Treating anxiety with either beta blockers or antiemetic antimuscarinic drugs: a review
Mental Health in Family Medicine 2015; 11:89-99
2015 Mental Health and Family Medicine Ltd
Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review
Thomas P. Dooley, Ph.D.
TPD LLC, 7100 Cabin Lane, Pinson, Alabama 35126, USA; Tel: 205-222-6145; E-mail: [email protected]
Beta adrenergic receptor antagonists and antiemetic scopolamine) or over-the-counter (e.g., meclizine) for the
muscarinic receptor antagonists are useful for mental health treatment of non-cardiovascular symptoms that manifest in
in primary care and family medicine settings, as they provide anxiety disorders. Antiemetic agents inhibit nausea, vomiting,
favorable risk/benefit profiles, and especially so relative to sweating, and in some instances other psychic (CNS) symptoms.
benzodiazepines. Beta blockers (e.g., propranolol) prescribed The symptoms affected by antimuscarinic agents represent the
off-label have been known for decades to provide some, "inverse" of the symptoms of acute anxiety affected by beta
albeit limited, anxiolytic benefit for patients affected by blockers. Thus, anxiety disorders can be treated by alternative
social anxiety disorder (social phobia), including performance biochemical pathways, as well as by affecting alternative
anxiety. Blockage of adrenaline's binding to cardiovascular symptoms thereof. The results of human clinical studies are
beta adrenergic receptors inhibits tachycardia, reduces blood summarized for both classes of anxiolytic agents that display
pressure, and thus diminishes palpitations in acute anxiety complementary pharmacologic approaches to a diverse array
and panic. However, beta blockers are not effective against of symptoms.
the psychic (CNS) symptoms, such as anxiousness, fear, and
avoidance. Another approach involves antiemetic muscarinic
Anxiety, Panic, Anxiolytic,
receptor antagonists that are available by prescription (e.g., Beta Adrenergic, Muscarinic, Cholinergic, Antagonist,
The biochemical pathways of the beta adrenergic receptor
and muscarinic receptor gene families are appropriate anxiolytic
The pharmaceutical marketplace in the Western World targets for treating the symptoms of social anxiety disorder
provides numerous medical treatments for anxiety disorders. (social phobia) including performance anxiety (e.g., stage fright),
Two classes of medications that have demonstrated some as well as panic attack (PA), panic disorder (PD), agoraphobia,
effectiveness and desirable risk/benefit profiles in the clinical
generalized anxiety disorder, and post-traumatic stress disorder
literature are beta blockers and antiemetic antimuscarinic drugs.
(PTSD). These various anxiety Disorders are delineated within
These agents have been widely used as monotherapies for a the Diagnostic and Statistical Manual of Mental Disorders
least half of a century around the globe.
(e.g., DSM-V). These molecular targets can be components
They are appealing in large part due to historic safety profiles
of the central nervous system (CNS), the peripheral nervous
and because they do not exhibit the potential for chemical system, and/or of target somatic tissues (e.g., cardiovascular
dependence or substance abuse. Therefore, these two classes
and gastrointestinal tissues). The multiplicity of symptoms of
of agents are not subject to the US Food & Drug Administration
anxiety disorders are under the complex regulation of different
(FDA) and Drug Enforcement Agency (DEA) as Controlled neurologic, neuroendocrine, and endocrine pathways.
Substances (i.e., "Scheduled" drugs). Furthermore, many
Let us consider the multiplicity of symptoms that occur
antimuscarinic drug products are sold without prescriptions, in an acute anxiety episode, of which a panic attack serves as
such as over-the-counter (OTC) or in some foreign settings the foremost and severe example. Perception of a "trigger"
behind-the-counter with pharmacists' assistance.
circumstance results in the autonomic release of epinephrine
Beta blockers and antiemetic antimuscarinic (adrenaline), as well as cortisol and norepinephrine. This in
(anticholinergic) active pharmaceutical ingredients (APIs) are
turn causes multiple effects consistent with a "fight-or-flight"
of particular interest for primary care physicians (PCPs), such
response. Symptoms include tachycardia, palpitations (self
as family practitioners, internists, and osteopaths, as well as perception of an elevated heart rate and/or of a strong heart beat),
physician assistants, nurse practitioners, and dentists. There hypertension, hyperventilation with reduced blood CO and
is a need to provide drugs to their affected patients with some
altered pH, dyspnea, nausea, vomiting, sweating, anxiousness,
anxiolytic efficacy, yet without incurring unnecessary safety
fear, avoidance, trembling (tremors), headache, among others.
risks. In contrast, this is problematic with the alternative, Many of the somatic and/or psychic (CNS) symptoms of panic
more potent, and risk-laden options, such as benzodiazepines.
attack are shared in common with other acute anxiety episodes.
The more potent drugs are more likely to be prescribed by Therefore, it follows that a treatment for an array of the
psychiatrists or hospitalists. Many prescribers in primary care
symptoms of panic per se
can also be effective against a broader
settings are reluctant to prescribe the more potent drugs (e.g.,
list of anxiety disorders.
benzodiazepines) or are restricted from doing so. Thus, beta
Some patients anticipate future episodes of panic or acute
blockers and antimuscarinic agents help address this need, anxiety based upon his/her history of prior encounters with a
wherein safety is the paramount decision factor.
known "trigger" circumstance. A trigger circumstance might
Thomas P. Dooley
be public speaking or music performance, flying or driving,
stated regarding benzodiazepines as a class of anxiolytic drugs,
a crowd, decision making, an unfamiliar setting, among "Only lorazepam is currently available in a form suitable for
others. Treatments may be tailored to be either prophylactic sublingual administration, which was developed in the hope
or therapeutic in nature. Given the patients' anticipation of a
that, by bypassing the gut, a more rapid onset could be achieved
trigger leading toward likely future symptoms, p.r.n.
similar to that with intramuscular administration. However
drug treatments can begin either during or immediately prior Greenblatt et al.,  found that the sublingual formulation was
to the time when symptoms would be expected to commence.
absorbed at a rate that did not differ significantly from that of
Alternatively prophylatics could be administered continuously
regular oral administration of the standard tablets or even from
over weeks or years, or within hours of the anticipated triggers.
that of sublingual administration of the standard oral tablets."
In aggregate anxiety disorders are extremely common, Thus, benzodiazepines are not suitable APIs for rapid treatment
affecting nearly 40 million in the US. With regard to the subset
of symptoms of panic attacks or acute anxiety episodes, even
experiencing the most severe episodes, the lifetime prevalence
when delivered sublingually (mucosally). When "time is of the
of PA is 28.3% of the adult US population . The 12-month
essence" for therapy, benzodiazepines are inadequate, regardless
prevalence of panic disorder (PD) is estimated to be 2.7% of the
of the oral or sublingual routes of administration. Perhaps the
adult US population , with 1.2% considered as "severe" .
perception of benzodiazepines' fast-action is due to comparison
More than half of affected adults (59.1% or 3.8 million) are
with SSRIs, which require a very slow dose-escalation approach
receiving treatment(s) . Patients affected by PAs are often over weeks of time to produce a beneficial effect. In that context
also affected by the co-morbid conditions of depression  as
benzodiazepines are faster than SSRIs. But, in spite of FDA
well as migraines and other forms of headaches [6,7].
approvals for p.r.n. use of certain benzodiazepines and their
broad availability, there still remains a need for fast-acting p.r.n.
The current standards-of-care for panic disorder are oral anxiolytics. In fact, an academic psychiatrist characterized this
psychiatric prophylactic pharmaceuticals, including: (a) Selective
need to the author as "…the Holy Grail of modern psychiatry."
serotonin reuptake inhibitors (SSRIs), which are considered as the
first choice medicines for PD. Examples include paroxetine
Benzodiazepine and SSRI drugs can produce disabling
(Paxil®), sertraline (Zoloft®), and fluoxetine (Prozac®); (b)
psychic and somatic side effects, such as sedation, lethargy,
Benzodiazepines, such as alprazolam (Xanax®), clonazepam chemical dependence, tolerance, impaired cognition, and sexual
(Klonopin®), lorazepam (Ativan®), and diazepam (Valium®);
dysfunction. As a result of these negative side effects and some
and (c) Serotonin-norepinephrine reuptake inhibitors (SNRIs),
potential for abuse, benzodiazepines are classified by the FDA
such as duloxetine (Cymbalta®) and venlafaxine (Effexor®). as Schedule 4 (IV) Controlled Substances. Many physicians
These oral therapies are taken daily for the prevention of and other prescribers are reluctant to prescribe or are restricted
panic attacks. Some of these drugs are FDA approved for the
from prescribing benzodiazepines. Therefore, beta blockers or
prophylaxis of PD, such as paroxetine, sertraline, alprazolam,
antiemetic agents that are generally perceived as historically
and clonazepam. Other anxiety disorders are also treated in the
safe or safer than benzodiazepines are often preferable. This
same or a similar manner. For instance, social anxiety disorder,
is especially true in the primary care and family practice
generalized anxiety disorder, agoraphobia, and PTSD are also
disciplines. Sedation and lethargy are often problems for many
treated using the same or similar oral daily pharmaceutical of the oral daily anxiolytic therapies, such as benzodiazepines.
It is not uncommon to note a "zombie-like" state in patients
taking benzodiazepines. By contrast, beta blockers are non-
The pharmaceutical standards-of-care in routine psychiatric
addicting and non-sedating. And, the antimuscarinic agents
care of panic and anxiety disorders involve two key aspects: are non-addicting, and are non-sedating or minimally sedating
(A) prophylaxis, rather than treatment of the symptoms per at appropriate antiemetic doses. However, high doses of some
se; and (B) the medications are routinely given as daily oral
antiemetics can produce sedation.
"maintenance" medications for persistent use (i.e., chronic
prophylaxis), rather than as occasional administration p.r.n.
: Beta adrenergic receptor antagonists are
"as needed" at the time of episodes of symptoms (i.e., acute prescribed "off label" (i.e., without FDA approval) for anxiety
disorders, and most notably for performance anxiety and social
phobia. Beta adrenergic receptor antagonist agents may be
Although oral benzodiazepines have been used as selected from a large group of APIs consisting of propranolol,
persistent daily medications for the prophylaxis of panic and atenolol, alprenolol, acebutolol, betaxolol, bisoprolol,
acute anxiety, they are not reasonable candidates for a "fast-
bucindolol, celiprolol, nadolol, sotalol, esmolol, carteolol,
acting" p.r.n. therapy approach. Benzodiazepines are often carvedilol, mepindolol, nebivolol, oxprenolol, penbutolol,
mistakenly considered to be "fast-acting", although multiple pindolol, landiolol, metoprolol, timolol, labetolol, among
clinical reports indicate otherwise. Zamorski and Albucher others. For convenient recall by prescribers the nomenclature
stated, "Benzodiazepines should not be used on an as-needed
for all beta blockers contains an "LOL" suffix (and not to be
basis for panic disorder. None of the oral benzodiazepines confused with the abbreviation for "laughing out loud").
works quickly enough to affect any but the most prolonged
panic attacks ." Altamura, et al. stated recently, "…it would
Propranolol is the most thoroughly studied and reported in
be desirable for the development of new anxiolytic drug(s) the literature of the beta blockers, having been discovered by
that are more selective, fast acting and free from the unwanted
Sir James Black in 1958. It serves as the prototype for this
effects associated with the traditional benzodiazepines as class of drugs, having also been the most prescribed medicine
tolerance or dependence ." Altamura and coworkers also
in the world at one juncture. Propranol is a beta adrenergic
Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 91
receptor antagonist that affects the autonomic nervous system
and reduces cardiovascular symptoms (e.g., tachycardia and
Clinical Evidence for Beta Blockers as Anxiolytics.
hypertension) resulting from epinephrine in the circulation.
Beta blockers interfere with receptor binding by catecholamines,
epinephrine and norepinephrine, of which epinephrine is the
principal catecholamine affecting the cardiovascular symptoms.
Propranolol is a lipophilic beta blocker that readily crosses the
blood-brain barrier. Therefore, it can affect both somatic and
CNS target tissues.
Propranolol is routinely delivered orally. Propranolol in
Inderal® is available in oral doses ranging from 10 to 80 mg per
dose for the treatment of hypertension. Multiple doses per day
may be permitted. This drug can also be absorbed mucosally, as
demonstrated by sublingual delivery , and its bioavailability
CO -induced panic
is higher when absorbed by this route rather than orally [13,14].
Propranolol has been delivered sublingually at 10 and 40 mg
per dose [12,13], although this can produce mouth paresthesia,
an undesirable effect. Also, propranolol has been delivered by
rectal administration in mammals . It does not demonstrate
chemical dependence or sedation that are common side effects
of many psychiatric medications.
Propranolol is prescribed for the treatment of various
cardiovascular indications with FDA approval, most notably
hypertension, arrhythmia, angina, as well as prophylaxis of
migraines. However, there is evidence that it can have some
benefit with regard to a subset of the symptoms of panic and
a single dose of 40 mg of oxprenolol prior to speaking to an
anxiety disorders. The drug's anxiolytic potential was recognized
audience suppressed tachycardia in performance anxiety .
as early as 1966, "Emotions are expressed through the autonomic
In contrast, in another clinical study daily oral propranolol was
nervous system, and anxiety states are associated with increased
not effective at treating panic disorder and agoraphobia with
secretion of catecholamines. Propranolol may therefore have a
panic attacks .
place in the treatment of anxiety, especially when the symptoms
There is some evidence suggesting that propranolol might be
are related to the cardiovascular system ." This prescient beneficial in academic test-taking among normal and anxiety-
comment five decades ago was subsequently validated by
prone students. Examination performance might be increased
clinical studies with regard to both aspects: (a) propranolol and
by pretreatment with this beta blocker [23, 24].
other beta blockers have been used "off label" in the USA for
the near-term prophylaxis of performance anxiety; and (b) the
To assess the clinical efficacy of an anxiolytic drug, trials
pharmacologic benefits of propranolol and other beta blockers
can be performed either "in life" or in a laboratory setting
are restricted to the cardiovascular system's effects per se. The
intended to induce anxiety. One established clinical trial design
evidence is provided below. The beneficial anxiolytic effects are
to provoke anxiety is the Trier Social Stress Test (TSST). This
limited to blocking the pharmacologic effects of catecholamines
method is used in a clinic and involves subjecting an individual
upon the cardiovascular system without addressing the psychic
to public speaking and mathematics questions as stressors.
(CNS) symptoms or other somatic symptoms of acute anxiety
The TSST method has been used to study the effects of oral
and panic, with the possible exception of tremors.
propranolol in volunteer subjects [25-28]. The assessments
(Table 1) summarizes the relevant evidence from clinical of psychic anxiety can be assessed by the State-Trait Anxiety
investigations in the literature regarding beta blockers used Inventory (STAI) or other similar tools [29,30]. The somatic
to treat anxiety conditions. Daily oral propranolol has been and psychic effects of oral propranolol were tested using the
demonstrated in one prophylactic study to suppress panic attacks
TSST method in healthy adult volunteers. Propranolol (40 mg)
in subjects diagnosed with panic disorder and agoraphobia one hour prior to TSST significantly reduced heart rate, reduced
. Tyrer and Lader demonstrated some effectiveness of systolic blood pressure, and enhanced cognitive flexibility
oral propranolol in treating somatic anxiety symptoms, but during stress. In another study propranolol (80 mg) one hour
not psychic (mental) anxiety [18,19]. Another daily oral prior to TSST significantly reduced heart rate, but paradoxically
prophylactic study compared propranolol (3 x 80 mg/day) to increased salivary cortisol, and did not significantly affect BP
oxprenolol (3 x 80 mg/day) and revealed that both beta blockers
or subjective stress . But, in another TSST study daily oral
reduced symptoms of anxiety at one or two weeks duration .
propranolol (80 mg) did not affect the salivary cortisol response
Both treatments reduced heart rate; propranolol by 21 - 32
bpm and oxprenolol by 16 - 23 bpm. However, propranolol
An alternative clinical trial design involves the intentional
was more effective at reducing palpitations when assessed on
chemical provocation of a panic attack in a clinic. Several
day 7 compared to oxprenolol. Another study demonstrated that
methods of provocation of PA have been reported, wherein
Thomas P. Dooley
atenolol has been delivered by a mucosal route in mammals
Clinical Evidence for Antimuscarinic Agents as
Another beta blocker is nadolol, which is non-selective and
with a preference for beta-1 receptors. It does not pass through
the blood-brain barrier. In a clinical trial with musicians, nadolol
reduced pulse rate and improved one aspect of performance
related to tremor . A similar result was obtained for nadolol
in students' singing performance . In spite of being non-
selective, nadolol might ironically benefit the pulmonary
function in asthma patients based upon the appropriate dosage,
an anti-intuitive result .
An alternative beta blocker is pindolol, a non-selective agent,
a physician intentionally stimulates a physiologic response which can enhance the effects of co-administered antidepressants
by CO inhalation , sodium lactate infusion [32,33], or
and has some 5-HT antagonist property. Pindolol reduced
cholecystokinin tetrapeptide (CCK-4) injection [32,34]. These
symptoms of performance anxiety in musicians .
chemical exposures are used as potent tools to design controlled
studies with predictable levels of PA episodes. In a study with
Another example is betaxolol that can also cross the blood-
healthy volunteer subjects using carbon dioxide inhalation to brain barrier. Daily oral betaxalol was delivered at 5 - 40 mg
provoke panic and anxiety, propranolol significantly decreased
per day in the treatment of generalized anxiety disorder and
heart rate, a cardiovascular somatic symptom, but did not other anxiety-related conditions. Anxiety and panic attacks
provide psychic anxiolytic benefit .
were reduced within several days . This anxiolytic benefit
is prophylactic, as the effects are observed in days, rather than
Propranolol has also been investigated in patients suffering
from severe posttraumatic stress disorder (PTSD). Two clinical
studies of this beta blocker have shown possible benefits in the
In view of the clinical studies and off-label use of various
early-stage interventional prevention and subsequent therapy beta blockers, psychiatrists are aware that beta blockers can
of PTSD [36,37]. Subsequent reports have also echoed that provide some symptomatic relief with regard to performance
propranolol might be effective for this condition [38-40], anxiety . However, beta blockers alone do not sufficiently
although other reports dispute this conclusion [41,42].
address the aggregate symptoms of panic and acute anxiety
episodes, and especially the psychic symptoms thereof (e.g.,
When considered in aggregate these clinical studies of fear, avoidance, and anxiousness).
propranolol, as the well known prototypical beta blocker,
provide convincing evidence that the drug can exert somatic (i.e.,
Beta blockers also exhibit some benefit with regard to
peripheral) effects on the cardiovascular system in the context of
alcohol and drug abuse. The abuse of alcohol, prescription
panic and anxiety disorders. With regard to affecting the psychic
drugs, and illegal drugs (e.g., opioids, opiates, and cocaine)
(CNS) symptoms, the results have been negative, inconsistent,
are major mental health care concerns. The repetitive abuse of
or inconclusive. That being said, there is some limited evidence
these chemicals can produce physiologic dependence, tolerance,
that propranolol can exert some psychic (CNS) benefits in
addiction, and neurologic damage. The symptoms of sudden
clinical stress trials. In a pair of clinical studies, propranolol
withdrawal depend upon the abused substance, the impairment
(a central and peripheral beta-blocker) significantly enhanced
of neurological and neuroendocrine pathways, as well as
problem solving during stress, whereas nadolol (peripheral only
somatic organ impairment. The withdrawal from addictive
beta-blocker) and lorezapam (benzodiazepine) did not [43, 44].
substances produces an array of symptoms, many of which
Thus, propranolol enhanced cognitive flexibility ("creativity")
overlap with the symptoms of panic and acute anxiety episodes.
during stress. It remains unclear whether propranolol alone can
Delirium tremens (DTs) occur in some alcoholics upon abrupt
appreciably reduce psychic effects. In aggregate the clinical cessation of drinking. The symptoms of alcohol-related DTs are
evidence does not support a benefit regarding psychic (CNS)
very similar to those of panic attacks, and are in part related to
beta adrenergic effects. The DTs can have serious and even life-
threatening consequences. The standards-of-care for DTs are
Numerous alternative beta blockers are available in lieu oral benzodiazepines. Withdrawal from opioid and/or opiate
of propranolol. Notable among these is the common drug, addiction is physiologically distinct from alcohol withdrawal.
atenolol, that is available in oral solid dose forms ranging from
25 to 100 mg for the treatment of hypertension. Multiple doses
With regard to beta blockers in substance abuse, atenolol
per day may be permitted. It has been used to suppress stage
has been shown in placebo-controlled trials to be beneficial
fright in performers when administered orally in advance .
in alcohol withdrawal [54-56]. Pindolol has been used to treat
Atenolol is a beta-1 selective peripheral-acting agent without alcohol withdrawal . Timolol had a minimal effect on a
CNS effects, which should reduce the risk for asthmatic subjects
subset of symptoms of patients experiencing alcohol withdrawal
. Thus, atenolol might be preferred over the nonselective
.With regard to cocaine abuse, propranolol has been used to
beta blockers for patients affected by asthma or COPD . treat withdrawal and overdoses [59, 60]. Note that propranolol
Oral atenolol at 50 - 200 mg doses suppressed heart rate by 23
has also been shown to suppress tremors , consistent with
- 24 beats per minute (bpm) vs. 10 bpm on placebo . Also,
one of the perceived benefits of beta blockers in performance
anxiety in musicians (above).
Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 93
Migraine is a co-morbid condition in approximately two-
mg, and a maximum daily dose of 1.2 mg . Scopolamine
thirds of patients suffering from panic disorder [6,62]. The can also be absorbed mucosally, as demonstrated by sublingual
prevalence of migraine in the USA according to the American
delivery [79,80]. It has been delivered sublingually at 0.15 mg/
Migraine Prevalence and Prevention (AMPP) study is 11.7% dose , intranasally at 0.4 mg [81,82], orally at 0.4 - 1.0 mg/
and probable migraine is 4.5%, for a combined total of 16.2%
dose [80,83], and transdermally (Transderm Scop®) at 1.5 mg/
. The rate is higher in females than in males. According
dose over 3 days as antiemetic treatments or prophylactics. Oral
to Smitherman and coworkers, "The first-line migraine
delivery, unlike mucosal or transdermal delivery, involves first-
prophylactics are not indicated for PD, and the selective pass hepatic metabolism of scopolamine, thus restricting its
serotonin re-uptake inhibitors used to treat PD are not efficacious
for migraine; thus, separate agents are often required to address
each condition ." Furthermore, according to Marazziti and
Antiemetic muscarinic receptor antagonist agents can be
coworkers, "…the comorbidity of headache with panic disorder
selected from a large group beyond scopolamine, examples of
renders this condition more severe and possibly responsive to
which include diphenhydramine, meclizine, buclizine, cyclizine,
different treatments compared to panic disorder alone ."
hydroxyzine, pirenzepine, benztropine (benzatropine),
atropine, hyoscyamine, butylscopolamine, methylscopolamine,
It is feasible that a beta blocker alone may provide therapeutic
doxylamine, promethazine, trihexyphenidyl, orphenadrine and
benefit for both conditions, panic and migraine. Beta-adrenergic
its metabolite tofenacine. Depending on the choice of country,
receptor antagonists are considered to be effective prophylactics
OTC or "behind-the-counter" antiemetic antimuscarinic
for chronic or episodic migraine [65-70]. Although one study
agents include diphenhydramine, orphenadrine, doxylamine,
reported no benefit from propranolol for treatment of acute
meclizine, buclizine, cyclizine, and scopolamine. This further
symptoms , there is some, albeit limited, evidence that underscores the perception by regulatory agencies of the safety
beta adrenergic receptor antagonists, especially when delivered
of antimuscarinic agents. Dryness of the mouth is a common
mucosally, can also have benefit in the therapy of acute migraine
side effect of antiemetic agents.
Structurally-related derivatives of scopolamine are
Beta blockers may be effective as a treatment for aggression.
alternative antimuscarinic APIs, such as butylscopolamine,
Systemic adrenaline can produce excited, anxious, and methylscopolamine, atropine, hyoscyamine (the levo
aggressive behavior in some individuals. Propranolol has been
isomer of atropine), and benztropine (benzatropine). For
shown to have a therapeutic effect with regard to aggressive instance, peripherally-acting butylscopolamine (scopolamine
butylbromide) is used for the treatment of abdominal spasms.
Although psychiatrists (and some other physicians) are aware
The butylbromide modification prevents the API from crossing
of off-label use of beta blockers as prophylactics for performance
the blood-brain barrier. However, direct pharmacologic action
anxiety (e.g., stage fright during musical performances), the by the antimuscarinic agent upon the CNS might be preferable,
current pharmaceutical standard-of-care for anxiety disorders if not necessary, for mediating psychic benefits in anxiety.
does not routinely include the use of beta blockers. But, beta
In addition to the scopolamine "family" of APIs,
adrenergic receptor antagonists can provide limited benefit, such
there are other closely-related families of APIs exhibiting
as the suppression of cardiovascular symptoms - tachycardia,
antimuscarinic activities. In some cases the APIs also exhibit
palpitations, and increased blood pressure, which are symptoms
antihistamine properties. Examples of other "families" of
of acute anxiety episodes and panic. That being stated, Zamorski
antiemetic antimuscarinic agents include: (a) Ethanolamines:
and Albucher concluded, "Beta blockers, once widely touted diphenhydramine (Benadryl®), doxylamine (Unisom® or
as effective antipanic medications, have proven disappointing
Nyquil®), orphenadrine (an OTC in Canada) and its metabolite
as monotherapy in subsequent placebo-controlled trials." The
tofenacine; and (b) Piperazines: meclizine (Dramamine®
multiplicity, severity, and short duration of symptoms in a panic
Less Drowsy Formulation or Bonine®), buclizine, cyclizine,
attack make it a difficult disorder to treat by p.r.n. therapies.
hydroxyzine (Atarax® or Vistaril®), and pirenzepine.
Muscarinic Receptor Antagonists:
Scopolamine is the Furthermore, other types of antiemetic antimuscarinic agents
prototypical antiemetic antimuscarinic agent. It is a plant-derived
are available, such as promethazine (Phenergan®) and
natural product derived from the Solanaceae "nightshade" trihexyphenidyl.
family of plants (e.g., jimson weed), and is commonly used for
(Table 2) summarizes the relevant evidence from clinical
the treatment of motion sickness, nausea, and vomiting. It is
investigations in the literature regarding antimuscarinic agents
a potent nonselective muscarinic receptor antagonist that can used to treat anxiety conditions. Hydroxyzine is an FDA-
inhibit all five human receptor subtypes with 0.34 - 5.3 nM Ki
approved prescription medicine for the treatment of anxiety .
values . It is lipophilic and crosses the blood-brain barrier
The package insert for Atarax® (Roerig) states it is indicated
to exert psychic parasympathetic (CNS) pharmacologic effects.
"for symptomatic relief of anxiety and tension associated
Scopolamine is sold by prescription in the USA as a with psychoneurosis and as an adjunct in organic disease
transdermal patch (Transderm Scop®) . However, states in which anxiety is manifested." As a first-generation
scopolamine is available without a prescription in many foreign
antihistamine this drug entered the healthcare marketplace in
markets, where it can be purchased OTC or behind-the-counter
the mid-1950's. It displays broad receptor binding, affecting
with pharmacist's assistance. For instance, in Australia it is an
histamine, muscarinic, and 5-HT receptors. Placebo-controlled
oral OTC product with a recommended adult dose of 0.3 or 0.6
studies with a total daily dose of 50 mg have revealed anxiolytic
benefit following weeks or months of treatment in generalized
Thomas P. Dooley
anxiety disorder [84-86]. This "old" drug is no longer among
of pharmacologic effects can precede the zenith of plasma
the frontline choices for anxiety, having been superceded levels, except for rapid intravenous administration wherein
by benzodiazepines and subsequently SSRIs and SNRIs.
pharmacologic effects might be concurrent or delayed slightly.
However, it has at least two beneficial properties -- an effect can
be perceived faster than many other oral anxiolytics, and like
The antidepressant dose via the i.v. route (4 ug/Kg) is likely
other antimuscarinic agents it has a desirable risk/benefit profile
to be above the blood levels attained during routine antiemetic
(i.e., doesn't produce dependency). In addition to treating dosing (e.g. transdermal patches or oral dose forms), wherein
generalized anxiety disorder, a few case reports suggests it sedation would be considered a significant and undesirable
might be beneficial in treating panic disorder [87,88].
side effect. For comparison, sedation is generally considered
in the literature to occur at 1.2 mg or higher by the oral route.
Promethazine is another antimuscarinic agent with Scopolamine has been used as a safe pre-sedative, for instance
antihistamine and CNS activities. Oral promethazine at 25 mg/
in pregnant women prior to delivery.
dose reaches a peak serum level (C ) in 2-3 hours, which is
relatively slow for an oral drug, and can result in drowsiness
In addition to scopolamine, two other muscarinic receptor
within a similar time window . As a premedication prior to
antagonists, orphenadrine and its major metabolite, tofenacine,
surgery, it produced an anxiolytic effect that was substantially
have also been reported to exhibit an antidepressant effect [99-
greater than placebo .
101]. Orphenadrine is beneficial in treating multiple symptoms
of Parkinsonism. Orphenadrine administered orally (300 mg/
Although depression per se
is not the focus of this review,
day) for three weeks in patients afflicted by Parkinsonism was
selected antimuscarinic agents can display psychic (CNS) very effective at blocking depression relative to placebo .
pharmacologic effects on mood, such as depression (e.g., Tofenacine at 120 – 240 mg/day for six weeks was effective
major depressive disorder). Scopolamine can exhibit an in treating neurotic depression, endogenous depression, mixed
antidepressant effect when administered intramuscularly ,
depression, and phobic anxiety diagnoses and within two weeks
intravenously [92-94], or orally . With regard to patients
of initiation of therapy .
treated with i.v. infusions of 4 ug/Kg (e.g., 0.28 mg/70 Kg),
"Significant clinical responses were observed in the evaluation
Although not common knowledge among physicians at
after the first scopolamine administration, 3 to 4 days after
present, there is some historic evidence that scopolamine can
the first treatment." And, "…those patients who observed an
exert anxiolytic effect(s). Scopolamine was described a century
improvement in their depression severity generally reported ago to have a "calming effect
" when injected hypodermically into
relief from their depressive symptoms on the first morning after
patients afflicted by various psychiatric disorders (e.g., manias)
scopolamine infusion (i.e., within 24 hours of drug exposure).
at doses of 0.2 - 1.0 mg . Coincidentally, these doses are
In contrast, no improvement in mood was evident within 150
still relevant in clinical use to this day. This 1906 publication
minutes of scopolamine infusion based upon the POMS" (i.e.,
mentioned, "…the calming effect of the medicament…The
Profile of Mood States) . Although i.v. administration at
action of scopolamine shows itself rapid in maniacal excitement
4ug/Kg can affect depression, many patients receiving this and in acute hallucinatory delirium. The patients become calm
treatment regime also experienced sedation. In addition, they gradually, and fall asleep if the dose is somewhat larger."
experienced dry mouth, blurred vision, and/or lightheadedness.
A genetic study of the human M2 muscarinic receptor gene
The efficacy and side effects of a drug are dependent upon
has revealed an association between specific genetic
the dose delivered and the route of administration. It should be
polymorphisms and the risk of depression in major depressive
noted that the pharmacokinetic magnitude of effect and the time
syndrome . Consistent with these pharmacologic and
to reach an effect of a "typical" API is very likely to exhibit a
genetic findings in humans are laboratory studies with rodent
range from intravenous > intramuscular or mucosal > oral >>
models for antidepressant activity. Both pharmacologic and gene
transdermal. This pattern is in fact the case for scopolamine
knock-out approaches in mice revealed that the antidepressant-
in humans. As an example thereof, intramuscular injection like effects of scopolamine are mediated via the M1 and/or M2
of 0.5 mg of scopolamine displayed only 57% of the absolute
receptors, but not the M3, M4, and M5 receptors . Thus,
bioavailability relative to i.v. infusion of the same dose, and is
the human M2 (and/or M1) receptor-linked second messenger
subject to some delay . Thus, an i.v. antidepressant dose signaling pathways in the CNS are likely to affect mood and
of 0.28 mg/70 Kg of scopolamine is very likely to have an mood disorders (e.g., depression).
immediate and more profound physiologic effect relative to
Alcohol dependence is comorbid with depression, and
the same dose via other routes of delivery, because there are no
has been genetically linked to the same human CHRM2
membrane and tissue barriers to entry into the circulation when
encoding the M2 muscarinic receptor. Scopolamine has an
injected intravenously. By contrast intranasal (mucosal) dosing
M1 receptor preference over M2, but it can also bind the M2
of 0.4 mg results in a C (i.e., the peak level in the blood) after
receptor [76,103]. Thus, there is a convergence between the
22 minutes . Oral dosage forms of 0.6 mg displayed a peak
genetic and the pharmacologic studies in both humans and
plasma level at 50 minutes . And, the 1.5 mg transdermal
laboratory mice, thereby providing a suggested rationale for
patch produces a C of 8 hours . Thus, the timing to
the use of scopolamine in treating alcohol addiction and/or
reach peak blood levels of scopolamine by various routes of withdrawal. These findings might also apply to other antiemetic
administration is or should approximate this progression: i.v. antimuscarinic agents beyond scopolamine.
at 0 min. > intranasal (mucosal) at 22+ min. > oral at 50
Scopolamine has also been shown to reduce aggressive
min. >> transdermal at 8 hours. In general, the perception
behavior in nonhuman primates under certain environmental
Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 95
circumstances . It is not yet clear whether this is also true
antimuscarinic agent in healthy volunteers when exposed
in humans. But, it can be argued that an anxiolytic calming to heat within a sauna . The beta blocker was selected
effect might similarly reduce aggression in some humans, which
because heat induces cardiovascular stress, especially elevated
is perhaps suggested by its historic effect in treating "maniacal
heart rate. Scopolamine was selected as it is known to reduce
sweating. The cardiovascular effects of oral atenolol (50 mg),
The Future – Beyond Monotherapy:
oral scopolamine (0.3 mg), and coincident administration of
mentioned above provide some, albeit limited, pharmacologic
both drugs were monitored before, during, and after heat stress.
efficacy for anxiety disorders, yet while being historically safe
The coincident administration of both drugs revealed essentially
approaches to therapy and/or prophylaxis in mental health. the same cardiovascular effects as atenolol alone (i.e., reduced
Reaching beyond current monotherapies, another approach is heart rate and blood pressure), and either at baseline prior to
combination therapies with two or more APIs. Combination heat exposure or during it. The relevant antiemetic oral dose
drugs can be sold legally to patients, albeit subject to various
of scopolamine alone or as an adjunct to atenolol displayed
alternative regulatory oversight processes.
essentially no effect with regard to the cardiovascular symptoms,
although a slight tachycardia occurred with scopolamine relative
Within the USA combination drug products may be FDA to placebo. Overall, the cardiovascular effects (i.e., reduced heart
approved for specific medical indications through the FDA's
rate and systolic BP) were due to atenolol. Thus, scopolamine
drug approval processes that can result in either approved co-adminstration did not abrogate the cardiovascular effects
prescription (Rx) drugs or approved OTC drugs. Alternatively,
of the beta blocker. The potential for any psychiatric and/or
compounding pharmacies may formulate multiple APIs into psychic (CNS) effects of scopolamine and/or atenolol were not
a compounded pharmaceutical product via either the 503A or
envisioned or addressed by this study.
503B regulatory pathways. But, key parameters must be met for
compounded products. For instance, several of the restrictions
In view of these results  and given that episodes of
include: (a) Each of the APIs must have been included in at least
acute anxiety and panic are driven physiologically in part by
one FDA-approved medication; (b) The compounded product
increased epinephrine's effects on the cardiovascular system,
must not be a copy of an FDA-approved combination drug; and
it is appropriate to include within a combination therapy a
(c) The compounded products are subject to USP 795 or USP 797
beta blocker to address the cardiovascular symptoms per se
standards and procedures during compounding or "outsource"
anxiety disorders. Based upon the literature an antimuscarinic
facility manufacturing, respectively. These compounded agent alone would not be anticipated to be of benefit for the
products are sold by prescription only as "unapproved" cardiovascular symptoms of these psychiatric conditions.
products, although subject to state boards of pharmacy and FDA
Coincidentally, the antimuscarinic agent atropine is known
to produce tachycardia, and scopolamine to a lesser extent.
Tachycardia is antithetical to the desired outcome.
In view of the historic scientific and clinical literature
mentioned above on beta blockers or antiemetic drugs as
It should be emphasized that palpitations (resulting from
monotherapies for anxiety disorders, the author recognized both
elevated heart rate and/or blood pressure) are considered to be
a need in the pharmaceutical marketplace and an opportunity to
the predominant symptom that patients are aware of during panic
augment the limited cardiovascular benefits of a beta blocker
attacks and acute anxiety episodes. The beta blocker, within a dual
with another type of API to produce a superior anxiolytic drug product, should address this primary (major) symptom of
therapy for p.r.n. administration. It would be advantageous for
panic and acute anxiety episodes.
the augmenting second agent: (a) to address other symptoms;
Recently the author has developed novel pharmaceutical
(b) to exert some psychic (CNS) pharmacologic benefits; (c) to
formulations to address the augmentation of a beta blocker's effects
have a rapid effect; and (d) to not be a Controlled Substance.
on the cardiovascular symptoms with an antiemetic antimuscarinic
Thus, the augmenting second API could not be an opiate, opioid,
agent's effects on non-cardiovascular symptoms (unpublished
benzodiazepine, SSRI, or cannabinoid. This led the author to an
results). This new dual drug approach holds substantial promise
innovative conclusion; a combination of a beta blocker plus an
to address p.r.n.
all or most of the symptoms of acute anxiety
antiemetic antimuscarinic agent should be of substantial clinical
episodes or panic, neither of which is addressed by a beta blocker
benefit and reaching beyond the pharmacologic benefits of
alone or an antiemetic antimuscarinic agent alone. The dual drug
either class of drugs acting alone as monotherapies.
compositions provide a complementary broad coverage of the
Searches of the literature did not reveal any precedents for this
symptoms of acute anxiety: the beta blocker provides benefits
dual drug combination therapy approach using these two classes
with regard to cardiovascular symptoms (e.g., palpitations, heart
of agents (i.e., beta blocker plus antimuscarinic agent) in any
rate, and BP); and, the antimuscarinic agent provides benefits with
medical indication in mental health or psychiatry. Secondarily,
regard to non-cardiovascular symptoms (e.g., nausea, vomiting,
searches did not reveal any record of both classes of APIs being
sweating, anxiousness, avoidance, fear, etc.).
formulated together into a single drug formulation. Thus, this
It should be noted that augmentation of a beta blocker with an
dual drug approach was novel with regard to both aspects, even
antimuscarinic agent, wherein the latter only affects a subset of
though both classes of drugs have been in commercial use for
the common symptoms of acute anxiety (i.e., nausea, vomiting,
over five decades.
sweating, and/or motion sickness) per se
would provide anxiolytic
That being said, one relevant article addressed the superiority over a beta blocker alone or an antiemetic agent
coincidental co-administration of a beta blocker with an alone. In other words, even without affecting psychic symptoms
(e.g., anxiousness, fear, avoidance, etc.), the dual drug approach
Thomas P. Dooley
has substantial merits for treatments of the symptoms of anxiety
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Oct 26, 2015Accepted Nov 23, 2015
Série des traités européens - n° 135 CONVENTION CONTRE LE DOPAGE Strasbourg, 16.XI.1989 STE 135 – Convention contre le dopage, 16.XI.1989 Les Etats membres du Conseil de l'Europe, les autres Etats parties à la Convention culturelle européenne, ainsi que les autres Etats, signataires de la présente Convention, Considérant que le but du Conseil de l'Europe est de réaliser une union plus étroite entre ses membres afin de sauvegarder et de promouvoir les idéaux et les principes qui sont leur patrimoine commun et de favoriser leur progrès économique et social;
Con il Patrocinio di: DEGLI STUDI DI TORINO IX CONGRESSO NAZIONALE S.I.T.O.D. ONDE D'URTO EXTRACORPOREE: PRESENTE E FUTURO Dalla ricerca di base alle nuove prospettive terapeutiche 23 - 24 ottobre 2008 .it Centro Congressi Torino Incontra Via Nino Costa, 10123 Torino oo2 Presidente Onorario