Table 5.

Preclinical pharmacological activity of natural-derived indole alkaloids related to neuropsychiatric disorders.

Type	Alkaloid	In Vitro Studies (Target Activity = _ nM)	In Vivo Studies (Preclinical Research)	Therapeutic Effects (Preclinical)	Ref.
Tryptamine	Psilocybin	h5-HT2A EC50 = 3475 m5-HT2B EC50 = 74 m5-HT2C EC50 = 506 5-HT1A Ki > 10,000 5-HT1B Ki > 10,000 5-HT1D Ki = 2119 5-HT1E Ki = 194.8 5-HT5 Ki = 6181 5-HT6 Ki = 413.5 5-HT7 Ki = 579.9	Antidepressant-like behavioral activity in chronically stressed mice with a single injection of psilocybin (1 mg/kg). Anti-compulsive-like behavior using the marble burying test in mice after treatment with a single injection of psilocybin (1 or 2 mg/kg). A single dose of psilocybin (1 mg/kg) improves stress-related behavioral deficits in mice, stimulating the growth of dendritic spines in the frontal cortex and promoting excitatory neurotransmission. A single intravenous dose of psilocybin (0.8 mg/kg) showed important changes in the pig brain, promoting synaptogenesis, increasing hippocampus density, and decreasing 5-HT2AR intensity. Psilocybin shown to down-regulate the functional connectivity within dopamine (DA)-associated striatal networks and increase the functional connectivity in cortical areas. A murine study showed that psilocin increases the concentrations of extracellular dopamine and serotonin in the mesoaccumbens and mesocortical pathways.	Antidepressant Anti-anhedonic Anxiolytic Anti-compulsive Cortical activation Promote synaptogenesis ↑ Neural density Potency neural circuitry ↑ Neuroplasticity	[67,80,83,84,85,86,87,88]
	Psilocin	h5-HT2A EC50 = 4.3 m5-HT2A EC50 = 9.9 m5-HT2B EC50 = 58 m5-HT2C EC50 = 30 5-HT1A Ki = 49.0 5-HT1B Ki = 219.6 5-HT1D Ki = 36.4 5-HT1E Ki = 52.2 5-HT5 Ki = 83.7 5-HT6 Ki = 57.0 5-HT7 Ki = 3.5 α2A Ki = 1379 α2B Ki = 1894 D3 Ki = 2645
	Baeocystin/Norpsilocin	h5-HT2A EC50 = 8.4 m5-HT2A EC50 = 19.0 (For norpsilocin)	Mice were treated with different intravenous doses of baeocystin, and the mouse head-twitch response was measured for 20 min. No significative psychotropic-like effects were detected at doses between 0.03 to 3 mg/kg.	No reported	[68]
	Aeruginascin metabolite *	h5-HT1D Ki = 486 h5-HT2B Ki = 128 DAT Ki = 792	No in vivo studies reported		[87]
	Bufotenine	5-HT2A Ki = 15 5-HT2C Ki = 145 5-HT1A IC50 = 55 5-HT1B IC50 = 29 5-HT3 Ki = 34	An effective dose of 0.63 mg/day administered in mice did not cause significant physiological and behavioral effects on the animals. Bufotenine concentrations after injection (100 mg/kg) were slightly higher in the hypothalamus than in the cortex; its effects were exerted predominantly on the peripheral nervous system.		[88,89]
β-Carbolines	Harmane	MAO-A IC50 = 340 MAO-A Ki = 220 MAO-B IC50 > 10,000 MAO-B Ki = 57,000 5-HT2A Ki = 268 5-HT2C Ki = 2490	The systemic administration of harmane (5–20 mg/kg) in male Sprague-Dawley rats enhanced 5-HT in a dose-dependent manner. Acute intraperitoneal administration of harmane (5–20 mg/kg) in male adult rats showed antidepressant and anxiolytic effects. Intraperitoneal injection of harmane (2.5 and 10 mg/kg) in rats demonstrated potential sedative effects, also increasing corticosterone, serotonin, and noradrenaline concentrations in different regions of the brain	Antidepressant Anxiolytic	[90,91,92,93,94]
	Harmine	MAO-A IC50 = 8.7 MAO-A Ki = 5.0 MAO-B IC50 > 10,000 5-HT2A Ki = 397 5-HT2C Ki = 5340	Mice treated with an intraperitoneal injection of harmine (20 mg/kg) for 10 days showed a significative reduction of depressive-like behaviors by ↓ of brain-derived neurotrophic factor (BDNF), ↑ the protein expression of the glutamate transporter. Male adult Wistar rats exposed to a chronic mild stress protocol were treated with harmine (15 mg/kg) for 7 days, which reversed anhedonia behavior and induced changes in the adrenal gland weight.	Antidepressant Anti-anhedonic Promote neurogenesis Stimulate neuroplasticity Repair astrocytic functions	[90,94,95,96]
	Harmaline	MAO-A IC50 = 11.8 MAO-A Ki = 48 MAO-B IC50 > 10,000 5-HT2A Ki = 5010 5-HT2C Ki = 9430	Intraperitoneal injection of harmaline (2.5 and 5 mg/kg) produced an anxiogenic-like response in male NMRI mice, whereas 10 mg/kg of this carboline induced antidepressant-like behavior in a forced swim test.	Antidepressant Anxiolytic	[90,97]
Ergot	Ergotamine	5-HT2A Ki = 20.4 5-HT2B Ki = 6.76 5-HT2C EC50 = 7.94 5-HT1A Ki = 12.9 5-HT1B Ki = 13.2 5-HT1D Ki = 4.36 5-HT1E Ki = 602 5-HT1F Ki = 169 5-HT6 Ki = 57.0 α1A Ki = 10 α2 Ki = 6.3 D2 Ki = 3.16	Extensive studies in animals related with the vasoconstrictor effect; however, no reports related to neuropsychiatric disorders were found.	Anti-migraine	[98,99]

* The putative metabolite of aeruginascin after dephosphorylation known as 4-hydroxy-N,N,N-trimethyltryptamine.