (or phone, or whatever) connects to your bank’s computer, you want to make sure that no one except you and your bank have access to the information you’re sending back and forth, like your password or your account balance. To make this possible, your computer and the bank’s computer work out what is essentially a brand new secret code, and use that to create what’s called a “secure connection.”
This process of negotiating a code is slow, so if you’re sending a lot of information back and forth (which you almost always are), you want a way of indicating that whatever you’re sending is part of an ongoing conversation. In other words, instead of creating a new code each time you type something or click on something on your bank’s website, you want some way of indicating that you want to keep using the code you have.
The mechanism for keeping a code active is called a “heartbeat,” and it’s pretty simple. You send an encoded message, and the other side decodes it and sends it back. It’s like you keep saying, “prove that you understand our secret code.” Because this is a code that you and your bank just created, no one else has it, so this is a pretty reliable system.
Of course, your bank’s computer has to write down your message on one of its pages. Let’s say it picks page 101. It writes down the message, then sends you page 101.
To make things even more secure, you get to choose how long your heartbeat message is. It might be one page. Or it might be 64 pages. If it’s 64 pages, the bank’s computer writes the whole thing down and sends back all 64 pages.
And here we come to the heartbleed bug: The way they programmed this thing, the computer at the other end doesn’t check if you sent as much as you said you did.
So if you say you’re sending 64 pages and only send one page, the computer will write down your message on page 101, but send you back pages 101-164. This means that you’ll get 63 pages of other people’s stuff!
And this could be anything. It could be someone else’s account balance. It could be someone else’s password. It could be someone else’s PIN number for their ATM.
But none of those are the worst case scenario. The secret codes that make secure communication possible all depend on keeping special keys (as they’re called) secret. Here the details really are complicated, but the bottom line is that the security of the Internet depends on the secrecy of these keys
Your bank — and only your bank — has one of the keys, which is why you can trust your on-line banking. But if that key just happens to be on page 102-164, which you just stole, you can pretend to be your bank!
This means that even once the bug is fixed on your bank’s computer, you can’t know for sure if you’re sending your information to your bank, or to a guy in Africa who’s robbing you blind.
In short, because the heartbleed bug reveals random pages in otherwise-secure computers, it’s not hard for malicious computer users to grab your private information and to grab the secret keys that will let them masquerade as a site you trust.
To many outside observers, it’s a waste to have employees sitting around and doing nothing more than chat. But the outside observers are wrong, we learn from MIT’s renowned Dr. Alex Pentland, who has studied how to increase productivity and creativity at work.
Among his conclusions are that interaction among workers is one of the best predictors of overall work productivity.1
For example, he studied a call center at Bank of America. Call centers are interesting because they have exact data on productivity. They know how much each person gets done per hour. Call centers are also interesting because, at first glance, it seems that any time an employee is not working is time wasted.
But it turns out to be just the opposite. By increasing the time employees spent together on coffee breaks, Dr. Pentland increased each worker’s productivity.
To be clear, in this case he didn’t give the workers more downtime. He rescheduled their downtime so that they would have breaks together.
I think the lesson for organizations that value productivity is to make sure their employees get to spend unstructured time together at work.
Dr. Pentland didn’t just study call centers, and he didn’t just study productivity. For instance, he also looked at an IT support department, one which — like the call center — has clear records on productivity. He found the same thing: he could predict the employees’ productivity by looking at how much they talked to each other.
Dr. Pentland investigated creativity, as well, and found, again, that interaction was crucial: “the difference between low-creative groups and high-creative groups is their pattern of face-to-face exploration outside the group.”
All of this (massive) research points in a single direction: Giving people time at work to talk to each other is good policy all around.
1. Social Physics: How Good Ideas Spread — The Lessons from a New Science by Alex Pentland. Penguin Press HC, 2014. Pp 93-97.
Sometimes the opposite of the right answer is another right answer.
It’s counter-intuitive, but it’s true. And I think it’s important.
Noble Prize-winning economist Thomas Schelling gives us a helpful example. Tying together sports and animal science the way only he can, he starts by quoting the first paragraph of a book by Leonard Koppett about baseball: “Fear.” That’s the whole paragraph, and it’s a good one. Then on the theme of fear, Schelling reminds us that dogs can actually smell fear, and their reaction to fear is aggression. This means that it makes perfect sense to be afraid of dogs. At least, it’s the experience of someone who’s afraid of dogs that there’s every reason to be afraid of them.
But the catch is that people who aren’t afraid of dogs find that it makes just as good sense not to be afraid of dogs. That is, it’s the experience of someone who’s not afraid of dogs that there’s no reason to be afraid of them.
Two people. Two different answers to the same question, both of them rational. But just because they’re both right doesn’t mean that they are both just as good.
Precisely because they are both right, we have a choice — in this case a choice between living in justified fear, or justifiably living free of fear. It seems to me that the better path is the one without fear and without dog bites.
But I can only imagine how hard it would be to convince someone who’s already been bitten a few times. In fact, if such a person and I tried to find the fearless path together without the proper preamble, the fearful person would join me, express entirely rational fear, cause the dog to get aggressive, and then the dog, seeing me as the easier target, would attack me.
The fearful person would leave vindicated (if unscathed). But my perception would be that the fearful person ruined my previously good relationship with dogs. We would never see eye to eye, and might never understand why the other one can’t grasp our own eminently sensible and correct position.
The truth is, I don’t know if dogs actually do smell fear. (Schelling’s other example is bomb diffusion officers, whose fingers tremble if they think the task is dangerous, but the task is only dangerous if their fingers tremble.) I only bring it up because there are usually lots of right ways to do something, with various combinations of freedom, constraint, trust, skepticism, praise, discouragement, encouragement, holiness, and banality.
Just for example, in an environment based on distrust, people will quickly find that they are right not to trust their fellow. But people who trust each other can be just as right to do so.
The more general point is that it might be helpful, the next time we think we know that other people are wrong, to ask if maybe all we really know is that we are right. Because if so, maybe they’re right, too.
Finally, returning to the dogs and the lessons we learn from them, a question presents itself: Which one do we want to be? The one who spreads fear or the one who spreads calm?
We get to choose.
The stories feature Police Chief Coyote “Kai” Goodman, whose past is so secret that even his cover story is classified. The setting is Warwick, NY, where, according to the official count, there are no spies.
In the inaugural story, “Checkpoint,” a man evades a police checkpoint and unknowingly triggers his own murder. Police Chief Kai Goodman knows why. Do you?
I wrote this to be a fun diversion from my research (even though I try to have fun with that, too). I hope you enjoy reading it as much as I enjoyed writing it.
Everyone knows the value of first impressions.
The ancient Romans had a saying: vestibulum domus ornamentum est (“the entrance hall is a house’s jewel”), by which they meant that people judge a house on what they first see. The Roman rhetorician Quintilian added that the worst impressions are also the most lasting (haec ipsa magis pertinaciter haerent quo deteriora sunt). The English playwright William Congreve agreed (“There is a great deal in the first impression”), and so did Dickens (“First impressions, you know, often go a long way”).
And our modern proverb that “you never get a second chance to make a first impression” is so common that it’s attributed to a variety of people.
Yet for all of this, at most not-for-profits and small businesses no one is responsible for first impressions. Frequently, the job of first impressions is left as an afterthought, relegated to someone with another job (a secretary, say) or to whoever happens to answer the phone. Other times, the people in charge of different kinds of first impressions — the website (on-line), office (phone), and physical space (in-person) — never talk to each other. Or just anyone is allowed to place a hastily written hand-scrawled notice on the front door. Sometimes the people in charge don’t even know how the phone is answered, let alone whether the entrance hall and website are coordinated to give the same first impression.
So here are my questions:
1. What kind of a first impression do you want to give people?
2. Do your entrance hall, website, and phone personas convey that impression?
3. Who is your Chief Impression Officer?