Evidence Based Herbal and Nutritional Treatments for Anxiety

in Psychiatric Disorders

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Foreword

A common theme today across many media articles about herbal and nutritional
treatments is there is no valid evidence for their efficacy, and the risk of harm is high
due to potential issues such as adulteration (sometimes deliberately with pharma-
ceutical drugs), idiosyncratic hepatotoxicity, and herb–drug interactions. While the
lack of data may have held true three or four decades ago, even a cursory search of
the published literature reveals an accumulating evidence of safety and efficacy for
such treatments, sometimes in a complementary role with mainstream pharmaceu-
ticals. For example, there are now more than 30 clinical trials on the herb kava
(Piper methysticum), including several by one of the editors of this text (Jerome
Sarris). The clinical research on the psychiatric applications of N-acetylcysteine is
particularly promising (as will be outlined in the context of anxiety in Chap. 5).
This growing evidence for herbal treatments is occurring in a landscape of
increasing challenges for the use of mainstream drugs in psychiatric disorders.
Again, even a cursory review of the literature highlights a few of these. Not the
least is the complexity of the modern patient and our increasing understanding of
the many factors involved in such conditions. Taking depression as one example,
one review highlighted that there are now more than five plausible hypotheses of
the cause of depression, with the likelihood that these aetiological factors interact
with each other in unique and complex ways in the individual patient [1]. Hence
‘a one size fits all’ approach to depression, especially using a single pharmaceuti-
cal intervention, might see many patients miss out on optimal treatment. It should
be no surprise therefore that the numbers needed to treat (NNTs) for a single
patient to respond to a selective serotonin reuptake inhibitor (SSRI) can be as high
as 12 [2]. Another review concluded that ‘Although recent work suggests that
cognitive impairment is a treatable component of major depressive disorder, and
regulatory agencies seem to be encouraging treatment development for this indi-
cation, existing treatments do little to return patients level of cognitive perfor-
mance to normal’ [3]. Hence, Chap. 4 on cognitive anxiolytics is a timely
contribution to the debate, as is Chap. 6 on herbal and nutritional treatments for
comorbid anxiety and mood disorders.
But there are other looming problems. One example is the renewed concerns
over the safety of SSRIs in teenagers, which are used to manage both anxiety and
mood disorders. A reanalysis of a decade-old trial on paroxetine and imipramine in
adolescence found no evidence of benefit over placebo, and found, in fact, evidence

vii
viii Foreword

of harm, including suicidal ideation and behaviour [4]. The authors concluded that
‘The extent of the clinically significant increases in adverse events in the paroxetine
and imipramine arms, including serious, severe, and suicide related adverse events,
became apparent only when the data were made available for reanalysis. Researchers
and clinicians should recognise the potential biases in published research, including
the potential barriers to accurate reporting of harms that we have identified.
Regulatory authorities should mandate accessibility of data and protocols’.
Not surprisingly, modern patients are increasingly looking for a third treatment
option for their psychiatric problems, and this becomes urgently relevant in the case
of children – an option that sits between taking a drug and doing nothing. However,
engaging this third option by using herbs and nutraceuticals must be credible; it
needs to be underpinned by evidence. On the other hand, it is acknowledged that
such agents are gentle and subtle; indeed that is their strength and what renders
them valid third options.
How can a pharmacologically mild agent render a clinically relevant outcome?
Here enters the new concept of network pharmacology, at least as it applies to
medicinal plants. Due to their chemical complexity, even a single herbal extract is a
nature-designed multi-agent medicine that can simultaneously target a range of
pharmacological effects. This helps to explain why identifying the ‘active constitu-
ent’ in many herbal extracts has proved to be so difficult. For most if not all herbal
extracts, the ‘active constituent’ is the whole extract itself, as illustrated by research
on the antidepressant activity of St John’s wort. The potential for chemical com-
plexity to confer polyvalent activity or polypharmacology can also explain the
apparent therapeutic versatility of herbal extracts.
In a review, Gertsch observed that herbal extracts might in fact be ‘intelligent
mixtures’ of secondary plant metabolites that have been shaped by evolutionary
pressures. As such, they could represent complex therapeutic mixtures possessing
an inherent and coherent synergy and polyvalence. Gertsch also notes that another
important concept related to polyvalence is that of network pharmacology, as origi-
nally proposed by Hopkins. In the context of plant extracts (which, for commonly
used herbs as described in this book, typically contain hundreds of potentially bio-
active natural products with only mild activity), it is possible that different proteins
within the same signalling network are only weakly targeted. However, this is suf-
ficient to shut down or activate a whole pathway by network pharmacology. In other
words, network pharmacology can explain how a number of weakly active plant
secondary metabolites in an extract may be sufficient to exert a potent pharmaco-
logical effect without the presence of a highly bioactive compound. In the context
of herbal network pharmacology, Paul Ehrlich’s concept of the magic bullet is sup-
planted by one of a ‘green shotgun’, to paraphrase Gertsch and James Duke.
The authors of this book have responded admirably to the considerable challenge
of reviewing the current evidence that supports the role of herbal and nutritional
treatments for anxiety (including anxiety comorbid with depression). They are well
published in the field, including a recent survey of herbal medicine use behaviour in
Australian adults experiencing anxiety [5]. The high level of self-prescribing dis-
covered is of significant concern in terms of both adequate treatment and potential
Foreword ix

herb–drug interactions. It highlights that clinicians of all persuasions need to be

better informed on this topic. What better resource is available then than this com-
prehensive text that, through its various chapters, systematically looks at the evi-
dence for and role of herbal anxiolytics, the all-important herbal adaptogens to
support stress management, and cognitive anxiolytics (again primarily herbal),
together with the key nutraceuticals for anxiety? The ever-pressing issue of herb–
drug interactions is covered by a handy table. Above all, the information is informed
and supported by the unique blend of research and clinical experience that the
authors bring to their work, something that is often lacking in texts from the com-
plementary medicine field.

Kerry Bone
Director Research & Development - MediHerb
Adjunct Professor - School of Applied Clinical Nutrition
New York Chiropractic College, USA
Queensland, Australia

References
1. Dale E, Bang-Andersen B, Sánchez C (2015) Emerging mechanisms and treatments for depres-
sion beyond SSRIs and SNRIs. Biochem Pharmacol 2015;95(2):81–97
2. Magni LR, Purgato M, Gastaldon C et al (2013) Fluoxetine versus other types of pharmaco-
therapy for depression. Cochrane Database Syst Rev 2013;(7):CD004185
3. Keefe RS (2016) Treating cognitive impairment in depression: an unmet need. Lancet
Psychiatry 2016;3(5):392–393
4. Le Noury J, Nardo JM, Healy D et al (2015) Restoring Study 329: efficacy and harms of par-
oxetine and imipramine in treatment of major depression in adolescence. BMJ 2015;351:h4320
5. McIntyre E, Saliba AJ, Wiener KK et al (2016) Herbal medicine use behaviour in Australian
adults who experience anxiety: a descriptive study. BMC Complement Altern Med
2016;16(1):60
Acknowledgements

We would like to thank all the people who generously contributed to this book, gave
their support to the project and were involved in its production: Rachel Arthur,
Richard Brown, Michael Coe, Patricia Gerbarg, Jane Hutchens, Dennis McKenna,
David Mischoulon, Naomi Perry, Danielle Mathersul, Genevieve Steiner, Kerry
Bone, Con Stough, Rodney Croft, Andrew Scholey, Corinna Schaefer, Geetha
Dhandapani and Saanthi Shankhararaman.

xi
Contents

1 The Need for Evidence-Based Herbal and Nutritional

Anxiety Treatments in Psychiatry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
David A. Camfield, Erica McIntyre, and Jerome Sarris

Part I Clinical Evidence in Support of Herbal and Nutritional

Treatments for Anxiety

2 Herbal Anxiolytics with Sedative Actions. . . . . . . . . . . . . . . . . . . . . . . . 11

Jerome Sarris and Erica McIntyre
3 Adaptogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Naomi L. Perry and David A. Camfield
4 Cognitive Anxiolytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Genevieve Z. Steiner and Danielle C. Mathersul
5 Nutritional-Based Nutraceuticals in the Treatment of Anxiety . . . . . . 81
David A. Camfield
6 Treatments for Comorbid Anxiety and Mood Disorders . . . . . . . . . . . 103
Jerome Sarris and David Mischoulon

Part II Traditional Treatments in Need of Further Study

7 The Therapeutic Potential of Ayahuasca . . . . . . . . . . . . . . . . . . . . . . . . 123

Michael A. Coe and Dennis J. McKenna
8 Potential Herbal Anxiolytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Erica McIntyre, David A. Camfield, and Jerome Sarris

xiii
xiv Contents

Part III Clinical Perspectives and Case Studies

9 Integrative Treatments for Masked Anxiety and PTSD in Highly

Sensitive Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Patricia L. Gerbarg and Richard P. Brown
10 SAMe in the Treatment of Refractory Depression with Comorbid
Anxiety: A Case Study in a High Histamine Patient . . . . . . . . . . . . . . 169
Rachel Arthur
11 A Complex Case of Undiagnosed Generalised Anxiety Disorder
with Episodic Panic Attacks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Jane Hutchens
Herb and Nutrient-Drug Interaction Table . . . . . . . . . . . . . . . . . . . . . . . . . 185
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
The Need for Evidence-Based Herbal
and Nutritional Anxiety Treatments 1
in Psychiatry

David A. Camfield, Erica McIntyre, and Jerome Sarris

1.1 The Experience of Anxiety

Anxiety is a ubiquitous part of the human condition, with anxiety disorders suffered
by 14.4 % of Australians over a 12-month period [1], and 26.3 % over a lifetime [2].
Similar figures exist for the USA, with a life-time prevalence as high as 33.7 % [3].
Whilst fear is an emotional response to imminent threat, anxiety involves the antici-
pation of future threat [4] and may be experienced in response to a wide range of
circumstances including public speaking, financial stress, separation, traumatic
experiences, or substance use [5]. To the individual who is experiencing symptoms
of anxiety, it is a distressing psychological state—and one that is associated with
both apprehensive thoughts together with physiological symptoms including a

D.A. Camfield (*)

School of Psychology, University of Wollongong, Wollongong, NSW, Australia
Centre for Human Psychopharmacology, Swinburne University of Technology,
Hawthorn, VIC, Australia
e-mail: [email protected]
E. McIntyre
School of Psychology, Charles Sturt University, Bathurst, NSW, Australia
Australian Research Centre in Complementary and Integrative Medicine (ARCCIM),
Faculty of Health, University of Technology, Ultimo, NSW, Australia
J. Sarris
University of Melbourne, Department of Psychiatry, The Melbourne Clinic,
The Professorial Unit, ARCADIA Mental Health Research Group,
2 Salisbury St, Richmond, Melbourne, VIC 3121, Australia
Centre for Human Psychopharmacology, Swinburne University of Technology,
Hawthorn, VIC, Australia

© Springer International Publishing Switzerland 2017 1

D. Camfield et al. (eds.), Evidence-Based Herbal and Nutritional Treatments for
Anxiety in Psychiatric Disorders, DOI 10.1007/978-3-319-42307-4_1
2 D.A. Camfield et al.

pounding heart, difficulties in breathing, nausea and a feeling of detachment from

the environment. Further, with chronic anxiety come additional problems such as
restlessness, fatigue, difficulties with concentration and sleep, as well as muscular
tension. Many individually additionally begin to adversely modify their lifestyles in
order to avoid anxiety-provoking situations [6]. Although many individuals will
experience transient anxiety as part of their day-to-day life, for other individuals,
the symptoms become severe enough to cause significant impairment in day-to-day
living. Current first-line treatments for anxiety include pharmaceuticals such as ben-
zodiazepines and serotonin-reuptake inhibitors (SSRIs), as well as cognitive behav-
ioural therapy (CBT) involving exposure to anxiety-provoking stimuli and the
targeting of dysfunctional cognitions.

1.2 Limitations of Current Treatment Approaches

Whilst pharmaceutical treatments may be effective in bringing symptomatic relief

to some patients, there are known issues which limit their efficacy. First, they do not
always work well in conjunction with psychotherapeutic approaches, having been
designed as standalone treatments rather than part of an integrative approach. For
example, benzodiazepines may limit the efficacy of exposure therapy by blunting
the experience of emotional arousal [7]. Antidepressants may also make it more dif-
ficult to access emotional states, with feelings of emotional numbness reported by
60 % of participants in a recent survey [8]. Second, many people do not respond to
pharmaceutical treatments, with response rates to SSRIs reported at between 60 and
75 % [9]. Third, pharmaceutical treatments have a range of unacceptable side
effects, including negative impacts on sexual functioning, appetite and sleep [10–
12], and discontinuing treatment can also lead to unwanted side effects and with-
drawal symptoms that require careful management [9]. The question of dependency
is also pertinent, particularly in the case of tranquilizers and benzodiazepines. But
perhaps the greatest issue to contend with is that pharmaceutical treatments for
anxiety are often not intended for chronic use, and have not been tested as such in
regulatory trials. Whilst more favourable response rates have been shown for CBT
in comparison to pharmaceutical anxiety treatments [13–15], cognitive approaches
also do not necessarily work for all individuals, particularly in cases where the
patient is not ‘psychologically minded’.

1.3 Nutritional and Herbal Treatments for Anxiety

As conventional treatments for anxiety are not always effective or suitable for all
individuals, it is important to consider other treatment options. As outlined in this
book, an evidence-base is building for the efficacy of herbal and nutritional medi-
cines in the treatment of anxiety. This evidence-base is particularly important con-
sidering the increasingly widespread use of these substances. For example, it has
been estimated that around 34 % of the population in the USA are now using com-
plementary medicines, and similarly 38.4 % of individuals in Australia [16, 17]. The
1 The Need for Evidence-Based Herbal and Nutritional Anxiety Treatments in Psychiatry 3

contemporary use of herbal medicine differs significantly from traditional use, as

nutraceuticals and herbal extracts are now predominantly commercialized products
that are widely accessible [18], and these products are most frequently self-
prescribed for anxiety symptoms, in addition to being prescribed by a range of
health practitioners [19, 20]. An Australian study of general practitioners found that
the majority of doctors did not have the confidence to discuss the use of comple-
mentary medicine with their patients as they believed that they lacked the knowl-
edge needed [21]. Another US study found that as little as 20 % of general
practitioners were comfortable discussing herbal medicines with their patients [22].
For these reasons, there is a need for greater access to reliable evidence-based infor-
mation in regards to these substances, both for consumers and health practitioners.
Research conducted so far indicates that there may be some important advan-
tages to the use of nutritional and herbal treatments in contrast to existing treat-
ments. Whilst a majority of pharmaceuticals rely on a single active constituent to
deliver therapeutic effects, nutritional substances and herbal extracts typically con-
tain a vast array of psychoactive components [23]. In one regard, this may appear to
be a problem for manufacturers wishing to provide a highly standardized treatment,
and a simplistic solution may be to try and isolate single active components for
extraction. However, any attempt to simplify the complex constellation of chemi-
cals would neglect the fact that synergistic and polyvalent interaction between the
components is a key aspect to their therapeutic advantage [24]. The interaction of
the various plant components is something that has been well understood in tradi-
tional medicinal systems such as Ayurvedic medicine or Traditional Chinese
Medicine (TCM) throughout the centuries [25]. Synergism refers to how the thera-
peutic effect is greater for a combination of substances than would have been
expected from a consideration of individual contributions [23]. Polyvalence refers
to the inclusion of substances that may not directly contribute to symptom relief, but
influence the overall clinical efficacy of the substance; for example, through modi-
fication of important processes, including absorption, distribution, metabolism and
excretion of bioactive constituents, or by aiding in the reduction of side effects [24].
Many of the natural substances described in this book are excellent examples of
synergy and polyvalence; for example, Salvia spp., Valeriana officinalis and
Hypericum perforatum.

1.4 Varied Mechanisms of Anxiolytic Actions

Herbal and nutritional treatments for anxiety may exert their effects according to both
direct neurotransmitter effects and more chronic cellular effects. It is often the case
that each treatment, particularly in the case of herbals, possesses multiple active con-
stituents with sometimes differing and complementary modes of action. In regards to
direct neurotransmitter effects, the gamma-aminobutyric acid (GABA) system is
often implicated. GABA is the primary inhibitory neurotransmitter in the central ner-
vous system, and also the target of benzodiazepines. Natural substances with known
actions on the GABA system include Piper methysticum (kava), Passiflora incarnata
(passionflower), Matricaria recutita (chamomile), Scutellaria lateriflora (skullcap)
4 D.A. Camfield et al.

and Valeriana spp. (valerian); these are typically found to exert sedative as well as
anxiolytic effects. Many natural substances have also been found to have effects on
serotonin (5-hydroxytryptophan [5-HT]; the biogenic amine that is targeted by antide-
pressants and is implicated in the regulation of both mood, anxiety and obsessional
thinking). Substances with serotonergic mechanisms of action include myo-inositol
(MI), Hypericum perforatum (St John’s wort), S-adenosyl methionine (SAMe) and
the traditional South American herbal combination Ayahuasca.
In contrast, other substances boost the action of acetylcholine (ACh), a neurotrans-
mitter important for cognitive functioning—these substances include Bacopa monn-
ieri, Ginkgo biloba, Salvia spp. (sage) and Rosmarinus officinalis (rosemary). Another
class of herbal medicines (adaptogens) aids in adaption to stress, via effects on gluco-
corticoids and the hypothalamic–pituitary–adrenal (HPA) axis. These medicines have
a long history of use in Eastern Europe and Asia, and include Withania somnifera
(Ashwagandha), Rhodiolarosea, Gotu kola, Eleutherococcus senticosus (Siberian
ginseng) and Schisandra chinensis. For other natural substances, effects across a num-
ber of other neurotransmitter systems have been reported, including glutamate, nor-
epinephrine and dopamine. In addition to direct neurotransmitter effects, perhaps an
even greater advantage associated with herbal and nutritional substances is that they
exhibit cellular effects that provide overall benefits to brain health, typically in asso-
ciation with chronic use. These include antioxidant and anti-inflammatory effects,
endothelial and blood flow effects, together with the lowering of homocysteine (HCy),
reduction of beta-amyloid proteins, improved mitochondrial function and the enhance-
ment of neurotrophins (e.g. brain-derived neurotrophic factor) [26].

1.5 Challenges for an Emerging Herbal and Nutraceutical

Industry

Notwithstanding the numerous benefits afforded by nutritional and herbal sub-

stances, this emerging field of research is still in its infancy. Whilst there is a long
history of traditional use associated with several of these substances, in many cases,
there are still only a handful of systematic scientific studies which have been con-
ducted to investigate their efficacy in clinical populations. Documented traditional
use has guided the therapeutic use of herbal medicines, and informed the focus of
further research. In many cases, treating clinicians with an interest in novel treat-
ments have published case studies showing favourable effects observed in their
patients. Following reports of clinical effectiveness, open-label studies are typically
published, and finally if researchers can secure sufficient funding, then randomized
placebo-controlled studies (RCTs) are conducted. It is the latter RCTs which are
considered the gold standard regarding evidence of efficacy—and over the past
decade, their numbers have been consistently growing.
Another challenge facing researchers, clinicians and consumers related to natural
medicines is the current lack of regulatory control. For instance, in Australia, the
Therapeutic Goods Administration (TGA) provides a two-tier system of product list-
ing for over-the-counter (non-prescription) health care products. Listed medicines
1 The Need for Evidence-Based Herbal and Nutritional Anxiety Treatments in Psychiatry 5

(AUST L), which are considered to have low-risk ingredients, are assessed for qual-
ity and safety but not efficacy (https://www.tga.gov.au/listed-medicines). In contrast,
registered medicines (AUST R) are considered to pose a higher level of risk and are
required to have comprehensive safety, quality and efficacy data (https://www.tga.
gov.au/registered-medicines). Notwithstanding one or two exceptions, complemen-
tary and alternative medicines are almost totally absent from the registered medi-
cines list. For this reason, high-quality products may coexist side-by-side with
low-quality extracts, and a consumer who wishes to purchase a product such as
Ginkgo biloba may be led to believe that they are equally as effective. However, it is
noteworthy that stricter regulation exists in Europe, with the Medicine and Healthcare
Regulatory Agency (MHRA) overseeing the sale of natural products.
Product reliability is an issue that relates to herbal products in particular. The
effectiveness of a herbal medicine product can be highly variable. In order to reduce
this variability, the concept of phytoequivalence needs consideration, whereby two
different types of extracts of the same herb are considered to have the same psycho-
pharmacological effect. Well validated herbal extracts such as Ginkgo biloba extract
EGb 716 or Hypericum perforatum extract LI 160 have been standardized to contain
minimum quantities of active ingredients, and are produced according to a protocol
which spans from seeding, cultivation, harvesting, drying, extraction, formulation
of the dry extract, as well as quality control monitoring [27]. Furthermore, valida-
tion studies (RCTs) that have been conducted using standardized extracts only
strictly apply to these same extracts. These standardized products ensure a level of
phytoequivalence that is more likely to provide a reliable clinical effect.
There are also numerous other important factors which need to be thoroughly
investigated and communicated clearly to clinicians and consumers in order to guar-
antee reliable and valid effects associated with natural products. These issues include:
(i) whether the substance is best used acutely and/or chronically, (ii) the effective
minimum dose that is required for reliable effects, (iii) the duration of supplementa-
tion required (in the case of chronic supplementation), (iv) the time to peak effects (in
the case of acute administration), (v) whether the supplement is best used as mono-
therapy or adjunctive to other treatments, (vi) whether there are any known interac-
tions with common medications, (vii) for which populations are the substances most
effective (i.e. non-clinical or clinical) and (viii) for which severity of symptom presen-
tation is the substance most appropriate. These questions are central to determining
the conditions associated with therapeutic effects. This is a complex amount of infor-
mation to navigate; therefore, there needs to be effective translation of this informa-
tion in order for both clinicians and consumers to make good treatment decisions.

1.6 The Scope of This Book

The aim of the current book is to provide an up-to-date and thorough assessment of
the evidence-base regarding herbal and nutritionally based treatments in clinical
samples—as well as to present an integrated picture of their routine use in clinical
practice. It is intended that the book will be of use to researchers, clinicians and the
6 D.A. Camfield et al.

interested layperson. The focus is on the treatment of DSM-5 anxiety disorders

(including panic disorder, agoraphobia, generalized anxiety disorder and social
anxiety disorder). Other disorders that typically express high levels of anxiety are
also discussed, including obsessive-compulsive and related disorders, together with
trauma and stress-related disorders; disorders that were previously subsumed under
the anxiety disorders in DSM-IV. Due to the common comorbidity of anxiety and
mood disorders, a separate chapter will also be devoted to this topic. Whilst anxiety
is also a common feature in psychotic disorders, the treatment of these disorders
with natural medicines is beyond the scope of the current book, as there is a current
scarcity of research in this area. Finally, the emphasis throughout the book is on the
evidence-base regarding single nutritional substances and herbal extracts rather
than traditional formulations such as those used in TCM—although this is a worthy
topic of discussion in its own right.
Each chapter will consider a different class of herbal or nutritional medicines,
categorized primarily according to their psychopharmacological effects (herbal
anxiolytics with sedative actions, adaptogens, cognitive anxiolytics, nutritional-
based nutraceuticals, treatments for comorbid anxiety and mood disorders, as well
as Ayahuasca and other potential anxiolytic phytotherapies, which are emerging
treatments in need of further research). The final three chapters of the book are pro-
vided by integrative practitioners and herbalists within the field—in order to dem-
onstrate the applied use of these substances in the treatment of patients with often
complex presentations of clinically significant anxiety. These chapters provide
important insight into the decision-making process around the selection of appropri-
ate combinations of phytotherapies in the treatment of anxiety. Finally, the conclud-
ing sections present a list of all known herb–drug interactions. We trust that you find
the book to be a valuable and informative contribution to this exciting new field of
research and clinical practice.

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 Part I
Clinical Evidence in Support of Herbal and
Nutritional Treatments for Anxiety
Herbal Anxiolytics with Sedative Actions
2
Jerome Sarris and Erica McIntyre

2.1 Introduction

Anxiety disorders such as generalized anxiety disorder (GAD), panic disorder,

social phobia, and post-traumatic stress disorder (PTSD) present with a marked element
of psychological anxiety and distress [1]. Further, as sleep disorders are highly co-
morbid, it is often useful to consider the sedative actions of herbal anxiolytics.
Herbal medicines that possess anxiolytic properties generally have effects on
gamma-aminobutyric acid (GABA), either via direct receptor binding, ionic chan-
nel or cell membrane modulation, GABA transaminase or glutamic acid decarbox-
ylase inhibition. The subsequent increased GABA neurotransmission has a damping
effect on stimulatory pathways, which ultimately provides a psychologically calm-
ing effect [2]. Mechanisms of action of these phytomedicines have been elucidated
via in vitro and in vivo studies. For example, Awad and colleagues [3] sought to
determine whether several common herbal medicines directly affected the primary
brain enzymes responsible for GABA metabolism. In vitro rat brain homogenate assays
revealed aqueous extract of lemon balm (Melissa officinalis) to exhibit the greatest
inhibition of GABA transaminase activity, while chamomile (Matricaria recutita) and
hops (Humulus lupulus) inhibited glutamic acid decarboxylase activity. In addition

J. Sarris (*)
University of Melbourne, Department of Psychiatry, The Melbourne Clinic,
The Professorial Unit, ARCADIA Mental Health Research Group,
2 Salisbury St, Richmond, Melbourne, VIC 3121, Australia
Centre for Human Psychopharmacology, Swinburne University of Technology,
Hawthorn, VIC, Australia
e-mail: [email protected]
E. McIntyre
School of Psychology, Charles Sturt University, Bathurst, NSW, Australia
Australian Research Centre in Complementary and Integrative Medicine (ARCCIM),
Faculty of Health, University of Technology, Ultimo, NSW, Australia

© Springer International Publishing Switzerland 2017 11

D. Camfield et al. (eds.), Evidence-Based Herbal and Nutritional Treatments for
Anxiety in Psychiatric Disorders, DOI 10.1007/978-3-319-42307-4_2
12 J. Sarris and E. McIntyre

to treating anxiety disorders, many anxiolytic plant medicines have additional appli-
cations, as discussed below in the “clinical considerations” section. The herbs out-
lined in this section have demonstrated clinical efficacy in treating various types of
anxiety disorders, as well as being sedatives. Table 2.1 provides an overview of
these herbal medicines.

2.2 Kava (Piper methysticum)

2.2.1 Overview

Apart from Kava’s (Piper methysticum) traditional use for cultural, social, and reli-
gious occasions, the plant also has a role as a medicine, and has been used in Western
society for its effects on anxiety via physiological and psychological relaxation [4].
It should be noted that while kava is detailed under this section of plants with “seda-
tive actions,” this effect is varied, with some consumers potentially experiencing a
mentally stimulating effect alongside physiological sedation (due to the combina-
tion of GABAergic and noradrenergic effects) [5]. The use of kava has been popu-
larised since the 1990s, with dozens of kava products (of varying quality) being
used worldwide for the treatment of anxiety. While selective serotonin re-uptake
inhibitors (SSRIs) and benzodiazepines are effective first-line pharmacological
treatments of anxiety disorders [6], both agents have unwanted side effects. While
there is compelling evidence in support of kava for the treatment of anxiety [7],
concerns over hepatotoxicity led to its withdrawal or restriction in many countries
since 2002 (overturned by a German court ruling in 2015) [8]. Although not con-
firmed, reasons for previous liver toxicity may have included: the use of low-quality
and inexpensive plant materials (e.g. plant peelings rather than the traditional peeled
rhizomes), incorrect use of kava cultivars, and the use of dangerous chemical sol-
vents during extraction [9].

2.2.2 Mechanisms of Action

2.2.2.1 Constituents
The pharmacodynamic anxiolytic mechanism is thought to be attributable to the lipo-
philic constituents of kava, known as kavalactones [4]. Collectively, kavalactones are
concentrated mainly within the rhizomes, roots and root stems of the plant [10, 11]. The
distribution of kavalactones progressively decreases towards the aerial parts of the plant
[11]. The aerial parts of the plant often contain toxic alkaloids such as piper methystine,
and are not used in traditional consumption [12]. Eighteen different kavalactones
have been identified to date, with approximately 96 % of the total pharmacological
activity attributed to the presence of six kavalactones: methysticin, dihydromethys-
ticin, kavain, dihydrokavain, demethoxy yangonin and yangonin [2, 11].
Several studies have documented a wide spectrum of pharmacological effects of
kava including anxiolytic [13], anti-stress [13], sedative [14], analgesic [15], muscle