Psychedelics vs Antidepressants – What You Won’t Hear at the Doctor’s Office

by Katie Simons, PharmD, CCHT

Originally published in Brainz Magazine

Millions of people take antidepressants every day, often without ever questioning how these medications actually work—or how effective they really are. At the same time, psychedelics are making headlines as a promising tool for depression, anxiety, and trauma, despite being largely illegal in much of the world. From ketamine to psilocybin to ayahuasca, the results continue to stack up. It’s no wonder people are starting to ask: Could psychedelics replace antidepressants? Could they help me get off my medication? Or even—can they fix my brain? 

The answers might surprise you—and they could change the way you think about healing the mind altogether. To understand the difference, we need to look at how each one actually works in the brain—and why that matters if you're seeking more than just symptom management.

Antidepressants vs Psychedelics — Two Very Different Approaches

At first glance, antidepressants and psychedelics both act on serotonin in the brain. But that’s about where the similarities end. Antidepressants are designed to create stability by quieting the emotional noise—smoothing over symptoms so that life feels more manageable. Psychedelics, on the other hand, do the opposite: they amplify perception, disrupt entrenched neural patterns, and invite what’s unresolved to rise to the surface.

You could think of it this way: antidepressants help you cope; psychedelics help you process. Coping can be useful, especially in crisis. But staying in that mode long term can lead to numbness, disconnection, and a sense of being stuck. You might be getting through the day, but not really living.

The deeper issue here is our cultural model assumes that anxiety, depression, trauma, and other mental health challenges are signs of a malfunctioning brain. But what if they’re not malfunctions at all? What if these symptoms are actually intelligent messages from your nervous system—letting you know that something in your internal or external environment is unsafe or unsustainable? What is your brain is actually doing exactly what it’s designed to do?

Polyvagal Theory, developed by Dr. Stephen Porges, helps us see symptoms in a new light. Feelings like anxiety, hypervigilance, overwhelm, and anger often arise when the autonomic nervous system (ANS) is in a sympathetic fight-or-flight state. Symptoms like depression, apathy, lethargy, or dissociation show up when the system shifts into freeze. In both cases, the body is trying to protect you. Your symptoms aren’t the problem—they’re a signal.

The trouble is, modern life doesn't make much room for listening. Most of us push through, ignore the signs, and turn to medication to mute the volume so we can keep up with the demands of a job, relationship, or life that, for some internal reason, doesn’t feel safe.

This is where psychedelics offer something radically different. As active processing tools, they temporarily quiet the brain’s usual defenses and make it easier to access the emotional material that needs attention. They help bring subconscious stress patterns to the surface, allowing the nervous system to release old stories, reprocess stored trauma, and recalibrate from the inside out.

Instead of suppressing symptoms, psychedelics invite us to listen to them—and to heal at the root.

How Antidepressants Work in the Brain

Most modern antidepressants work by blocking the reabsorption of neurotransmitters, effectively increasing the availability of these neurotransmitters in the brain. Which neurotransmitters are affected depends on the type of antidepressant. SSRIs increase serotonin levels. SNRIs affect serotonin and norepinephrine. Atypical antidepressants, like Wellbutrin (bupropion), work on norepinephrine and dopamine. The list goes on, and you get the point. 

In theory, the increase in "happy" neurotransmitter levels should make people feel happier. And for some people, it does. But it's worth noting that we still don’t fully understand how these medications work. If the mechanism of action were as straightforward as boosting serotonin levels, we’d expect immediate results. Instead, most antidepressants take 4–6 weeks to begin working—suggesting that their effects may involve more complex changes in brain function over time.

In practice, what most people feel is a kind of buffering effect. Emotions feel a little flatter, but also a little more manageable. This can help prevent the lows from feeling so low—but it can also blunt the highs. Many people report feeling emotionally "muted" or "blunted": not deeply sad, but not deeply joyful either. This is part of the mechanism: less volatility, less internal chaos, and more ability to function.

The problem is that these medications don’t address the root cause of why someone feels anxious, hopeless, or disconnected in the first place. They simply dampen the signals. And over time, the brain can become dependent on that buffering effect. Tapering off antidepressants, especially after long-term use, can be extremely difficult. Withdrawal symptoms—often called "discontinuation syndrome"—can include brain zaps, mood swings, fatigue, and a resurgence of the very symptoms the medication was meant to treat.

And here’s the kicker: large meta-analyses have shown that, for mild to moderate depression, SSRIs perform no better than placebo. Their strongest benefits appear in cases of severe depression, but even then, results are highly variable depending on the individual, the environment, and the support system in place.

In short: antidepressants work by quieting the mind. But they don’t teach it how to heal. They sometimes offer relief—but not resolution.

How Psychedelics Work in the Brain

In contrast to antidepressants, psychedelics don’t mute emotions—they often amplify them. But they do so in a way that creates space for new understanding, healing, and release. At the core of this effect is their interaction with the brain’s 5-HT2A serotonin receptors. These receptors are heavily involved in mood regulation, imagination, introspection, and emotional processing. Psychedelics like psilocybin, LSD, and DMT activate these sites leading to expanded perception and heightened emotional insight.

But the real magic unfolds in the brain’s default mode network (DMN). This network, responsible for our sense of self, autobiographical memory, and habitual thought loops, is often hyperactive in individuals with depression and anxiety. When psychedelics enter the system, they dramatically disrupt activity in the DMN. This disruption can feel like stepping out of the “autopilot mode” most of us live in—where old beliefs, fears, and internal narratives run unchecked.

When the DMN quiets down, other brain regions start communicating in new and more flexible ways. This creates what researchers call a state of enhanced neuroplasticity—a temporary window where the brain is more adaptable, more open to learning, and more capable of change. This neuroplastic window is believed to be one of the key reasons psychedelics show so much promise in treating depression, trauma, addiction, and anxiety.

Clinical studies back this up. In recent years, psychedelics have shown rapid and lasting efficacy in treatment-resistant depression, PTSD, and end-of-life anxiety. In many cases, a single high-dose psychedelic session—paired with therapeutic support—has led to significant improvements that last weeks or even months.

Where antidepressants dampen the emotional system to make life feel less overwhelming, psychedelics open a window into the emotional system to help us process, release, and transform what’s been stuck there all along.

Psychedelics vs Antidepressants — What the Research Reveals

There’s a growing body of clinical research comparing psychedelics to traditional antidepressants—and the results are worth paying attention to.

In the most widely cited study to date, researchers at Imperial College London compared two sessions of psilocybin with six weeks of daily escitalopram (a popular SSRI) for people with moderate to severe depression. Both groups showed improvement, but the psilocybin group had double the remission rate—57% compared to 28%. People in the psilocybin group also reported greater emotional connection and increased well-being.

In another large trial, Compass Pathways studied a single dose of synthetic psilocybin in people with treatment-resistant depression. They found that 29% of participants were in remission after just three weeks, compared to only 7.6% in the placebo group. Even more impressive, long-term data from Johns Hopkins showed that 58% of people were still in remission a full year after their psilocybin session.

Other psychedelics are showing similar promise. A recent study in JAMA Psychiatry found that nearly half of participants receiving one dose of LSD experienced full remission of generalized anxiety at 12 weeks. Ketamine, now used clinically for depression in many countries, is known for rapid relief—sometimes within hours—especially for those who haven’t responded to other treatments.

While most of this research is still emerging, the trend is clear: psychedelics aren’t just numbing symptoms—they’re helping people experience profound shifts in perspective, emotion, and meaning. And when paired with therapeutic support, they may offer a path to healing that’s faster, deeper, and longer-lasting than what most antidepressants can provide.

Can I Use Psychedelics While I'm On Antidepressants?

Ok, so where do we go from here? I see clients all the time that are on antidepressants, and they are over it—they are sick of feeling numb and having zero sex drive, they aren't sure what joy feels like anymore, and they don't even know if the antidepressants are working anymore. So how do you make the switch and start getting yourself back?

We'll start with one of the most common questions people ask—whether it's safe to take psychedelics while still on antidepressants. The short answer? It depends on the medication—and the psychedelic.

Some classical psychedelics like psilocybin and LSD do not carry a known risk of serotonin syndrome when used in combination with SSRIs or SNRIs. Unlike MDMA, which has a more complex interaction with serotonin and demands greater caution, psilocybin and LSD work via a different mechanism and have been co-used with antidepressants without serious complications.

That said, antidepressants may blunt the effects of psychedelics, particularly at the emotional or perceptual level. People often report that the experience feels muted or less immersive. So while the combination may be physically safe, it may not offer the full range of benefits unless the antidepressant is reduced or tapered.

This is where individual context matters. For some, a gentler experience is actually preferable—especially early in the healing process. For others, the medication may need to be addressed before deeper psychedelic work can unfold. Either way, consulting with a knowledgeable professional is critical.

Can Psychedelics Help Me Get Off Antidepressants?

And how about whether psychedelics could help you get off antidepressants? If this is your next logical question, you’re not alone. More people are asking this question as studies show the potential of psychedelics to support emotional healing in ways antidepressants often don’t. But transitioning off medication isn’t something to do impulsively—especially if you’ve been on them for a long time.

Tapering is essential. Antidepressants alter your brain’s neurochemistry, and stopping suddenly can trigger withdrawal symptoms like mood swings, insomnia, anxiety, and brain zaps. A gradual, individualized taper allows your nervous system time to recalibrate. Many people find it takes months—not weeks—to taper safely and effectively.

This is where psychedelics, especially psilocybin, may offer support. While they are not meant to directly replace antidepressants, they can create the right conditions for change: increased emotional clarity, enhanced neuroplasticity, and a deeper sense of meaning or purpose. For some, this can make the emotional work of tapering more productive. For others, it can reignite a spark that’s been dulled by years of symptom suppression.

Professional guidance matters. Coming off antidepressants and working with psychedelics are both nuanced processes. When combined, they require even more care. Working with someone who understands both pharmaceuticals and psychedelic integration—ideally with trauma-informed training in nervous system regulation—can be the difference between a rough transition and a truly healing one.

Microdosing vs. Macrodosing — What's the Difference?

As we continue down this rabbit hole, the next logical question is how does one go about interacting with psychedelics? Do you need to go to the jungle and have a huge experience? This is naturally the place to introduce the hot topic of microdosing—taking sub-perceptual doses of a psychedelic like psilocybin or LSD, often a few times per week. Unlike macrodosing, where the goal is to induce a full psychedelic journey, microdosing aims to create gentle shifts in mood, energy, and perspective without the altered state. Some people compare it to a “mood vitamin” that makes the day feel a little brighter, lighter, or more creative.

While the research is still catching up, thousands of anecdotal reports and small studies suggest that microdosing may support nervous system regulation, emotional awareness, and subtle shifts in ingrained patterns—especially when paired with practices like meditation, hypnotherapy, or breathwork. Over the course of a 6-8 week microdosing practice, these subtle shifts can add up to profound changes. There is also data showing that you get those magical neuroplasticity effects when using certain microdosing protocols. It's not a replacement for deeper therapeutic work, but it can serve as a helpful support.

Macrodosing, by contrast, involves a larger, immersive experience that can bring deep subconscious material to the surface. For some, this kind of journey catalyzes big shifts—emotional breakthroughs, spiritual insights, and perspective changes that echo for weeks or even months. But that doesn’t make it better or more effective than microdosing—just different. Some nervous systems are ready for the depth that macrodosing offers, while others benefit more from the slower, steadier rhythm of microdosing.

Both approaches offer valuable tools and have their place. Microdosing can gently build awareness and create momentum, while macrodosing can shake things loose and show you what’s been running the show underneath the surface. And when used intentionally, both can support the larger process of healing, growth, and self-sovereignty.

The Bigger Picture — Can Psychedelics Fix Your Brain?

It’s tempting to hope for a silver bullet—especially when you’ve been struggling with anxiety, depression, or emotional numbness for a long time. And while the early research on psychedelics is exciting, here’s the truth: psychedelics can open the door, but they don’t do the work for you.

Lasting change doesn’t typically come from just one powerful trip. It comes from what you do after. Psychedelics may help reset your brain’s default patterns and boost neuroplasticity—but it’s up to you to build the new pathways. That means creating safety in your body, setting boundaries in your life, and practicing habits that support mental and emotional health.

We know from earlier in this article that many symptoms of depression and anxiety are rooted in nervous system dysregulation. Psychedelics can help you access and process the subconscious material driving those patterns—but you still have to identify what’s triggering your system. You still need to do the work of creating safety signals and repatterning old beliefs. This is where somatic therapies, hypnotic work, and trauma-informed modalities like EMDR or bilateral stimulation can make a big difference.

In other words, psychedelics can amplify the healing process, but they’re not a shortcut. They won’t fix your brain if you’re not willing to participate in your own healing. The good news? You’re more powerful than you’ve been taught to believe. When you begin listening to your body and working with your nervous system, you start to reclaim that power.

This is what self-sovereignty looks like. Psychedelics can remind you of who you are—but you’re the one who has to live it.

Ready To Take The Next Step?

If you’re exploring the role of psychedelics in your healing journey—or questioning whether antidepressants are still serving you—you don’t have to do it alone. This path is complex, personal, and full of potential. With the right support, you can navigate it safely and powerfully. Learn more about working with me or grab my free guide to microdosing here.