Thursday, February 19, 2009


Here's a link to a very interesting study which shows that the beta-blocker propranolol can interrupt the consolidation of fear in humans:

This study suggests a novel use for beta-blockers, which could facilitate behavioural therapy for PTSD. The study demonstrates a variety of things:
1) as was well-known before, when people experience something fearful or traumatic, it sensitizes them to react more strongly to the same fearful stimulus in the future
2) when people re-experience a fearful or traumatic memory, this re-experience consolidates, or strengthens, the strong fearful reaction. This is consistent with the evolution of PTSD and other anxiety disorders, in which an expanding variety of daily events can trigger and consolidate the fear (e.g. a survivor of a bad traffic accident may constantly re-experience traumatic symptoms when hearing traffic noise, loud sounds, etc.--and may start to avoid these situations. Every time this happens, the anxiety disorder becomes more entrenched).
3) Fears can be "extinguished" by re-experiencing the feared stimulus repetitively, in a safe setting. But the fear can be "re-kindled" after extinction more easily than in non-traumatized people (this suggests a permanence to "emotional memory" that can be only temporarily over-ridden by psychological techniques)
4) If the consolidation phase of fear or traumatic memory could be interrupted, then a person might not develop ongoing post-traumatic symptoms at all. In this experiment, there is evidence that propranolol can interrupt this consolidation.
5) Propranolol may disrupt the "emotional memory" consolidation but not the "declarative memory"--the former process may occur primarily through the amygdala, whereas declarative memory is consolidated mainly in the hippocampus. So, the use of propranolol would not "erase the memory" of a traumatic event--the facts of the event would still be remembered normally--but it might reduce the painful, reflexive feeling of emotional trauma associated with the event.

The study does NOT show that "propranolol erases memories", as some of the news headlines seem to be proclaiming. It DOES suggest that adjunctive propranolol may greatly enhance the effectiveness of behavioural therapy. It requires that the person use propranolol while engaging in exposure therapy. So, for example, a possible technique for treating PTSD or panic (especially new-onset) might be to use a 40 mg dose of propranolol 1-2 hours before a therapy session. In the therapy session, the memories of the upsetting events could be discussed. The propranolol might interrupt the process of these upsetting memories getting further consolidated, might facilitate a behavioural therapy process which would help the person feel emotionally comfortable with their thoughts and memories. This process may occur because of direct beta-blockade in the amygdala, which may interrupt consolidation of emotional memory directly.

Despite this encouraging study, there are a number of negative studies looking at using propranolol similarly, for example:

I think the main thing to take from the first study is that propranolol may help, but probably only as an augmentation to enhance the effectiveness of behavioural therapy (or CBT) for treating post-traumatic stress or other anxiety disorders.

Beta-blockers are drugs used primarily in cardiology. Some beta-blockers, such as atenolol, act only peripherally, that is they do not enter the brain very much. Others, especially propranolol, can more easily enter the brain, and therefore can act in the central nervous system as well as peripherally.

In psychiatry, propranolol has been useful to treat performance anxiety, especially if there is a component of tremor (e.g. shaking hands) accompanying the anxiety. Many musicians use doses of propranolol to reduce tremor during performances. The anti-tremor mechanism is most likely peripheral beta-blockade (i.e. outside the brain), but the accompanying reduction of subjective anxiety may also be due to central beta-blockade (i.e. inside the brain). This is consistent with some studies which show that peripherally-acting beta-blockers reduce tremor as well as propranolol, but people subjectively prefer the propranolol.
(Reference: )

Beta-blockers have been studied in the treatment of panic disorder, decades ago. They don't work. Here's a link to one of the many studies showing this:

Yet, these old studies don't look at the possibility that the beta-blocker could work as an "augmentation" to psychological therapy. Many effective treatments do not work on their own, they work only in conjunction with something else.

Beta-blockers have also been used to treat irritability or rage problems. Here are a few references:
{one of the studies in the geriatric psychiatry literature, showing possible benefit for using propranolol to help agitated dementia patients}
{an example of a study showing some benefit of propranolol treatment for reducing rage outbursts -- however the study is of low quality}
{another study from the Mayo Clinic in 1985, showing some success using propranolol to treat patients with rage outbursts}
{a review paper from 1997, looking at various pharmacologic treatments for aggression; some of the research about beta-blockers is reviewed here}

In summary of the above studies, beta-blockers may help a bit for irritability, aggression, rage outbursts, and agitation, due to a variety of causes, but the evidence base is mainly from before 1990, and the studies are not very rigorous.

Beta-blockers also help diminish a very uncomfortable symptom called "akathisia". Akathisia is a state of external, and internal, restlessness, that can be caused by older antipsychotic drugs.

Beta-blockers are also useful in migraine prophylaxis. Migraine is associated with depression, so a beta-blocker could be a good therapeutic choice in someone with migraines as well as anxious, irritable, or agitated depression.

There were a few studies suggesting beta-blockers could cause or worsen depression, but many of these studies are weak. Here is a review:

In a more recent major JAMA review, beta-blockers were not found to be causative of depression or fatigue:

In my opinion, beta-blockers should be used cautiously in people who have or develop depressive symptoms, but I don't think they are contraindicated, since they may be beneficial overall if they help other symptoms. Also, if there are depressive effects, these may be dose-dependent, and may disappear just by reducing the dose.


Beta-blockers literally "block" beta-adrenergic receptors in the body. These beta receptors are normally stimulated by the catecholamines adrenaline and noradrenaline (also called epinephrine and norepinephrine), which are hormones secreted by the adrenal glands and by a small area of cells deep in the brain called the locus ceruleus. There is always a little bit of these hormones in circulation (in quantities in the order of parts per trillion, concentrations which would be achieved by adding a single drop of hormone to the volume of 1-10 olympic-sized swimming pools).**

Here is a reference showing resting adrenaline and noradrenaline levels in healthy subjects:

These tiny quantities of hormone are nevertheless enough to stimulate beta receptors; such stimulation is required to maintain or increase the output of the heart, also many other actions in the body, including in kidneys and muscle tissue.
{An excellent study looking at peripheral catecholamine levels (norepinephrine and epinephrine) in groups of patients with anxiety, patients with pheochromocytoma (a disease causing huge increases in catecholamine levels), and normal controls; they found that peripheral norepinephrine levels correlate with anxiety, but NOT in the pheochromocytoma patients; this supports a theory that anxiety states cause central, and secondary peripheral, stimulation of catecholamine release--but the catecholamines themselves do not necessarily CAUSE the anxiety, but are a RESULT of it. Incidentally, Psychosomatic Medicine is another excellent journal worth following}
{a study showing that norepinephrine levels in the brain correlate highly with blood pressure in normal controls; but do not correlate at all with blood pressure in people with PTSD, suggesting that in PTSD there is an abnormality in catecholamine regulation}

{a study from The American Journal of Psychiatry showing that people with PTSD have levels of CSF norepinephrine almost twice as high as normal, and that the norepinephrine levels correlate with the severity of PTSD symptoms}
{a study from Archives of General Psychiatry in 1984, showing higher levels of plasma catecholamines in panic disorder subjects; but less responsiveness to further adrenergic stimulation in the panic subjects--this suggests that anxious subjects have chronically high catecholamines, and consequently are actually LESS sensitive to catecholamine changes}
(an article about the role of norepinephrine released in the brain's locus ceruleus, and its importance for optimizing performance of tasks)

**For the math, let us assume that the resting concentration of epinephrine is 100 pMol, or 10^-10 moles/litre; a litre of water has about 55.5 moles of water, so the concentration can be expressed as one part in (55.5 / 10^-10) or one part in 555 billion. A drop of water has a volume of about 1/20 mL. So this concentration of epinephrine corresponds to an analagous concentration of one drop in (555 billion/20) mL, which is about 1 drop in 28 million litres. An olympic swimming pool has a volume of about 2.5 million litres ( So this concentration corresponds to 1 drop in a volume of over 10 swimming pools.


L said...

Hi Dr. K,
Just an idea...

You mentioned ,"In psychiatry, propranolol has been useful to treat performance anxiety, especially if there is a component of tremor (e.g. shaking hands)...[and that] the accompanying reduction of subjective anxiety may also be due to central beta-blockade (i.e. inside the brain)"

Maybe it is like the test you posted about in your "Singing" post? Maybe the beta blocker makes the hands stop shaking, and when the hands stop shaking anxiety is reduced in much the same way the reduced hand tremor is like "..changing the position of facial muscles". And it, "leads to a change in emotional response".

Is that a possibility?

GK said...

Yes, I think so.

When an external manifestation of anxiety is relieved, it can lead to a whole cascade of effects breaking an anxiety cycle. This could occur on a behavioural level, through conditioning -- but also, as you are implying, I suspect that the brain areas responsible for emotion are connected (literally) to all the other parts of the body, including the hands; thus the state of having steady, non-tremulous hands (or voice) may actually induce a state of emotional calm.

L said...

That is so interesting. So, maybe if there was a medication that woud stop you from crying, depression levels could be taken down?