Active vs. Passive Coping Distinguishes Antidepressants and Psychedelics

As the antidepressant effects of serotonin (5-HT) agonists and antagonists become more widely researched, the roles of different 5-HT receptor subtypes are becoming more distinguished. Serotonin has a rich neurochemistry with 14 identified receptor subtypes.¹ This article focuses on two primary subtypes, 5-HT_1AR and 5-HT_2AR, and their roles in brain functioning. Distinguishing the two is particularly important in understanding how psychedelics (LSD, 2-CB, psilocybin, etc.) differ from classic antidepressants.²

5-HT_1AR vs. 5-HT_2AR Signaling

SSRIs modulate 5-HT_1AR signaling, whereas psychedelics modulate 5-HT2AR signaling.² The receptor subtype that has been associated most greatly with the antidepressant effects of SSRIs so far is the 5-HT_1AR.³ Some antidepressants (e.g., trazodone) even downregulate 5-HT_2AR signaling.³ It is important to note that common antipsychotics blockade the 5-HT_2AR functioning in order to mitigate symptoms of psychosis.

On the other hand, psychedelics, also known for their antidepressant effects, possess agonist properties at the 5-HT_2AR subtype. This receptor subtype is known to be the trigger of the psychedelic experience. In fact, the blockade of the 5-HT_2AR receptor diminishes the subjective effects of LSD: experience of unity, blissfulness, and overall positive therapeutic effects, as confirmed by ketanserin studies.⁴

Despite their differing roles, 5-HT_1AR and 5HT_2AR signaling are both crucial in the maintenance of healthy brain functioning.

Active vs. Passive Coping

5-HT_1AR signaling offers basal control, moderating emotion and anxiety; 5-HT_2AR signaling engages more during times of crisis.² 5-HT_1A and _2AR signaling are endogenous pathways that drugs like antidepressants and psychedelics can stimulate. Researchers employ the terms “passive” vs. “active” coping to these two serotonin signaling pathways.^2,5

The dual model suggests that under passive coping one tolerates but does not “deal with” a source of psychological distress whereas during active coping one actively deals with psychological distress and can even change their relationship to it.²

5-HT_1ARs are widely distributed whereas 5-HT_2ARs are more common in regions dedicated to higher-level cortical processing­–suggesting that 5-HT_2ARs are involved in processes that evolved later.² 5-HT_1ARs are found most commonly in the limbic system, alluding to their role in stress management. Increases in postsynaptic^[1] 5-HT_1AR signaling decrease stress and anxiety while increasing patience and tolerance of stress. 5-HT_2ARs are found across the cortex and in areas involved in higher-level cortical processing such as the neocortex and somatosensory cortex. Increases in 5-HT_2AR signaling decrease rigid thinking, pessimism, and increase neural plasticity, environmental sensitivity, and adaptability. Both pathways ultimately decrease depression while increasing overall well-being.

^[1] Localization of receptor subtypes (i.e. postsynaptic or presynaptic) plays a role in the function of signaling.² SSRIs inhibit serotonin reuptake, causing increased downstream signaling of serotonin at 5-HT_1ARs. Psychedelics are agonists of 5-HT_2ARs, affecting both presynaptic and postsynaptic receptor signaling.

Figure 1: The two-part model of brain serotonin function.² This image depicts the two pathways of serotonin function in the brain, illuminating the basic functions of 5-HT_1AR-mediated passive coping and 5-HT_2AR-mediated active coping, as well as functions reduced and enhanced in correlation.

Emotional Lability and 5-HT_2AR Signaling

The potential for psychedelics to induce emotionally labile, or sensitive states, can be a great agent of therapeutic change (and can also lead to neuroplasticity and increased creativity). This is in line with the “entropic” brain hypothesis, suggesting that psychedelics can induce a plastic, malleable brain state.⁶  

It is suggested that the benefits of active coping can be maximized if the support of psychotherapy is added during the emotionally labile state of 5-HT_2AR agonism.² An emotionally labile state can be used to facilitate neuroplasticity and healing under the right therapeutic setting.^2,7

Limitations & Takeaway

While many other receptor subtypes also play a large role in antidepressant activity, this article solely discusses two prevailing serotonin receptor subtypes. It is important to highlight the contributions of 5-HT_2AR, as it is linked to an active coping model, the psychomimetic effects of psychedelics, and many of the therapeutic outcomes of psychedelic therapy. Thus, 5-HT_2AR agonists are a viable avenue for the treatment of depression, despite the incidence of 5-HT_1AR antagonists in antidepressants.

Melody Pezeshkian, BS

Melody Pezeshkian holds a B.S. in Psychological and Brain Sciences and has worked in the fields of brain science, mental health, and psychedelic medicine.

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