Is 7’8 DHF safe long term?

Chronic supplementation with lion's mane actually normalized both BDNF and TrkB expression. The reason people are concerned with 7,8-DHF and TrkB is that 7,8-DHF is a BDNF mimetic. So it actually directly binds to the TrkB receptors. That's why people fear it might down-regulate TrkB. However, those interactions are complex. 7,8-DHF actually partially up-regulated TrkB receptors in mice in an Alzheimer's model, while showing lower levels in healthy mice.

https://www.nature.com/articles/npp2011191

Notably, repeated administration of 7,8-DHF once daily for 10 days partially rescued the downregulation of hippocampal TrkB receptors found in 5XFAD mice (∼74%) (p<0.05). In contrast, 10-day treatments with 7,8-DHF showed a trend toward reducing total TrkB levels in wild-type mice (∼69%) (p=0.15), probably reflecting the adaptive downregulation of receptors in response to repeated exposures to the agonist. Meanwhile, a two-way ANOVA for mature BDNF levels showed only a main effect of genotype (F(1, 24)=70.06, p<0.05) in the absence of a main effect of drug or a significant genotype × drug interaction (Figure 3d). Post-hoc Bonferroni tests revealed that levels of mature BDNF were similarly reduced in the hippocampus of 5XFAD mice treated with vehicle (∼49%) (p<0.05) and 7,8-DHF (∼46%) (p<0.05), as compared with wild-type controls.

Interestingly enough, 7,8-DHF also increases BDNF levels. So you have a direct TrkB activation AND an increase in endogenous BDNF levels.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240709/

Previous studies have shown that BDNF/TrkB signaling can self-amplify BDNF actions through its TrkB and end-product, CREB [8], [29]. To determine whether 7,8-DHF would trigger further BDNF production, we measured the brain levels of BDNF and CREB phosphorylation, a key transcription factor for BNDF induction. The BDNF protein levels were significantly decreased in both the contralateral and ipsilateral cortex at 4 days after CCI compared with sham-injury, but DHF20 substantially increased BDNF to 166% of the vehicle-level in the ipsilateral cortex (P = 0.002; Figure 5A). Similarly, the mRNA level of BDNF also increased to 203% of the vehicle-level in the ipsilateral cortex at 4 days after DHF20 treatment (P = 0.002; Figure 5B). Consistent with this, CCI induced a decrease in CREB phosphorylation level whereas DHF20 caused an increase in CREB phosphorylation level (158% of the vehicle-level, P = 0.021; Figure 5C) at 4 days. Double immunofluorescence further showed that CREB phosphorylation was mainly localized in neurons. The colocalization of p-CREB and NeuN decreased in the peri-contusional margin of vehicle-treated mice compared with the sham control at 4 days. However, DHF20 treatment increased CREB phosphorylation in neurons (Figure 5D). These data suggest that increased endogenous BDNF protein contributes to the neuroprotective effects of 7,8-DHF.

So the mechanisms are complex, and the BDNF/TrkB situation is not as simple as one might assume at first. Even so, polygala up-regulates TrkB receptors. So cycling in polygala can be used as a way to help protect from any TrkB down-regulation that might be occurring.