Growing research into hallucinogenic drugs is demonstrating that—contrary to what was previously believed—depression and anxiety cannot be reduced to a simple equation of chemicals in the brain. So, will psychedelics be able to bring a decisive paradigm shift to how we view and treat these mental health conditions?
According to the World Health Organization, over 300 million people worldwide are estimated to experience depression and a similar number of people are thought to live with anxiety. As people often experience such mental health conditions simultaneously, which is referred to as comorbidity, and many do not seek treatment, the real number likely is a lot higher.
Until now, researchers’ approach to treating anxiety and depression has largely focused on striking a delicate balance between chemical messengers in the brain. The plethora of medications prescribed, such as SSRIs (selective serotonin reuptake inhibitors) all work around that principle.
Studies on hallucinogenic compounds, however, have shown that such drugs can help the neurons in the brain “talk with each other” via neurotransmitters, or chemical messengers. This has led to the emergence of the “network theory.”
“There really has been almost like a paradigm shift in the way that we looked at the pathophysiology of depression; it used to focus on chemical imbalance. Now, it has shifted to look at it a little bit more as a disorder of synaptic plasticity, as well as neural interconnectivity.”
— Dr. Adrian Jacques Ambrose, adult, child/adolescent psychiatrist
In the latest episode of our In Conversation podcast, we discuss the newest research into the neuroscience of anxiety and depression and how this may change the future of treatment with Dr. Adrian Jacques Ambrose, medical director of the Columbia Psychiatry Practice Office. Dr. Ambrose also specializes in interventional neurotherapeutic psychiatry, working with ketamine, electroconvulsive therapy (ECT), and transcranial magnetic stimulation (TMS) in the treatment of resistant mood disorders.
Our other interviewee is Olivia, who has been living with anxiety and depression for a number of years, and she shares her experience.
You can listen to our podcast in full below, or on your preferred streaming platform.
Describing difficult feelings
Our conversation starts with spotting the signs and symptoms of these conditions. On talks of anxiety, Olivia chimes in:
“[When anxious] I can feel like butterflies inside and my hands are sweaty, and you just feel very, I don’t know, on edge. But then with panic attacks or anxiety attacks, I get very hyperventilated and struggle to breathe.”
In contrast, Olivia says, depression makes her feel very different emotions.
“[F]or me, very obviously [it’s a] low in mood. I feel [w]orthless, and then have periods [where I] find it hard to get out of bed, be motivated. It’s like, being weighed down. [Y]ou want to come up, but you can’t.”
— Olivia, who has experienced depression for many years
“[W]hen you’re depressed, you kind of feel a bit numb, I find [that] it’s very different [compared to anxiety]. [Y]ou just feel empty rather than on edge. They’re very different ends,” she said.
A changing brain
Without treatment, depression and anxiety disorders can alter the way the brain functions, and cause physical changes.
For example, with prolonged episodes of anxiety, the amygdala, or the tiny almond-shaped center of emotions and motivation, grows larger and becomes hypersensitive. The stress caused by constant anxiety also shrinks the hippocampus, the structure involved in learning and memory.
These physical changes can also bring about more psychological symptoms or worsen them.
During anxiety, the constant ‘danger’ signaling to the hypothalamus—the smart control and coordination center deep in the brain—also eventually weakens the connections between the amygdala and prefrontal cortex, which is responsible for planning, and decision-making. As a result of this chain of reactions, an individual may start to lose their ability to think analytically or logically.
“For example, in [depressed] adults, we see abnormally increased amygdala, as well as ventral striatal and medial prefrontal cortex activity. What that means is that the patients are more attuned toward negative emotional stimuli. They also show abnormally reduced ventral striatal activity toward positive emotion and emotional stimuli,” said Dr. Ambrose.
The pathophysiology of anxiety and depression
One of the earliest hypotheses about the pathophysiology of depression is that it was an imbalance of chemicals in the brain. But, in reality, it is a rather complex interplay of multiple factors. Similar theories have been put forth for anxiety as well—research has implicated biochemical imbalances and an often-inherited defensive mechanism in the brain.
“Our prior understanding of [depression and] anxiety disorders primarily focused on neurotransmitters because those were what we used SSRIs for in order to treat these conditions,” said Dr. Ambrose explaining the current approach.
Newer studies instead have found dysfunction in neural circuits to be a factor, with researchers identifying “hot and cold” areas within the brain.
With regard to circuitry affected by depression and anxiety, Dr. Ambrose said there are different aspects of the brain that get hyperactivated and hypoactivated.
“For anxiety disorder, as well as panic disorder, there’s hyperactivation of what we call the fear network. [By this] I mean specific parts of the brain that includes the thalamus, the amygdala, the hippocampus, and the striatum,” he said.
Dr. Ambrose said this fear network essentially magnifies some of the sensory inputs a person may be experiencing during anxiety attacks. As the human brain is wired to hold onto negative memories and emotions, such as those of fear, failure, and danger, these keep replaying in the mind.
“In panic disorder, you get this overdrive of fear and over-evaluation of fear by the orbital frontal cortex, which is the part of the frontal lobe of the brain that is involved in the cognitive process of decision making. So, it makes you feel very fearful when you have to make decisions that appear to be a threat,” he further explained.
“When in objective evaluation, it may not necessarily be a threat, but you perceive it as a threat,” he added.
Current treatments
In evaluating all the medications currently used to manage and treat anxiety and depression, three classes of drugs stand out from the rest.
Tricyclic antidepressants, also known as TCAs, are the oldest class of antidepressants and were introduced in the late 1950s. However, they were often associated with many side effects.
Apart from talking therapy, the next most popular first line of treatment is SSRIs, which are drugs that act on serotonin molecules and manipulate their level to indirectly boost other neurotransmitters. The FDA approved them in the 1980s. One of the most widely used SSRIs is fluoxetine, more commonly known under the brand name Prozac.
The latest addition to the modern era of antidepressants came in the 90s with SNRIs (serotonin-norepinephrine reuptake inhibitors), with medications such as venlafaxine (Effexor). These were deemed a lot safer in terms of side effects.
As for anxiety, short-term treatment includes calming drugs like benzodiazepine and psychotherapy. In the longer term, doctors often prescribe antidepressants and anti-anxiety drugs like buspirone.
However, research has indicated that antidepressants may only improve symptoms in about 40% to 60% of people.
“For major depressive disorder, unfortunately, what we find is that antidepressants are not as effective as we would hope. So roughly, [half] of patients will say that their antidepressants don’t really work well for them. And even after multiple medication trials, about a third of patients will still show no response to antidepressant trials,” said Dr. Ambrose.
Psychedelics enter the scene
The term psychedelic comes from “psyche” and “dēlos”, Greek for “mind-manifesting”. It was coined in the 1950s by British psychiatrist Humphry Osmond.
When one talks of psychedelics, they refer to drugs and psychoactive substances that invoke a certain type and extent of experience. Some examples are: LSD (lysergic acid diethylamide, or acid), psilocybin (magic mushrooms), and DMT (dimethyltryptamine).
If we were to compare regular antidepressant medication with psychedelics, the most apparent difference would be in their mechanism of action.
Antidepressants work by manipulating the levels of neurotransmitters that are typically too low (or too high) in the brains of people experiencing depression or anxiety. Meanwhile, psychedelics act on neural circuits, stimulating, suppressing, or modulating the activity on the networks that use serotonin.
One of the advantages of using psychedelics in depression or anxiety treatment, as studies have shown, is that researchers have managed to improve or get rid of symptoms with just a few uses, particularly with psilocybin. Antidepressants, on the other hand, usually have to be taken every day for months or years.
One such study was a randomized clinical trial involving 24 participants with major depressive disorder. The participants who received immediate therapy with psilocybin (in addition to psychotherapy) had less severe depressive symptoms compared to those who received delayed treatment. By the 4th week after initial treatment, 54% of the participants were no longer classified as depressed.
Researchers have also found that psychedelics can increase neural connections in the brain.
“I think that antidepressants are not as efficacious because of their lack of specificity. We don’t necessarily have the current technology to be really targeted in the way that we’re using psychopharmacologic treatments,” said Dr. Ambrose.
Why ketamine may be different
Ketamine is, first and foremost, an FDA-approved anesthetic and dissociative drug. While it does produce similar effects as psychedelics and leads to a similar expanded state of awareness, it has a different mechanism of action. In that sense, some researchers refrain from labeling ketamine as a classic psychedelic.
Ketamine works by relaxing the brain’s inhibitory architecture, whereas psychedelics work by overriding this system.
Due to this mechanism, many people describe their experience with psychedelics as challenging and powerful, either constructive or destructive, depending on the settings and individual circumstances. With ketamine, participants in trials describe it as a gentler experience in comparison.
However, animal studies have also found that ketamine may require more regular intake to prolong its anti-depressant effects, raising concerns around addiction.
A new age of consciousness medicine?
Mounting evidence is suggesting that hallucinogenic drugs can be effective therapies for treatment-resistant depression and anxiety. A renewed understanding of the neuroscience behind anxiety and depression is also prompting researchers to rethink such therapies for these conditions.
Dr. Ambrose said that as technologies such as neuroimaging and functional MRIs get more advanced, it is becoming clearer to see the areas of hypoactivation and hyperactivation in the brain as well as areas that might be a little bit more sensitive when people are experiencing conditions like anxiety.
As with any type of medication, each has its own set of benefits and risks. This rings true for non-conventional therapies like hallucinogenic drugs as well.
Psychedelics may hold the potential to “open up” people’s brains, helping it become more flexible and fluid. Dr. Ambrose said that they may be best for people with treatment-resistant mental health conditions who have failed to gain positive results from a variety of treatments.
The only way to get access to these treatments, currently, is through clinical trials, where rigorous safeguards are in place. Every individual’s needs may also be different depending on their personality, circumstances, and health conditions.
“As a physician, I want to be really agnostic in the space and let the clinical evidence really speak for itself. I don’t want to quit any judgment surrounding psychedelics or any particular predilection.My main focus is trying to be mindful of potential.”
— Dr. Adrian Jacques Ambrose
Dr. Ambrose said he saw psychedelic therapy as an additional tool to current treatments.
“It’s not meant to be a panacea. I think just trying to be mindful of the fact that there are, unfortunately, a lot of social and sociological traumas like poverty and racism [surrounding such treatments and therapies] that it’s really hard to treat with a medication or a pill,” he added.
For the foreseeable future—whether due to a lack of resources or technology, or stigma—it is unlikely that psychoactive compounds will become mainstream treatments for mental health conditions.
However, interest in ketamine and psychedelics as treatment avenues for anxiety and depression is likely to grow.
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