Pharmacological treatment of anxiety disorders: Current treatments and future directions

doi:10.1016/j.janxdis.2012.07.009

Journal of Anxiety Disorders

Volume 26, Issue 8, December 2012, Pages 833-843

https://doi.org/10.1016/j.janxdis.2012.07.009 Get rights and content

Abstract

Modern pharmacological treatments for anxiety disorders are safer and more tolerable than they were 30 years ago. Unfortunately, treatment efficacy and duration have not improved in most cases despite a greater understanding of the pathophysiology of anxiety. Moreover, innovative treatments have not reached the market despite billions of research dollars invested in drug development. In reviewing the literature on current treatments, we argue that evidence-based practice would benefit from better research on the causes of incomplete treatment response as well as the comparative efficacy of drug combinations and sequencing. We also survey two broad approaches to the development of innovative anxiety treatments:the continued development of drugs based on specific neuroreceptors and the pharmacological manipulation of fear-related memory. We highlight directions for future research, as neither of these approaches is ready for routine clinical use.

Highlights

► Incomplete treatment response is common and should be studied using novel methods. ► Neurogenesis-promoting drugs appear promising but are in early development. ► Drugs that enhance memory consolidation may augment exposure-based therapy, but long-term data are needed. ► Adjunctive use of psychedelic and narcotic drugs with psychotherapy has poor empirical support.

Introduction

Pharmacological treatments for anxiety disorders have become more tolerable, available, and numerous over the past half century. At the same time, research has yielded a vastly improved understanding of the neurobiological and physiological mechanisms involved in chronic anxiety and stress responses, suggesting new approaches to the treatment of anxiety disorders. Despite these impressive changes, however, between one-third and one-half of patients on a modern antidepressant do not achieve sustained remission from anxiety (Pollack, Otto, et al., 2008).

Why does this efficacy gap exist, and what should be the next step in treatment for these patients? Unfortunately, although patients often use antidepressant medications for years, high-quality data on the drugs’ long-term efficacy are limited. The problem is compounded by the growing number of different drug classes, which has prompted clinicians to combine drugs and change dosing regimens without good data on optimal treatment combinations. Billions of research dollars later, have we hit a wall in the development and application of pharmacological treatments for anxiety? What hope might there be for a genuine breakthrough treatment for treatment-refractory anxiety?

To evaluate these questions, we first review evidence for the safety, tolerability, and efficacy of first- and second-line drugs in the anxiety disorders. We discuss the strength of evidence for drug–drug and drug–psychotherapy combinations used as adjunctive or augmenting treatment approaches to treatment-refractory anxiety. In the remainder of this review, we evaluate potential innovations in the treatment of anxiety disorders, including novel molecular targets, memory-modulating drugs, and psychedelic and narcotic drugs. The results have largely been disappointing so far; in many cases, however, we identify concrete questions for future research, many of which may best be addressed through innovative research methods.

Section snippets

Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs)

The widely studied SSRIs, and to a growing degree, the SNRIs (and for obsessive–compulsive disorder [OCD] the mixed noradrenergic and serotonergic reuptake inhibitor tricyclic clomipramine), are considered the first-line pharmacological treatments for anxiety disorders (see Ravindran & Stein, 2010, for a review). Specific phobia is the exception. In specific phobia, these medications have rarely been studied or used clinically because exposure therapy is considered the first-line treatment. The

Future directions in pharmacological targets

While much drug development is concerned with improving the efficacy and tolerability of existing anxiety medications (Nemeroff, 2003), considerable resources have been invested to identify novel molecular targets over the past decade (Miller, 2010). Recent research in this area has largely focused on drugs that act more selectively on specific subtypes of serotonergic receptors.

Pharmacological modulation of learning and memory

While the search for new drugs based on novel molecular targets has been faltering in recent years, preliminary human research into the use of memory-modulating drugs has been flourishing. The goal of this research is to develop drugs that enhance or disrupt specific learning or memory processes to improve outcome. The approach departs substantially from traditional psychopharmacology, which has primarily evaluated drugs that have more direct effects on anxiety and depression. Adjunctive memory

3,4-Methylenedioxymethamphetamine (MDMA) and cannabidiol

Although most psychedelic drugs have been illegal or heavily regulated in the U.S. and abroad for the past several decades, some researchers (e.g., Bouso et al., 2008, Doblin, 2002) have argued that psychedelic and other drugs may be able to augment exposure-based treatments for anxiety disorders (Bouso et al., 2008, Doblin, 2002). Indeed, correlational evidence links psychedelic substances to increased activation in the ventromedial prefrontal cortex (vmPFC) and to decreased amygdala

Discussion

Today, patients with anxiety disorders benefit from decades of psychopharmacological research that has yielded safer, more tolerable side-effect profiles than before – but without improved efficacy. As we have reviewed above, first-line antidepressants, such as the SSRIs and possibly the SNRIs, do a reasonable job of reducing anxiety, but they act slowly and often do not lead to sustained remission. Faced with incomplete response, clinicians and patients must decide how treatment should

References (152)

M.E. Bouton
Context, ambiguity, and unlearning:sources of relapse after behavioral extinction
Biological Psychiatry
(2002)
L. Cahill et al.
A novel demonstration of enhanced memory associated with emotional arousal
Consciousness and Cognition
(1995)
V. Coric et al.
Riluzole augmentation in treatment-resistant obsessive–compulsive disorder:an open-label trial
Biological Psychiatry
(2005)
M.G. Craske et al.
Optimizing inhibitory learning during exposure therapy
Behaviour Research and Therapy
(2008)
J.R.T. Davidson et al.
Mirtazapine vs. placebo in posttraumatic stress disorder:a pilot trial
Biological Psychiatry
(2003)
R.A. de Kleine et al.
A randomized placebo-controlled trial of d-cycloserine to enhance exposure therapy for posttraumatic stress disorder
Biological Psychiatry
(2012)
D.J.-F. de Quervain et al.
Glucocorticoids for the treatment of post-traumatic stress disorder and phobias:a novel therapeutic approach
European Journal of Pharmacology
(2008)
D.J.-F. de Quervain et al.
Glucocorticoids and the regulation of memory in health and disease
Frontiers in Neuroendocrinology
(2009)
C.M. Grilo et al.
Pretreatment patient factors predicting attrition from a multicenter randomized controlled treatment study for panic disorder
Comprehensive Psychiatry
(1998)
A.J. Guastella et al.
A randomized controlled trial of d-cycloserine enhancement of exposure therapy for social anxiety disorder
Biological Psychiatry
(2008)

M. Heilig

The NPY system in stress, anxiety and depression

Neuropeptides

(2004)

S.C. Heinrichs et al.

Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist

Neuropsychopharmacology

(2002)

S.G. Hofmann et al.

Cognitive enhancers for anxiety disorders

Pharmacology, Biochemistry, and Behavior

(2011)

A. Holmes et al.

Pharmacological facilitation of fear extinction and the search for adjunct treatments for anxiety disorders--the case of yohimbine

Trends in Pharmacological Sciences

(2010)

A. Holmes et al.

Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders

Trends in Pharmacological Sciences

(2003)

R.J. Katz et al.

Clomipramine in obsessive–compulsive disorder

Biological Psychiatry

(1990)

J.H. Krystal et al.

N-methyl-d-aspartate glutamate receptors and alcoholism:reward, dependence, treatment, and vulnerability

Pharmacology and Therapeutics

(2003)

K. Kuriyama et al.

d-Cycloserine facilitates procedural learning but not declarative learning in healthy humans:a randomized controlled trial of the effect of d-cycloserine and valproic acid on overnight properties in the performance of non-emotional memory tasks

Neurobiology of Learning and Memory

(2011)

S.J. Mathew et al.

A selective neurokinin-1 receptor antagonist in chronic PTSD: a randomized, double-blind, placebo-controlled, proof-of-concept trial

European Neuropsychopharmacology

(2011)

U.D. McCann et al.

Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings

Lancet

(1998)

M.H. Milekic et al.

Temporally graded requirement for protein synthesis following memory reactivation

Neuron

(2002)

H. Möhler

The GABA system in anxiety and depression and its potential for novel therapeutics

Neuropharmacology

(2012)

S.A. Montgomery et al.

Characterization of the longitudinal course of improvement in generalized anxiety disorder during long-term treatment with venlafaxine XR

Journal of Psychiatric Research

(2002)

C.D. Mullins et al.

Comparison of first refill rates among users of sertraline, paroxetine, and citalopram

Clinical Therapeutics

(2006)

M.M. Norberg et al.

A meta-analysis of d-cycloserine and the facilitation of fear extinction and exposure therapy

Biological Psychiatry

(2008)

M.W. Otto et al.

Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder:further evaluation

Behaviour Research and Therapy

(2010)

J.E. Aikens et al.

Adherence to maintenance-phase antidepressant medication as a function of patient beliefs about medication

Annals of Family Medicine

(2005)

J. Aranda-Michel et al.

Nefazodone-induced liver failure:report of three cases

Annals of Internal Medicine

(1999)

L. Arborelius et al.

The role of corticotropin-releasing factor in depression and anxiety disorders

The Journal of Endocrinology

(1999)

D. Bakish et al.

Moclobemide and specific serotonin re-uptake inhibitor combination treatment of resistant anxiety and depressive disorders

Human Psychopharmacology: Clinical and Experimental

(1995)

B. Bandelow et al.

Meta-analysis of randomized controlled comparisons of psychopharmacological and psychological treatments for anxiety disorders

World Journal of Biological Psychiatry

(2007)

D.H. Barlow

Psychological treatments

American Psychologist

(2004)

M.E. Becker et al.

A placebo-controlled trial of bupropion SR in the treatment of chronic posttraumatic stress disorder

Journal of Clinical Psychopharmacology

(2007)

C. Belzung et al.

Neuropeptides in psychiatric diseases:an overview with a particular focus on depression and anxiety disorders

CNS and Neurological Disorders Drug Targets

(2006)

M.M. Bergamaschi et al.

Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients

Neuropsychopharmacology

(2011)

M.H. Bloch et al.

Meta-analysis of the dose–response relationship of SSRI in obsessive–compulsive disorder

Molecular Psychiatry

(2009)

J.C. Bouso et al.

MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder

Journal of Psychoactive Drugs

(2008)

C.K. Cain et al.

Adrenergic transmission facilitates extinction of conditional fear in mice

Learning and Memory

(2004)

J. Cami et al.

Human pharmacology of 3,4-methylenedioxymethamphetamine (“ecstasy”): psychomotor performance and subjective effects

Journal of Clinical Psychopharmacology

(2000)

D.S. Charney et al.

Noradrenergic function in panic anxiety:effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder

Archives of General Psychiatry

(1984)

J. Christiana et al.

Duration between onset and time of obtaining initial treatment among people with anxiety and mood disorders:an international survey of members of mental health patient advocate groups

Psychological Medicine

(2000)

M.I. Colado et al.

The hyperthermic and neurotoxic effects of “Ecstasy” (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype

British Journal of Pharmacology

(1995)

J.A.de.S. Crippa et al.

Effects of cannabidiol (CBD) on regional cerebral blood flow

Neuropsychopharmacology

(2004)

J.A.de.S. Crippa et al.

Uso terapêutico dos canabinoides em psiquiatria

Revista Brasileira de Psiquiatria

(2010)

J.A.de.S. Crippa et al.

Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder:a preliminary report

Journal of Psychopharmacology

(2011)

J.R.T. Davidson

Seizures and bupropion:a review

Journal of Clinical Psychiatry

(1989)

J.R.T. Davidson et al.

Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder

Journal of Clinical Psychiatry

(1999)

D.J.-F. de Quervain et al.

Glucocorticoids enhance extinction-based psychotherapy

Proceedings of the National Academy of Sciences of the United States of America

(2011)

J. Debiec et al.

Noradrenergic enhancement of reconsolidation in the amygdala impairs extinction of conditioned fear in rats – a possible mechanism for the persistence of traumatic memories in PTSD

Depression and Anxiety

(2011)

A.M. Depping et al.

Second-generation antipsychotics for anxiety disorders

Cited by (108)

Prevalence of insomnia and associations with depression, anxiety among adults in guangdong, China: A large-scale cross-sectional study
2024, Sleep Medicine
Insomnia is a common sleep disorder, often associated with some mental disorders or mental health concerns, especially when accompanied by depression or anxiety, but very limited research has been reported in China. The purpose of this study was to investigate the prevalence of insomnia and associations with depression, anxiety in Chinese adults.
We conducted this large-sample cross-sectional study (51774 adults) in Guangdong province from October to December 2022. We used multistage stratified equal-volume random sampling under a complex sampling design to select the sample and standardized structured questionnaires to collect the necessary information. Descriptive analysis and logistic regression model were used for statistical analysis.
The weighted prevalence of insomnia was 24.8 %. Insomnia was significantly associated with depression (OR:11.29, 95 %CI: 9.58–13.29), and anxiety (OR:10.98, 95 %CI: 8.78–13.72). Risk factors as being associated with insomnia were female, higher years of education, suffering from chronic diseases, previous drinking and current drinking, while protective factors were living in a rural area, married or cohabited, divorce or separation and being older. Risk factors as being associated with depression in the insomnia group included 10–16 years of education and suffering from chronic diseases, while protective factors were being older, married or cohabited, and normal BMI. Risk factors associated with anxiety in the insomnia group included 7–12 years of education and suffering from chronic diseases, while protective factors were being older, married or cohabited, and having a normal BMI.
Insomnia is associated with the development of depression and anxiety. Women and unhealthy lifestyle were at high risk for insomnia, had chronic diseases is an important factor, and insomnia with depression or anxiety.
Angiotensin II Regulates the Neural Expression of Subjective Fear in Humans: A Precision Pharmaco-Neuroimaging Approach
2023, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Rodent models and pharmacological neuroimaging studies in humans have been used to test novel pharmacological agents to reduce fear. However, these strategies are limited with respect to determining process-specific effects on the actual subjective experience of fear, which represents the key symptom that motivates patients to seek treatment. In this study, we used a novel precision pharmacological functional magnetic resonance imaging approach based on process-specific neuroaffective signatures to determine effects of the selective angiotensin II type 1 receptor (AT1R) antagonist losartan on the subjective experience of fear.
In a double-blind, placebo-controlled, randomized pharmacological functional magnetic resonance imaging design, healthy participants (N = 87) were administered 50 mg losartan or placebo before they underwent an oddball paradigm that included neutral, novel, and fear oddballs. Effects of losartan on brain activity and connectivity as well as on process-specific multivariate neural signatures were examined.
AT1R blockade selectively reduced neurofunctional reactivity to fear-inducing visual oddballs in terms of attenuating dorsolateral prefrontal activity and amygdala-ventral anterior cingulate communication. Neurofunctional decoding further demonstrated fear-specific effects in that AT1R blockade reduced the neural expression of subjective fear but not of threat or nonspecific negative affect and did not influence reactivity to novel oddballs.
These results show a specific role of the AT1R in regulating the subjective fear experience and demonstrate the feasibility of a precision pharmacological functional magnetic resonance imaging approach to the affective characterization of novel receptor targets for fear in humans.
A paradigm shift in the treatment of emotional memory disorders: Lessons from basic science
2023, Brain Research Bulletin
Experiments demonstrating post-reactivation amnesia for learned fear in animals have generated a novel and influential hypothesis on the plasticity of memory, usually referred to as memory reconsolidation. The clinical potential of pharmacologically disrupting the process of memory reconsolidation has sparked a wave of interest into whether this phenomenon can also be demonstrated in humans, and ultimately harnessed for therapeutic purposes. In this essay we outline how the work of Karim Nader and colleagues has moved the field forward from a focus on extinction learning to the prospect of disrupting memory reconsolidation. We then review some promising findings on the necessary conditions, as well as potential boundary conditions, of pharmacologically disrupting the process of memory reconsolidation obtained in our laboratory. Even though laboratory experiments in animals and humans suggest that we may be at the brink of a breakthrough in fundamentally changing emotional memories, the necessary and sufficient conditions for targeting and disrupting memory reconsolidation in clinical practice are largely unknown. There is likely no universally effective reactivation procedure for triggering the reconsolidation of clinically significant emotional memories, and the impact of subtle boundary conditions observed in basic experiments compounds this issue. Notwithstanding these challenges, the discovery of changing emotional memory through disrupting the process of memory reconsolidation has unquestionably invigorated the field.
Anxiolytic-like effects and impact on memory of Hydrocotyle umbellata L. spray-dried extract in mice and toxicological assessment
2022, Brain Disorders
Anxiety disorders are one of the most common psychiatric illnesses in the world's population. As current pharmacotherapy is not effective and safe for all patients, seeking complementary treatment has increased. Hydrocotyle umbellata L., Araliaceae, is an herb long recognized for its anxiolytic and memory stimulant effects. This work aimed to evaluate the anxiolytic-like effects and the impact on memory of the spray-dried Hydrocotyle umbellata L. extract (SDHUE) in mice and to assess its toxicological potential. The anxiolytic-like effects of SDHUE (75, 150, 300, or 600 mg/kg) were assessed on elevated plus maze (EPM) and light-dark box (LDB) tests, and the participation of the benzodiazepine site of GABA_A and 5-HT_1A receptors was investigated. The memory retention of the animals was evaluated in the step-down avoidance (SDA) test, and the possible effects on learning and memory processes were assessed by ex vivo cholinesterase (ChE) activity. The toxicity assays were evaluated in terms of cytotoxicity in RAW macrophage cells, mutagenic effects by the Ames test, and embryotoxic potential using the zebrafish (Danio rerio) model. Pretreatment with flumazenil (2 mg/kg) prevented the anxiolytic-like activity induced by SDHUE. No signs of memory impairment on short- and long-term memory were detected with SDHUE treatment in the SDA test. The inhibition of ChE activity in the prefrontal cortex and hippocampus was also observed with SDHUE treatment. Moreover, it was verified an absence of apparent toxic effects. Thus, this extract may offer a promising approach for further safe and effective application in the treatment of anxiety.
Sleep and anxiety: From mechanisms to interventions
2022, Sleep Medicine Reviews
Citation Excerpt :
SSRIs and SNRIs (e.g., clomipramine for OCD) inhibit the reuptake of serotonin or norepinephrine, respectively, thus augmenting serotonin synaptic levels [15]. They are deemed as first-line pharmacological treatments for most anxiety/anxiety-related disorders, although up to ∼30% of individuals may experience side effects and/or may be nonresponsive due to insufficient dose, poor adherence, treatment resistance, or inadequate treatment duration [15]. Of note, individuals who experience both GAD and MDD and undergo pharmacological treatment with SSRI (e.g., fluoxetine, venlafaxine) may experience disrupted sleep, particularly insomnia [111].
Anxiety is the most common mental health problem worldwide. Epidemiological studies show that sleep disturbances, particularly insomnia, affect ∼50% of individuals with anxiety, and that insufficient sleep can instigate or further exacerbate it. This review outlines brain mechanisms underlying sleep and anxiety, by addressing recent human functional/structural imaging studies on brain networks underlying the anxiogenic impact of sleep loss, and the beneficial effect of sleep on these brain networks. We discuss recent developments from human molecular imaging studies that highlight the role of specific brain neurotransmitter mechanisms, such as the adenosinergic receptor system, on anxiety, arousal, and sleep. This review further discusses frontline sleep interventions aimed at enhancing sleep in individuals experiencing anxiety, such as nonbenzodiazepines/antidepressants, lifestyle and sleep interventions and cognitive behavioral therapy for insomnia. Notwithstanding therapeutic success, up to ∼30% of individuals with anxiety can be nonresponsive to frontline treatments. Thus, we address novel non-invasive brain stimulation techniques that can enhance electroencephalographic slow waves, and might help alleviate sleep and anxiety symptoms. Collectively, these findings contribute to an emerging biological framework that elucidates the interrelationship between sleep and anxiety, and highlight the prospect of slow wave sleep as a potential therapeutic target for reducing anxiety.
Fear-related anxiety disorders and posttraumatic stress disorder
2022, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, Second Edition
Significant progress has been made in the expansion of our understanding of the biological basis of anxiety disorders. Preclinical research examining the biological basis of fear learning, emotional memory regulation, and the expression of fear in animal models has, in conjunction with clinical research in patients with anxiety disorders, promoted the development of a biologically based understanding of the pathophysiology of fear-related anxiety disorders and suggested points of clinical intervention that may yield novel treatments for these disorders. This chapter will review the historical classification, clinical manifestations, psychobiology, and treatment of anxiety disorders, with an emphasis on fear-related anxiety disorders and posttraumatic stress disorder.

View all citing articles on Scopus

^☆: This manuscript was supported in part by NIH grants R34MH087375 and R01MH066347. The authors thank Gerald Rosen for his excellent comments on earlier drafts of this manuscript.

View full text

ReviewPharmacological treatment of anxiety disorders: Current treatments and future directions☆

Abstract

Highlights

Introduction

Section snippets

Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs)

Future directions in pharmacological targets

Pharmacological modulation of learning and memory

3,4-Methylenedioxymethamphetamine (MDMA) and cannabidiol

Discussion

Biological Psychiatry

Consciousness and Cognition

Biological Psychiatry

Behaviour Research and Therapy

Biological Psychiatry

Biological Psychiatry

European Journal of Pharmacology

Frontiers in Neuroendocrinology

Comprehensive Psychiatry

Biological Psychiatry

Neuropeptides

Neuropsychopharmacology

Pharmacology, Biochemistry, and Behavior

Trends in Pharmacological Sciences

Trends in Pharmacological Sciences

Biological Psychiatry

Pharmacology and Therapeutics

Neurobiology of Learning and Memory

European Neuropsychopharmacology

Lancet

Neuron

Neuropharmacology

Journal of Psychiatric Research

Clinical Therapeutics

Biological Psychiatry

Behaviour Research and Therapy

Adherence to maintenance-phase antidepressant medication as a function of patient beliefs about medication

Annals of Family Medicine

Nefazodone-induced liver failure:report of three cases

Annals of Internal Medicine

The role of corticotropin-releasing factor in depression and anxiety disorders

The Journal of Endocrinology

Moclobemide and specific serotonin re-uptake inhibitor combination treatment of resistant anxiety and depressive disorders

Human Psychopharmacology: Clinical and Experimental

Meta-analysis of randomized controlled comparisons of psychopharmacological and psychological treatments for anxiety disorders

World Journal of Biological Psychiatry

Psychological treatments

American Psychologist

A placebo-controlled trial of bupropion SR in the treatment of chronic posttraumatic stress disorder

Journal of Clinical Psychopharmacology

Neuropeptides in psychiatric diseases:an overview with a particular focus on depression and anxiety disorders

CNS and Neurological Disorders Drug Targets

Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients

Neuropsychopharmacology

Meta-analysis of the dose–response relationship of SSRI in obsessive–compulsive disorder

Molecular Psychiatry

MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder

Journal of Psychoactive Drugs

Adrenergic transmission facilitates extinction of conditional fear in mice

Learning and Memory

Human pharmacology of 3,4-methylenedioxymethamphetamine (“ecstasy”): psychomotor performance and subjective effects

Journal of Clinical Psychopharmacology

Noradrenergic function in panic anxiety:effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder

Archives of General Psychiatry

Duration between onset and time of obtaining initial treatment among people with anxiety and mood disorders:an international survey of members of mental health patient advocate groups

Psychological Medicine

The hyperthermic and neurotoxic effects of “Ecstasy” (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype

British Journal of Pharmacology

Effects of cannabidiol (CBD) on regional cerebral blood flow

Neuropsychopharmacology

Uso terapêutico dos canabinoides em psiquiatria

Revista Brasileira de Psiquiatria

Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder:a preliminary report

Journal of Psychopharmacology

Seizures and bupropion:a review

Journal of Clinical Psychiatry

Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder

Journal of Clinical Psychiatry

Glucocorticoids enhance extinction-based psychotherapy

Proceedings of the National Academy of Sciences of the United States of America

Review
Pharmacological treatment of anxiety disorders: Current treatments and future directions☆