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Microdosing Versus Antidepressants for Depression: Which One Is For You?

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Microdosing has become increasingly common since James Fadiman, Ph.D. popularized the practice in his 2011 book, The Psychedelic Explorer’s Guide. In the Global Drug Survey ten years later, one in four people who used psychedelics also reported microdosing for mental health benefits like alleviating depression symptoms. Many people discontinued antidepressant medications as a result.

Today, more and more people are microdosing or taking low, sub-hallucinogenic psychedelic doses for mental health and reevaluating their relationships with pharmaceuticals like Prozac, Zoloft, and Lexapro.

Watch the video above highlighting the critical differences between microdosing classic psychedelics and antidepressants for treatment-resistant depression and anxiety. Read on for a comprehensive overview of recent psychedelic research comparing microdosing to antidepressants in clinical and real-world settings.

Antidepressants: Efficacy and Mechanism of Action

Patients have been using pharmaceutical antidepressants, like selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) since the first MAOI in the 1950s.

SSRIs are the most common antidepressant medications in modern psychiatry. Known as antagonist antidepressants, SSRIs increase serotonin levels by activating the brain’s 5-HT1A receptors and inhibiting the 5-HT2A receptors.

SSRIs’ serotonin action purportedly treats depression and anxiety by improving mood, enhancing positive emotions, and improving sleep. However, longitudinal research indicates selective serotonin reuptake inhibitors have serious limitations.

A systematic review of 232 double-blind placebo-controlled trials revealed that antidepressants are more effective than placebo, but the difference is minimal statistically speaking. Antidepressants only provide limited benefits to a small population subset.

Of  73,000 patients reviewed, less than a quarter experienced significant symptom relief. Of those patients, just  15% showed benefits beyond a placebo effect.  Interestingly, the study focused on near-term efficacy and didn’t identify long-term trends.

A 2022 panel survey analysis published in PLOS One analyzed patients over 11 years. The study determined that patients on antidepressants didn’t experience improved quality of life compared to those not on SSRI-type medications.

MAOIs and SNRIs claim to be more effective than SSRIs because they increase levels of serotonin and other neurotransmitters.

SNRIs increase norepinephrine levels, which are associated with energy and attention.
MAOIs increase serotonin, norepinephrine, and dopamine, which can improve mood and reduce panic.

Still, research indicates SNRIs are no more effective than traditional SSRIs for treating anxiety disorders. And MAOIs have significant side effects beyond the standard sleepiness, nausea, and diarrhea that many antidepressant patients report. MAOIs can also cause blood pressure spikes and seizures when mixed with common foods like chocolate, aged cheeses, processed meat, and red wine.

How Psychedelics Act Differently

psychedelic image reflecting psychedelics neural action - third wave image

Antidepressants’ lackluster results may be due to the neuroscience of how SSRIs and SNRIs act on the brain, compared to psychedelics. Both drugs interact with the body’s serotonin system, but in distinct ways.

Traditional psychedelic compounds bind with postsynaptic serotonin receptors known as 5-HT1A, while classic psychedelics primarily act on 5-HT2A receptors.

Renowned psychedelics researcher Robin Carhart-Harris published a notable paper on this topic, illustrating why antidepressants’ and psychedelics’ receptor preferences matter to mental health outcomes.

According to Carhart-Harris, serotonin neurotransmission correlates to “two distinct adaptive responses to adversity.” 5-HT1A agonists like Prozac lead to “passive coping,” while 5-HT2AR activation mediates “active coping.”

Image reflecting difference between 5-HT1A and 5-HT2A serotonin receptors

Photo credit: Serotonin and brain function: a tale of two receptors

In other words, antidepressants dampen emotional intensity, reducing the mental and physical sensations associated with stress, depression, and anxiety.

Such numbing effects can be profoundly beneficial, especially for those who feel suicidal. But SSRIs’ 5-HT1A affinity may also lead to emotional repression, compartmentalization, and lack of motivation, ultimately making people emotionally stunted, less resilient, and less patient when faced with challenges. In some cases, antidepressants can cause or exacerbate anhedonia, a condition where life feels gray and bleak.

Classic psychedelics, like LSD and psilocybin, act on various neurotransmitters, including serotonin, dopamine, glutamate, and adrenergic. Most research, however, focuses on LSD and psilocybin’s strong affinity for particular serotonin channels.

Acting on 5-HT2A and 5-HT2C receptors, these traditional hallucinogenic compounds quiet brain regions associated with mind-wandering, fear, and hypervigilance while activating networks responsible for visual input, higher learning, memory, planning, goal-setting, and instinct regulation.

Psychedelics’ ability to reorganize the brain’s ordinary communication networks through neuroplasticity brings people face to face with the root causes of their depression and anxiety, typically with less judgment and distress.

In the process, psychedelics promote catharsis, an emotional release, and meaning-making, allowing people to reframe traumas into stories with transformative lessons. “Active coping” helps free people from clinical pathologies like treatment-resistant depression by confronting rather than avoiding discomfort.

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