Depression is a disease that affects millions of people but unfortunately is neglected. In addition, many drugs have the risk of dependence or do not show remission of symptoms, which poses major challenges for science. Thus, we seek through theoretical approaches of docking and molecular dynamics to understand the mechanism of the compounds that make up St. John's wort and the tea known as Ayahuasca. Docking protocols were determined using the GOLD genetic algorithm (version 5.8.1). All receptors were previously prepared using the Schrodinger Maestro 2021-2 software, where the missing hydrogen atoms in the structures were added. We exploit all the conformational degrees of freedom of the ligand along with the partial flexibility of the protein in the amino acids closest to the binding site. Among the functions available in GOLD, the ChemPLP empirical scoring function was used. We performed Molecular Dynamics (MD) simulations using the Desmond algorithm integrated to the Schrodinger Maestro 2021-2 software. We used the integration time at 2 fs so that the trajectories were produced over 10 ns. Initially, we performed the docking with drugs of reference and already consolidated in the treatment of depression, such as escitalopram and aripiprazole. In this we obtained the value of -79.8967 kcal/mol for the 5-HT1B receptor (PDB ID: 4IAQ) when interacting with escitalopram, while aripiprazole presented -89.6657 kcal/mol with the same receptor. From the simulations, we came to important indications that the compound Adhyperforin from the species Hypericum perforatum expresses great affinity with 5-HT1B, where we obtained an affinity of -94.7333 kcal/mol. On the other hand, N,N-Dimethyltryptamine from the species Banisteriopsis caapi appeared not interacting remarkably with 5-HT1B and 5-HT1A (PDB ID: 7E2Z) receptors with affinity value of -54.0776 kcal/mol and -44.0687 kcal/mol, respectively. From the molecular dynamics, we noticed a predominance of structural stability in the complex with Adhyperforin, measured by low values of protein RMSD (4.541Å), RMSF (1.779Å) and Radius of Gyration (27.439Å), which reflects a greater interaction in the protein-ligand complex. In addition, we found that the amino acid Trp48 was predominant in the interaction between Adhyperforin and the 5HT-1B receptor. This behavior not occurred in the ligand N,N-Dimethyltryptamine with not so expressive affinity for the 5HT-1B receptor with protein RMSD (7.584Å), RMSF (11.542Å) and Radius of Gyration (27.688Å) with many fluctuations. Therefore, reinforcing the data in the literature that its main mechanism of action of N,N-Dimethyltryptamine is in the interaction with the MAO enzyme. Therefore, the plant St. John's wort, in addition to being easily found, has great theoretical potential with central nervous system receptors and antidepressant effect.