Abstract
There is an urgent unmet medical need to develop therapeutic options for the ~50% of depression patients
suffering from treatment-resistant depression, a form of depression resistant to treatment by existing psycho-
and pharmaco-therapies. Classical psychedelics, such as the 5HT2A agonists lysergic acid diethylamide (LSD)
and psilocybin, have re-emerged as a treatment option for patients with depression that is treatment-resistant.
Recent clinical trials highlight the potential effectiveness of 5HT2A agonists to improve mood and
psychotherapeutic growth in treatment-resistant depression patients, even in those who have failed a median of
4 previous medications in their lifetime. Accordingly, the FDA recently granted “Breakthrough Therapy”
designation to psilocybin for treatment-resistant depression. The improvements associated with 5HT2A agonist
pharmacotherapy last for weeks to months, a marked increase relative to ketamine, but administration requires
a 6-8-hr psychological support session, an approach which is unlikely to scale. Moreover, many patients find
their symptoms recur and need repeat administration. ‘Microdosing’ – ingesting subperceptual doses of
psychedelics every 3-7 days to improve mood and/or creativity – represents an alternative, potentially long-term
treatment option. Microdosing has become prominent in the lay public, with recent scientific studies corroborating
anecdotal claims that it improves mood, energy levels, social connectedness, and decreases craving for
addictive substances. However, there are a gamut of practical barriers that stymie further investigation of 5HT2A
agonists microdosing in the clinical setting, including: low compliance with the complicated dosing regimen, high
risk of diversion of controlled substances, and difficulty and cost administering the long-term treatment regimens
in controlled settings. Here, we propose to overcome the above limitations by developing a bioresorbable
microdosing implant (MDI) composed of “microfluidic fuses”, or µfuses, that enables long-term, intermittent
delivery of sub-perceptual microdoses of 5HT2A agonists. The µfuses are composed of a 70:30 mixture of
Cellulose Acetate Phthalate (CAP) and Pluronic® F-127 (P) polymers which form a surface-eroding film. CAPP
µfuses will be embedded in a slowly biodegrading polycaprolactone (PCL) body and sit atop 5HT2A agonist-
containing drug reservoirs in series. As the CAPP µfuse erodes, the reservoirs will be exposed to the surrounding
fluid and release pulses of 5HT2A agonist, where the timing between pulses is controlled by the distance between
reservoirs beneath the µfuse. We will develop the CAPP µfuse technology in two aims. 1) Microfabricate and
validate the function of µfuse devices in vitro. 2) Characterize the in vivo pharmacokinetics and biocompatibility
of prototype µfuse devices in immune-competent, healthy mice. Successful development of this technology will
enable unprecedented studies into the merits of 5HT2A microdosing as a therapeutic strategy to overcome
treatment-resistant depression.
