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Common Side Effects of Antipsychotic Drugs | AP Topic Index | How Antipsychotics Work

When confronted with the need to take some kind of crazy med for the first time, practically everyone flips out over the potential side effects1. If that med is an antipsychotic (AP), everyone gets extra paranoid about side effects that, like the side effects of most neurological and/or psychiatric medications, are usually short-lived, blown out of proportion, or far less common than imagined. Of course there are some potential adverse reactions that are bad enough to warrant some warning, because if they do happen, and you don’t do anything about it, your life could suck a lot more than it does already. All antipsychotics can - but probably won’t - cause three problems. Most prescribers will discuss the first one with you. Good pharmacists will cover the first two. Rarely are all three discussed, unless a doctor is talking to your family because you’re locked up. Which is actually OK, because the last one rarely happens and, when it does, it happens to people when they are in psychiatric hospitals (in patients) far more often than to people taking their meds on their own.

While mostly associated with APs, these problems are possible, albeit extremely rare, at the highest dosages of Lexapro and Paxil. That is due to the nature of getting too much serotonin at your 5HT2A receptors.

1.  The Sweetest Side Effect

The best known, and most complained about, adverse reaction of APs - all crazy meds really, whether it’s true or not - is weight gain. And while many APs can cause you to gain weight (Zyprexa (olanzapine) and Seroquel (quetiapine) being the worst offenders), that’s not the issue here. Hell, people who don’t even take it know Zyprexa makes you fat. The real problem is metabolism (or metabolic) syndrome, with the focus being on type 2 diabetes. Even Abilify (aripiprazole) can cause you to turn diabetic after you’ve lost ten pounds.

1.1  Easy as Pie a la Mode with a Side Order of Chocolate Cake. Oh, and a Dozen Doughnuts to Go.

Stahl thinks the mechanism by which APs mess with insulin is antagonism of histamine H1, muscarinic M3, and serotonin 5HT2C receptors (which are all responsible for increased appetite), and, possibly, the as-yet-unidentified “factor X” he uses as a placeholder for antipsychotics’ mechanisms of action that haven’t been fully explained. Even without factor X those all explain why Zyprexa, Seroquel, and Clozaril (clozapine) pack on the pounds and screw up your glucose tolerance, but not why Risperdal (risperidone) and Invega (paliperidone) can do the same thing, or why Abilify will mess with your blood sugar without affecting your weight. While the worst offenders are atypical antipsychotics, my money is on dopamine antagonism itself being the key factor. Why? Because your pancreas has dopamine D2 receptors that affect how much insulin you make, that’s why. Just as hay fever meds make you sleepy because they affect the histamine receptors in your brain, crazy meds affect neurotransmitter receptors you have in other parts of your body2. There doesn’t seem to be much difference in the diabetes rate (of people taking APs) between smokers and non-smokers, and if M3 antagonism is a factor, smoking should help prevent AP-induced diabetes. There’s no doubt smoking will make the cardiovascular and triglyceride problems worse, but if M3 were involved, there should be plenty of evidence of smoking preventing diabetes in the same way it helps to prevent Parkinson’s. It’s documented all over the place that antihistamines and 5HT2C antagonists can cause obesity (see the bibliography page), which is why Remeron (mirtazapine) will make you fat, yet may even make it somewhat less likely you’ll get diabetes than someone with untreated MDD.
Oh, and bromocriptine, a D2 agonist, is approved by the FDA to treat type 2 diabetes because it improves glycemic control.

Even if you want to stay in the brain, dopamine and eating might be as entwined as dopamine and sex, or sex and food3:

Eating and dopaminergic signaling are closely related. Food reward and food-reward associated stimuli both elevate dopamine levels in crucial components of the brain reward circuits. In fact, food might be the most important natural stimulator of the reward system in the brain. Therefore, overeating may represent an attempt to compensate for hedonic reward deficiency under conditions of reduced dopaminergic activity. --Compensatory weight gain due to dopaminergic hypofunction: new evidence and own incidental observations

However, Stahl could still have it right. The rates of diabetes, obesity, and metabolism syndrome in general are low with Geodon (ziprasidone), and Geodon doesn’t do squat with the muscarinic receptors, is comparable with Seroquel as an antihistamine, is more potent than Zyprexa when it comes to 5HT2C receptors, and doesn’t have that mysterious X factor. These two Pfizer-sponsored studies show that Geodon sucks less than Zyprexa when it comes to glucose intolerance, and switching from Risperdal, Zyprexa, or miscellaneous first-generation antipsychotics to Geodon leads to weight loss, lower cholesterol, increased attractiveness, and immortality. OK, I made up the last two. Sometimes the brown-nosing in drug company-sponsored studies is as obvious as the product placement in Bones.
Then again, Geodon is also a serotonin and norepinephrine reuptake inhibitor, a potent 5HT2A antagonist, and a partial 5HT1A agonist. If someone could develop a drug with only those four actions they’d have an antidepressant that causes weight loss and boosts sexual function.

1.2  You Know the Drill

So, what can you do about it? The usual crap every health care professional should tell you. Cut back on the fatty foods and eat more fruits and vegetables. Try to exercise. Quit smoking and don’t drink as much, or any alcohol. You know, all the stuff I don’t do4. While it failed to do anything after people already developed diabetes, there’s still a chance a quarter teaspoon of cinnamon a day might help prevent its onset. The only money I’m putting on that one is the cost of 0.25 tsp a day of cinnamon.
In spite of my cynicism, Geodon does have a good track record of usually not messing with your insulin, lipids, etc. So if you have a history, including a family history, of diabetes, your cholesterol levels shoot up when you see a bacon cheeseburger commercial, reading about Zyprexa makes you gain weight, etc., Geodon might be the first best broad-spectrum AP to consider if you need one, or to switch to if you develop metabolism/metabolic syndrome from taking another one. While I think choosing a med to avoid a side effect is usually a dumb idea, this is one of the few times when it’s a good idea. Bear in mind a low rate of weight gain, etc. doesn’t mean it never happens, so don’t eat a shitload of candy every day because you might go into a diabetic coma after all.

2.  I Can’t Sit Still!

Movement disorders are a relatively common problem with APs, with estimates ranging around 10–20% of people who take them getting some form of Parkinson’s-like side effects, and possibly up to half experiencing akathisia to some degree. This time some of the first-generation APs are more likely to cause you problems than the modern second- and third-generation APs. While there are as many different types of AP/neuroleptic-induced movement disorders as there are crazy meds, extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) get most of the attention from prescribers and consumer-oriented sites5, mainly for being around since day one of antipsychotics6, with akathisia coming in third. If they are discussed at all. Who cares if movement disorders cause people to stop taking all crazy meds, and akathisia can be bad enough to cause suicide, right? Because most of the information out there is on EPS, TD and akathisia, that’s about all I can cover.

2.1  Cause…

EPS, TD, and dystonia, also known as parkinsonism, are caused by APs being a little too effective at preventing dopamine from reaching your dopamine D2 receptors, and possibly D3 with TD. Parkinson’s and Restless Leg Syndrome (RLS) drugs do the exact opposite, they enhance the effect of dopamine. Although considered to be a form of EPS, akathisia doesn’t respond to standard treatments like anticholinergics, and responds to things that don’t touch EPS ranging from beta blockers (not great, but better than nothing) to . TD used to be considered a form of EPS as well, so there you go. Other risk factors for EPS and TD (but not akathisia) include:

  • Age. The older you are, the more likely you are to get them.
  • Gender. Women are twice as likely as men to get parkinsonism.
  • CYP2D6 polymorphism. AKA being a poor metabolizer of some drugs. AKA actually being medication-sensitive instead of just another whining baby rationalizing a reason not to take their meds.
    • This affects TD more than EPS.
    • It doesn’t matter if the drug you’re taking is not metabolized by CYP2D6. It’s like redheads and anesthesia, there’s probably a good reason for it, but damned if I know what it is.
  • The potency and dosage of the drug. Duh.
    • That’s at D2. Drugs that are also potent anticholinergics, like Zyprexa and Clozaril, make it far less likely you’ll get EPS or TD.
    • To the point where if you get EPS or TD from other APs, switching to Zyprexa is a first-line treatment, if not always the best.
    • Here is a good chart of meds grouped by likelihood they’ll cause parkinsonism. On the plus side it includes non-crazy meds like antifungals and antibiotics. On the minus side they leave out a bunch of APs and use “others” instead.
  • If you or your family has a history of actual Parkinson’s. Double duh.
  • The bipolar are more likely to get EPS than the schizophrenic, and those with BP2 are more susceptible than those with other types of BP7.
  • If you had any drug-induced movement disorder other than akathisia, it indicates that you’re susceptible to all of the non-akathisia movement disorders. So EPS, TD, dystonias, whatever falls under the parkinsonism umbrella.
  • If you have AIDS, because your life just doesn’t suck enough, does it?

2.2  …and Effect

It would probably help to describe the symptoms of various movement disorders caused by APs. First the Parkinson’s-like ones.
EPS usually happens soon after you start taking a medication and essentially looks a lot like Parkinson’s, hence the terms parkinsonism and the outdated pseudo-Parkinson’s:

  • Tremors.
  • Rigid muscles.
  • Bradykinesia8 - slow movement, stiff muscles, and trouble walking.

The “Tardive” in TD means late. The dyskinesia part can happen at any time, TD tends to be worse so it is a lot easier to notice. You may not be aware of a dyskinesia that happens soon after you start taking a drug, so a lot of TD is just plain old D that got progressively worse. The symptoms are basically a group of specific uncontrolled movements including:

  • Tongue movements
  • Lip smacking
  • Eye blinking
  • Finger wiggling
  • Some arm and leg movements

In other words, you could look like a real perv. When I had TD thanks to Risperdal I was constantly licking my lips and looked like an owl blinking Morse code.

Dystonia would have made you really popular in the 1960s, as you would be doing the Twist non-stop. Your muscles are powerfully contracting and you wind up twisting and contorting, usually in your upper body and head. Including your eyes. This is a tardive form that won’t start until years after you’ve started taking whatever medication was working so wonderfully for you.

Akathisia is completely different. In some ways it more mental than physical, but the initial expression is physical. You literally can’t sit still. Your legs (usually) shake and jitter, but in ways that are different from restless leg syndrome (RLS). The jitteriness of your legs reflects your inner restlessness. Getting up and walking around offers some relief, but not enough. You have a literal feeling of ants (or other bugs) in your pants (or elsewhere)9. You’re restless and irritable as all hell. All of this leaves you exhausted. Little wonder that akathisia often leads to suicidal ideation.
Like the other drug-induced movement disorders, there is a tardive form of akathisia. Which can become permanent if not dealt with immediately.

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2.3  If You Don’t Stop Fidgeting, I’m Turning this Car Around…

If you do get a neuroleptic-induced movement disorder, regardless of which one it is, you must deal with it quickly. While they won’t kill you, if left untreated for too long they could become permanent, especially tardive dyskinesia and tardive dystonia. As in even if you stop taking all medications of any kind, move to the woods and live on nuts and berries you’d still be blinking, twitching, and twisting. So, what can you do about movement disorders?

  • The first thing that comes to mind is lowering the dosage of your med, but you’d want to consider that only if the side effect started after you’ve been on your current dosage for at least three months and the symptoms aren’t severe.
  • Switching to another med, especially Zyprexa or Seroquel for EPS or TD is worth a shot if you haven’t taken them already.
    • But you may be swapping one suck-ass side effect for another - metabolic/metabolism syndrome (see above).

EPS and TD-specific treatments:

  • You could just take an anticholinergic like Cogentin (benztropine mesylate). While not as effective as switching to Zyprexa or Clozaril (clozapine), if you’re taking an AP with a relatively simple mechanism of action (e.g. Thorazine (chlorpromazine), Haldol (haloperidol), or even Risperdal and Invega) that has been working well for you, switching to a really broad-spectrum AP like Zyprexa or Clozaril could do something like make your symptoms worse, or cause other side effects that would encourage you to stop taking your medication.
  • The D2 agonist bromocriptine is frequently used to treat EPS and TD. Like Cogentin it’s approved to treat Parkinson’s.
    • You don’t want to use the more modern Parkinson’s/RLS meds like like Requip (ropinirole) and Mirapex (pramipexole) because they are as likely to make the symptoms you’re treating with the AP worse as they are treating your AP-induced movement disorder. They are just too potent. You’ll have to stick to the crappier, old-school stuff.
  • If you really want to go old school, and/or really need to stay on the med you’re taking, (i.e. you’re grasping at fucking straws here), you and your doctor can look into adding amantadine to your cocktail of benztropine, Cogentin, and barely-therapeutic dosage of whatever AP you’re taking.
    • This does increase the risk of NMS (see below), as well as your symptoms getting worse, so this is a desperation move.
  • For TD there are also a few other third-line treatments:
    • the anti-Alzheimer’s drugs such as Aricept (donepezil).
    • Melatonin.
    • Calcium channel blockers (just not verapamil, as verapamil can cause parkinsonism).

Treatments for dystonia:

  • For acute dystonia intramuscular shots of Cogentin (benztropine mesylate) or Benadryl (diphenhydramine) are supposed to work well.
    • Otherwise treat it as you would EPS.
  • For tardive dystonia you’re not quite up shit creek, but you may feel like you are, especially as it strikes after you’ve been taking a medication for years. Your options are limited, and they suck, but at least you have some, like:
    • Switching to Risperdal, and getting parkinsonism instead.
    • High dosages of Artane (trihexyphenidyl).
    • Dopamine depleting drugs, such as tetrabenazine or reserpine10.
    • Botox. At least you can look happy.
    • Deep brain stimulation. Since this can fix a lot of things where nothing else works, maybe the tardive dystonia is the final symptom you need to get your insurance to approve DBS.
    • Thalamotomy. When all else fails, start cutting out bits of your brain, right?

Akathisia-specific treatments:

  • 15mg a night of Remeron. Combined with your existing AP you may wind up sleeping 10 hours a night, and with Remeron making you want to eat sugar straight out of the bag you’ll have to be really careful about weight gain and glucose intolerance.
    • If Remeron isn’t a good fit, other 5HT2A antagonists such as cyproheptadine and mianserin might work. They just don’t have enough in the way of studies and case reports to back them up like Remeron does. Although they, too, will give you the same side effects, those side effects just may not be as bad.
  • Get tested for an iron deficiency. If you don’t have enough, which appears to be common in akathisia, you’ll need a prescription for pharmaceutical-grade iron.
    • You may even need to get iron shots, the way a lot of the mentally interesting get B-12 shots.
  • Benzodiazepines don’t do squat for EPS and TD, but they’re great for akathisia. They are a second-line treatment because you can build up a tolerance to their effect and there is a potential for abuse.
  • Beta-blockers such as propranolol have long been the standard method of treatment. Unfortunately they aren’t all that effective. File under “better than nothing.”
  • Clonidine is fairly effective, but its side effects tend to suck too much. This is third-line.
  • When you’re getting into desperation territory you’ve got amantadine, Keppra, BuSpar, TCAs, opioids, dopamine depleters, and everything they throw at parkinsonism.

2.4  Don’t Smoke if You Got’em

While EPS, TD, and some other drug-induced movement disorders are called “Parkinsonism,” smoking will make it more likely to happen and make the symptoms worse if you have EPS or TD, instead of making it less likely to happen and have little-to-no positive effect on symptoms, as with actual Parkinson’s. Why? Because nicotine is a procholinergic drug, and anticholinergics, including the potent anticholinergic effects of Zyprexa, Seroquel and Clozaril are why EPS and TD are so rare with those meds. Plus smoking cause Zyprexa to clear out of your system faster, so you’re just asking for EPS or TD if you take Zyprexa and smoke heavily.

2.5  I’ll Have a Lithium Shake

While lithium is an antipsychotic its tremors it causes are due to something completely different as lithium doesn’t affect dopamine. No one seems to care what causes them, as they get better over time for most people11, and have been successfully treated with beta blockers like propranolol for the last forty years, as well as other things.
When it comes to lithium and its side effects make sure you drink enough water. Lithium isn’t metabolized, it’s processed by your kidneys. Not enough water = a build-up of residual lithium.

For even more information see our forum on AP-induced movement disorders.

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3.  Malignant, Like a Brain Tumor or Something?

Neuroleptic Malignant Syndrome, or NMS, is similar to Serotonin Syndrome. While there is some overlap in symptoms, they are mostly alike in their risk being blown way out of proportion. However, since they are both potentially fatal, you do need to be aware of them. As NMS is associated with APs and anti-Parkinson’s medications, we’ll deal with NMS here.

3.1  Untreated Schizophrenia or Bipolar Disorder is Way More Likely to Kill You than NMS

Fatal reactions to APs with the symptoms of NMS were first described in the mid-1950s12. Back then the incidence of NMS could have been as high as 12% with a mortality rate around 25%. Today NMS happens, at most, in 0.2% of people taking APs, and even then it’s usually high dosages of the more potent ones (Risperdal, Zyprexa, Haldol (haloperidol), fluphenazine e.g.), or if they suddenly stopped taking high dosages of Parkinson’s medications (think potentially fatal SSRI discontinuation syndrome). Of all those people maybe 5% die.
I think the fear of NMS hangs around because the symptoms are rather unpleasant:

  • Intensely high fever - which is one of the things that causes death.
  • Autonomic instability - or all the stuff you do on autopilot, like breathing, goes haywire. If the fever didn’t kill you, this will.
  • Rigid muscles. Tonic seizure/Las Vegas magic act rigid. Half the ER wouldn’t be able to bend your arm.
  • Blood pressure swinging all over the map. This can cause a stroke and kill or cripple you.
  • Incontinence.
  • Delirium, paranoia, agitation, and all sorts of other symptoms of what you’re taking an antipsychotic for.
  • Parkinsonism (see above), especially if you suddenly quit taking your Parkinson’s medication.

3.2  Same with the Psychos Running the Asylums

One of the reasons the death rate used to be so high is because APs were inappropriately given to elderly patients in long-term care facilities (i.e. dumping grounds for grandma & grandpa). I worked in such a place, and restraining residents in wheelchairs, especially when they were delirious, agitated, couldn’t walk straight, and peeing all over the place, was common practice. The same thing happened in psychiatric hospitals during the Dark Ages of psychiatric “care” up through the 1980s (and later in many places). Not only were patients restrained when they shouldn’t have been, the dosages of the drugs they were given were too high. Thousands of people died due to the convergence of cruelty and stupidity.
I don’t recall anyone dying from NMS at the place where I worked during my time there, but looking back I now guess that many of the residents had dyskinesia, pseudobulbar affect, and even days-long partial seizures.

3.3  At Least Treating NMS is Fast and Easy

If you have a very high fever and rigid muscles within 30 days of starting a new AP you need to:

  • Call your doctor immediately.
  • Do whatever your doctor tells you to do.
  • If your doctor is not available, you go to the nearest hospital with an emergency room. Bring the medication with you.
    • Tell the triage nurse you’re taking an antipsychotic and you have a high fever, rigid muscles, and whatever other symptoms you have.
    • Or if you can’t do that, how the fuck are you on the Internet in the first place? If you’re looking this up for someone who is really sick, just take them to the ER already and bring every medication they take along with you.

No matter what, you’re not taking that med ever again. Or you should have learned your lesson about how stupid it is to abruptly discontinue your medication.

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1 Most people with the misfortune of riding the med-go-round more than a few times usually stop worrying about every potential side effects after the fourth or fifth med they take. The freaky rare side effects section on the drug pages is for those of you who still insist on imagining the worst before you take a pill. Gallows humor is your friend.

2 Which is why SSRIs, especially Paxil, are great for irritable bowel syndrome (IBS). You've got serotonin receptors all over the place, including a shitload of them in your gut. There may be even more serotonin receptors in the human digestive system than in the brain.

3 Thanks to CM Forum member dookie for finding this article.

4 Except for the not drinking part. As mixing alcohol with my drug cocktail has such unpredictable results that range from changing the efficacy of the meds to killing me, giving up booze was incredibly easy. It's one of the reasons I'm far less social than I used to be, but I'd rather be a living loner than a dead not-that-much-of-a-loner.

5 I told you Mom always hated them more.

6 1. I still think it's because Mom hated them more. 2. Movement disorders exactly like EPS and TD were described as side effects of Rauwolfia serpentina (AKA Chota-Chand, Indian snakeroot, and a bunch of other names), around 3,000 years ago. No, really. You want to use an herb to treat schizophrenia? Fine. Use this one. It has a 3,000-year-long proven track record and you can still get EPS or TD. Anything that doesn't have potential side effects doesn't work.

7 Or this is yet another example of how people with BP2 are inclined to complain about things more often than people with other forms of brain cooties.

8 From the Greek meaning to move like Tom Brady. Thank you! I'll be here at least 72 hours. Be sure to tip your attendants. Tonight's special is brand Ativan.

9 But it's not delusional parasitosis, or Ekbom's syndrome, where you actually think you have nonexistent bugs crawling under your skin.

10 I know I'm flogging a dead horse, but once again: the original modern antipsychotic, first synthesized in India in the 1930s, and ignored for 20 years because white people didn't discover it. It's derived from the aforementioned Rauwolfia serpentina and is still used today.

11 Either the tremors go away completely, or they diminish to the point where they are bearable. Because if you don't have many treatment options left, lithium has your symptoms under control, and you've gone through a lot of meds already, living with a minor tremor is probably better than risking lithium not working for you as well as it does now.

12 One reason why I collect really old reference books like The New Chemotherapy in Mental Illness: PubMed doesn't have everything.

Metabolic Syndrome, Movement Disorders, & Neuroleptic Malignant Syndrome (NMS) by Jerod Poore is copyright © 2011
Page created by: Jerod Poore. Date created: 12 July 2011 Last edited by: JerodPoore on 2016–04–18

Metabolic Syndrome, Movement Disorders, & Neuroleptic Malignant Syndrome (NMS) by Jerod Poore is copyright © 2011 Jerod Poore

Last modified on Monday, 18 April, 2016 at 15:53:26 by JerodPoorePage Author: Jerod PooreDate created: 12 July 2011

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Very little information about visitors to this site is collected or saved. From time to time I look at search terms used and which pages they bring up in an effort to make the information I present more relevant. And the country of origin, just because I’m geeky like that. That’s about it. Depending on how you feel about Schrodinger, our privacy policy should either assuage or exacerbate your paranoia.
Crazymeds is optimized for ridiculously large screens and browsers that don’t block ads. I use Firefox and Chrome, running under Windows 72. On a computer that sits on top of my desk. With a 23 inch monitor. Hey, at least you can make the text larger or smaller by clicking on the + or - buttons in the upper right hand corner. If you have Java enabled. Like 99% of the websites on the planet, Crazymeds is hosted on domain running an open source operating system with a variety of open source applications, including the software used to display what you’ve been reading. As such Crazymeds is not responsible for whatever weird shit your browser does or does not do when you read this site3.
Crazymeds now uses a secure server, but it is not so secure that you can discuss anything having to do with nuclear power facilities, air traffic control systems, aircraft navigation systems, weapons control systems, or any other system requiring failsafe operation whose failure could lead to injury, death or environmental damage. Just so you know. So if you’re mentally interesting and have a job that deals with that sort of thing, talk about said job elsewhere. Otherwise feel free to discuss your meds and brain cooties.
No neurologists, psychiatrists, therapists or pharmacists were harmed in the production of this website. Use only as directed. Void where prohibited. Contains nuts. Certain restrictions may apply. All data are subject to availability. Not available on all mobile devices, in the 12 Galaxies Guiltied to a Zegnatronic Rocket Society, or in all dimensions of reality. Hail Xenu!

‘Everything is true, nothing is permitted.’ - Jerod Poore

1 While there are plenty of books to help you with hypochondria, for some reason there’s not much in the way of websites. Then again, staying off of the Internet is a large part of curing/managing the disorder.

2 Remember kids, Microsloth operating systems are like TOS Star Trek movies with in that every other one sucks way, way more. With TOS Star Trek movies you don’t want to bother watching the odd-numbered ones. With Microsloth OS you don’t want to buy and install the even-numbered ones. Anyone who remembers ME and Vista knows what I mean.

3 Have I mentioned how open source operating systems for commercial applications is one of the dumbest ideas in the history of dumb ideas?* I don’t even need my big-ass rant any more. Heartbleed has made my case for me. And that’s just the one that got all the media attention. The very nature of an open source operating system makes security as much of an illusion as anonymity on teh Intergoogles. Before you flip out too much: the domain Crazymeds is hosted on uses a version of SSL that is not affected by the Heartbleed bug. That’s one of the many reasons why I pay a lot of money and keep this site on Lunarpages.

* Yes, I know I’m using open source browsers. I also test the site using the now-defunct IE and Safari browsers. Their popularity - and superiority - killed IE and Safari, so that’s why I rely on the open source browsers. It’s like brand vs. generic meds. Sometimes the generic is better than the brand.

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