Table 3.

Study characteristics

Author and year	Substance used	Country of study	Study design	Cell line	Outcome
Ramer et al.[30]	CBD	Germany	In vitro and in vivo	A549	CBD reduces the invasiveness of A549 cells, this effect is mediated by cannabinoid receptors and the TIMP-1 protein; CBD did not induce significant cytotoxicity in A549 cell line.
Ramer et al.[31]	CBD	Germany	In vitro and in vivo	A549, H460, cancer cells isolated from metastatic brain tumor	CBD induces apoptosis in lung cancer cells by a mechanism independent of cannabinoid receptors mediated by PPAR-γ signaling and COX-2 activity.
Haustein et al.[32]	CBD, THC, R(+)-methanandamide	Germany	In vitro	A549, H460 Brain metastasis cells isolated from a single patient	CBD induces ICAM-1 expression in lung cancer cells but not in non-cancerous cells. Increased ICAM-1 expression is mediated by cannabinoid receptors and as a result, cells are more vulnerable to natural killer cell-mediated cytotoxicity; the other cannabinoids tested also increased the expression of ICAM-1 but to a lesser degree of CBD.
Todorova et al.[33]	CBD	Bulgaria	In vitro	A549, H1299	CBD induces apoptosis in A549 cells which express p53 in a dose dependant manner; The effect is much less pronounced in H1299 cell line which did not express p53 and no dose response relationship was observed.
Choi et al.[34]	CBD	South Korea	In vitro	A549	CBD induces tumor cell death in both time- and dose-dependent manner; CBD induces lactate dehydrogenase dose dependant increase from tumor cells; the underlying mechanism of time dependent CBD cytotoxicity is probably due to the activation of caspases 3, 8, and 9, which induce apoptosis.
Ramer et al.[35]	CBD, THC, and R (+)-methanandamide	Germany	In vitro	A549, H460, H358	Cannabinoids reduce cancer cell migration potential by inhibiting angiogenesis via TIMP-1 regulation. This effect is mediated by cannabinoid receptors or TRPV-1.
Ramer et al.[36]	CBD, THC and R (+)- ethanandamide	Germany	In vitro and in vivo	A549, H460, H358	CBD and other cannabinoids induce immediate upregulation of ICAM-1 and delay upregulation of TIMP-1; in an in vivo model CBD prevented the formation of metastatic nodules and upregulated ICAM-1 and TIMP-1 expression.
Ramer et al.[37]	CBD	Germany	In vitro and in vivo	A549, H460, H358	CBD reduces the invasiveness of A549 cells by reducing PAΙ-I in a concentration depending manner; treatment with CBD resulted in a reduced tumor size and low PAΙ-I levels in A549 xenografts in athymic mice.
Milian et al.[38]	CBD and THC	Spain	In vitro	A549, H1792, H460, cancer cells isolated from 157 patients.	CBD and THC both inhibit cell migration and epithelial to mesenchymal transition; combined exposure to CBD and THC resulted in a greater effect than either substance used alone.