Key Insights

• Anxiety disorders are the world’s most prevalent mental health disorders, affecting roughly 300 million people globally and accounting for 3.4% of all years lived with disability (YLD).

• Several psychedelics are showing promise for treating the various forms of anxiety. It is often experienced alongside depression and is a symptom of PTSD. Therefore, psychedelics trials also often measure anxiety to treat other disorders. Early trials with psilocybin and MDMA are proving to be effective in alleviating symptoms of anxiety.

• Anxiety disorders are the target of several companies. MindMed is working with the team at the University of Basel to explore the potential of using LSD to treat generalised anxiety disorder (GAD). Cybin has been investigating social anxiety disorder (SAD) and GAD as the target of their proprietary CYB004 molecule.

What is anxiety?

Anxiety is an emotion characterised by feelings of tension and worrying thoughts [1]. Experiencing occasional anxiety in response to stressful situations is a normal part of life as it can alert us to dangers and help us prepare and pay attention [2].

However, an array of anxiety disorders exist, and there are estimated to be over 284 million people experiencing anxiety disorders across the globe. With such a large number of people experiencing anxiety disorders, they are now the most prevalent mental health disorders globally and account for 3.4% of all years lived with a disability (YLDs) [3].

Types of anxiety disorders include; generalised anxiety disorder (GAD) and social anxiety disorder (SAD). Obsessive-Compulsive Disorder (OCD) and PTSD are also understood to be anxiety disorders. These are covered in separate articles.

According to the DSM-V (a manual for assessment and diagnosis of mental disorders), anxiety disorders are generally diagnosed when a person experiences symptoms including; the presence of excessive anxiety and worry about a variety of topics, events, or activities for periods longer than six months, the worry or distress interferes with daily living and other symptoms such as edginess or restlessness, irritability and sleep disturbances [4].

Given the nature of these disorders, anxiety is often experienced alongside depression, with both disorders shouldering a significant global economic burden [5]. Common anxiety treatments include medications like SSRIs, SNRIs (both antidepressants) and anxiolytics like benzodiazepines.

Medication used in tandem with psychotherapy is often considered a fundamental aspect of treatment [6]. Unfortunately, many people do not respond adequately to these conventional treatments [7]. It is estimated that around 40% of patients with anxiety don’t respond to treatments.

With psychedelic-assisted psychotherapy tipped to be the next big treatment model in mental health care, research into the potential of psychedelic drugs to treat anxiety disorders is well underway.

Psychedelics and Anxiety

Psychedelics including psilocybin, LSD, MDMA, and ketamine show great promise in alleviating the symptoms of various anxiety disorders. Clinical trials involving these substances occur across the globe, each at various stages of the clinical trial process.

Both psilocybin and MDMA effectively treat end-of-life anxiety (ELA), a common occurrence for most patients in palliative care [8]. One of the many endeavours of MAPS is a recent Phase II trial led by Phil Wolfson. Patients experiencing ELA were administered 125mg of MDMA in combination with two eight-hour psychotherapy sessions in the trial.

At the end of this trial, the MDMA group had a greater mean reduction in STAI-Trait scores (a standard checklist used to measure anxiety) when compared to the control group. With MDMA being awarded ‘breakthrough therapy’ status by the FDA in 2017 for the treatment of PTSD, in which severe anxiety is a significant symptom, the use of MDMA to treat anxiety disorders may soon follow suit. 

A 2018 double-blind placebo-controlled trial exploring the effects of MDMA-assisted therapy to treat social anxiety in autistic adults yielded promising results. Led by Alicia Danforth and Charles Grob, this pilot study found a significant reduction in social anxiety following two MDMA-assisted therapy sessions in which eight participants received 75 to 125 mg of MDMA. Noteworthily, improvements in social anxiety remained the same, even continuing to improve slightly, in the MDMA group at the six-month follow-up [9].

“We believe MDMA-Assisted therapy is particularly well-situated to be a novel, efficient, and effective intervention to help individuals with [social anxiety disorder] alleviate psychological suffering and improve social functioning.”

Lear & Luoma, 2021

Roland Griffiths and his colleagues at Johns Hopkins reported similar reductions in symptoms of both anxiety and depression in a Phase II study upon administering varying doses of psilocybin to patients experiencing ELA [10]. Furthermore, 80% of participants in this study continued to show clinically significant decreases in depressed mood and anxiety at the six-month follow-up.

Chia-Ling Yu and colleagues provide further evidence for the efficacy of using psilocybin to treat ELA [11]. Their recently published (2021) systematic review of five studies using psilocybin to treat ELA found that psilocybin-assisted therapy could ameliorate ELA symptoms without serious adverse events. These effects were superior to that of the placebo. In addition, psilocybin exhibited effectiveness in managing anxiety at the time points of 1 day and 1, 3, and 6 months after a single treatment session [11].

Paul Liknaitzky has also announced that Monash University will lead the world’s first trial investigating psilocybin-assisted psychotherapy to treat generalised anxiety disorder. The study has just passed through ethics approval and will start in 2022.

“High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety … and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety.”

Griffiths et al. 2016

Another psychedelic drug that has re-emerged in recent years and is making headway for its ability to treat anxiety is ketamine. Ketamine stands alone in the world of psychedelics, given that it is readily available and accessible off-label for those with both depressive and anxiety disorders. In a study of 12 patients with a refractory generalised anxiety disorder or social anxiety disorder who were not depressed, ten of the 12 participants (83%) found relief within one hour of a single ketamine infusion. This relief lasted for up to seven days [12].

In 2017, Jerome Taylor and colleagues investigated the effects of ketamine in 18 adults with social anxiety disorder. A significant reduction in anxiety was observed in those who received intravenous ketamine (35mg/70kg over 40 min) when compared to the control group. While reductions were observed when using the Lebowitz Social Anxiety Scale (LSAS), the contrary was true on the self-reported Visual Analog Scale (VAS-anxiety). The researchers attributed this observation to inadequate blinding as 17 of the 18 participants correctly identified if they received ketamine [13]. Issues surrounding blinding are continuing to create problems for researchers across all areas of psychedelic science.

A retrospective pilot study involving eight patients in palliative care found that treatment with esketamine, sold under the brand name Spravato, had a positive impact while they were receiving therapy for pain. The study found that esketamine reduced psychological distress in these patients and that this positive effect is primarily related to reductions in symptoms of anxiety, measured using the STAID. Interestingly, the effect ketamine had on measures of depression was mild in comparison to the anxiolytic effects [14].

Ketamine is usually administered intravenously within a clinical environment and can rapidly alleviate anxiety-related symptoms [15]. Given its availability, many ketamine clinics exist in many major US cities whilst in Europe, Ovid Clinic (Germany), Awakn, and Save Minds (United Kingdom) are some of the few available options.

How might psychedelics treat anxiety?

As with many psychedelics, the exact mechanisms by which they act remain speculative [16]. Here are the key psychedelics and the main mechanisms through which they can help alleviate anxiety. These mechanisms are somewhat simplified for clarity.

In the case of MDMA, it acts in the brain by binding to the serotonin transporter. It is transported into the nerve terminal, thereby stimulating the release of serotonin. This key neurotransmitter stabilises our mood, feelings of well-being, and happiness [17]. By stimulating the release and reuptake of serotonin and the neurotransmitters dopamine and norepinephrine, people feel more open, have a greater sense of empathy, sensory pleasure and less anxiety.

Psilocybin is a 5HT-2A receptor agonist, stimulating the release of serotonin in the brain through a mechanism of action different to MDMA [18].

Both MDMA and psilocybin are believed to reduce activity in the amygdala, a region of the brain associated with regulating emotions, reducing this region’s response to negative emotional stimuli [10].

Additionally, psilocybin is thought to “turn off” the default mode network (DMN) in turn, disrupting the brain circuitry underlying mental disorders like anxiety [19]. The DMN is a collection of neural pathways that govern our self-image, autobiographical memories, and deeply ingrained beliefs and thought patterns [20]. Thus, by disrupting the neural circuitry in this region, psilocybin allows people to alter the ingrained beliefs and thought patterns that may be underlying their anxiety.

In doing so, these psychedelic drugs reduce anxiety in the face of emotionally challenging thoughts with patients reporting overall increases in their quality of life which they attribute to these psychedelic therapy sessions.

Ketamine exerts its effects through a different mechanism of action. Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist. Its anxiolytic effects are presumed to occur through increasing secretion and translation of brain-derived neurotrophic growth fact (BDNF), which, in turn, activates synaptic plasticity i.e. strengthening the connection between neurons [21].

The impact ketamine has on plasticity is rapid, occurring within hours of administration. Although the ability of ketamine to alleviate symptoms of anxiety may be rapid, the anxiolytic effects are transient compared to classic psychedelics such as psilocybin, lasting in the region of one to two weeks [22].

“Ketamine may be a potential therapeutic alternative for patients with refractory generalized anxiety disorder/social anxiety disorder.”

Glue et al. 2017

Notwithstanding, it is worth noting that side effects associated with the use of ketamine exist. A review of 60 articles in which ketamine was used to treat depression identified that headache, dizziness, dissociation, elevated blood pressure, and blurred vision were the most common in response to intravenous infusion. Furthermore, the most common acute psychiatric side-effect was anxiety [23]. Thus, long-term, large-scale clinical trials are needed to assess the safety of the long-term regular use of ketamine.

Psychedelic industry and anxiety

As psychedelics are gradually entering the mainstream, several companies have entered the field with hopes to use psychedelic drugs to treat anxiety.

One such company is the New York-based MindMed which has raised over $200 million since its founding in 2019. In 2020, MindMed launched Project Lucy in collaboration with Dr Matthias Liechti and Dr Peter Gasser and their team at University Hospital Basel, Switzerland. Project Lucy is exclusively dedicated to exploring the potential of LSD to treat anxiety disorders, with Phase IIa trials nearing completion.

Project Lucy builds on the work of Dr Gasser, who in 2014 led a team of researchers, including Rick Doblin, as they carried out one of the first double-blind placebo-controlled trials (n=12) investigating the safety and efficacy of using LSD to treat end-of-life anxiety. The results of this trial demonstrated that when administered safely in a methodologically rigorous supervised psychotherapeutic setting, LSD can reduce anxiety [24].

Cybin is also focusing on progressing psychedelic therapeutics from Toronto, Canada. Before commencing trading on the NYSE as of August 2021, Cybin had raised over $88 million and had filed 13 patent applications for synthetic derivatives of psychedelic compounds like psilocybin and DMT. Cybin has chosen social and generalised anxiety disorders as the initial primary targets for their molecule CYB004.

Following trials for investigational new drug applications (INDs) as required by the FDA, upon successful completion, results will be submitted to regulatory agencies like the EMA to advance into Phase I studies [25]. In October 2021, Cybin announced they had made significant progress in preparing CYB004 and another compound to treat alcohol use disorder (AUD), CYB003 [26].

While companies like MindMed and Cybin are directly focusing on anxiety disorders, other companies, like COMPASS Pathways, and research groups across the globe using psychedelics to treat depressive disorders are indirectly aiding anxiety research as these disorders are experienced comorbidly, more often than not [27].

As COVID-19 has exacerbated the demand for mental health services [28], the time is right to continue exploring and investing in the therapeutic application of psychedelic drugs for anxiety, and other mental health disorders, to advance the clinical trial process and improve the quality of life of millions of people on a global scale.

References

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