I've dealt with a chronic illness since 1995, when I was 15. This started me on my search to learn what could sustain me, to learn what could make staying alive worth the effort - or else, to learn that there was no such thing. Despite already feeling a deep-seated existential urgency these past 22 years, it's become even more critical in recent years as yet another chronic illness arose, and more recently a minor form of cancer.
Because people have always given me such a wide variety of answers about meaning - answers which usually contradicted one another - it's been essential to find a way to assess them. This requires an epistemology, a study of what sorts of claims are based on good reasons and which sorts aren't.
The mind can fool us into taking up all sorts of speculations as though they were facts: there are hallucinations and dreams; biological, cultural, political, & other biases; and so forth ad infinitum. This is exactly where the struggle becomes most acute, where a lack of certainty intersects with disease and distress to create confusion, fear, and hopelessness.
Mindfulness-Based Stress Reduction was one of the first tools that actually helped me... but, to cut a long story short, it was with Early Buddhism that I could finally start building a cohesive response to the question, "What matters?"
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1. All possible human experience is sensory. We can count the senses in quite a few different ways, such as "seen, heard, sensed, cognized" or "six sense spheres". This is an empiricism, the idea that all knowledge comes in through the senses. The Buddha called this "the All", e.g. at SN 35.23.
2. A significant aspect of this empiricism is that the mind is treated as a sense alongside the others. It's unique in that it has access to the other sense processes as well as its own (MN 43), but the operation of contact & feeling is the same in all cases.
3. When we have views, it's always based on feeling. This is because all views are based on the senses, and the senses always contain a hedonic tone (feeling). We could also point out the presence of other aggregates, such as perception, but it's feeling that motivates us to reject or accept certain ideas. DN 1 discusses this, pointing out that all views are "only the feeling of those who do not know and do not see; that is only the agitation and vacillation of those who are immersed in craving."
4a. Most Buddhists adhere to what's called "tainted right view", as found at MN 9. This is another view, just like everything else in DN 1. In fact, at AN 10.29 annihilationism is held to be a comparative advantage over such views because it better supports dispassion.
4b. Most Buddhists also adhere to related ideas about Noble attainments. Nobles know that certain fetters are gone, that certain views are accurate, and so forth... don't they? Well... no. As we can see with AN 10.86 & MN 105 (as well as with common sense) everyone can overestimate themselves, which means that the possibility of error is ever-present. AN 9.12 demonstrates another problem with this pseudo-certainty: laziness. Consider also AN 10.93 & MN 72: the certainty expressed with the phrase "only this is true, all else is worthless" also falls to the criticism DN 1 presents. MN 95 demonstrates yet another way that such a lack of certainty can be understood.
4c. What about psychic powers? These cases involve a mind-made body, which is to say, the mental sense sphere. Since all input to the mind comes through other senses first, in order to demonstrate something like astral travel we would have to prove that a mental datum related to that experience had not previously come in through the senses as usual - but this doesn't occur. (For example, Iron Age people saw past lives in Iron Age settings; they saw animals and social structures and cosmologies that they expected; they didn't report that e.g. dogs are red-blue colorblind, some snakes have senses to pick up the infrared spectrum, there are penguins and polar bears, etc.)
5. So, what's Buddhism all about if supernatural ideas are unnecessary (SN 12.70) and Noble attainments are under perpetual doubt? Here, the combination of AN 6.47 & AN 10.51 demonstrates that the process of training the mind is something one can observe for oneself, here and now. It's still possible to overestimate ones progress, but it's also possible to make improvements that have positive consequences, ones that don't require illegitimate assumptions (e.g. that aping Iron Age Indian culture is somehow important).
6. With AN 10.51 et al discussing how to train the mind & SN 47.19 discussing how to use this to help everyone, both oneself as well as others, it appears that the Dhamma presents an ongoing practice of mental development alongside efforts to sustain a tenderhearted patience in the face of the terrors of lived experience.
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Training the mind, healthy ways to pass the time, and helping others: these seem to be the best one can reasonably do in the face of existential distress. As long as this practice is possible, it's (probably) best to embody it. When this practice is no longer possible - for whatever reason(s) - well... it gets complicated. These sorts of things require safe, hands-on care in order to sustain a clear mind while considering one's options.
It really brings out the poignancy of AN 4.5:
"And what is the person who goes against the stream? Here, someone does not indulge in sensual pleasures or perform bad deeds. Even with pain and dejection, weeping with a tearful face, he lives the complete and purified spiritual life. This is called the person who goes against the stream."