What determines a drug's speed of onset?
There are tens of thousands of recognized psychoactive compounds, with each of them having quite unique properties. One attribute of a drug that is often vital to know is the drug's average time of onset. In other words,
How Long Before I Feel This Drug?
The speed of onset of a substance is a complex topic, but there are a few major factors that play a part, with many of them being related to the pharmacokinetics of the drug.
PHARMACOKINETICS
Pharmacokinetics is the science of the movement, absorption, metabolism, and eventual fate of drugs ingested into the body. Pharmacokinetics is one of the branchs of pharmacology and plays a major role in speed of onset and duration of effects.
Primary Factors
1) Route of administration. Different route of administration impacts how a drug initially enters the body, with different routes having different speeds. Generally, intraveneous (IV) is the fastest, with intramuscular (IM), insufflation, buccal (absorbing through mouth cavity), rectal next, and vaping, smoking, after and then drank, and with the slowest being oral.
This is for a few different reasons. IV is fast due to directly injecting the drug into the bloodstream, reducing the time it has to take to cycle through your system. This is part of why oral is slow as well, but also due to potentially requiring first pass metabolism (will be covered later).
2) Bioavailability. Not all drugs are absorbed fully by your system. Depending on whether the drug is fat or water soluble, its primary pharmacokinetic pathways, the efficacy and availability of the relevant enzyme, and various other factors, your body might only be able to absorb a certain amount of a substance per hour. A famous example of this being the case is with gabapentin, where staggering your dose out (take a couple pills every 30 mins instead of taking a bunch at once) is required to achieve a high dose. Drugs with a low bioavailability for the chosen route of administration will take longer to onset and potentially require staggering.
3) Prodrugs. Not all compounds are directly active on its own; many drugs are actually inactive prodrugs for an active metabolite. For example psilocybin is understood to be mostly inactive. The only way we can trip from shrooms is by your body dephosphoralyating the 4-PO-DMT (psilocybin) into 4-HO-DMT (psilocin). This process takes some time to achieve, and is part of the reason for the delay in coming up. Different strains of shrooms also contain different ratios of psilocybin to psilocin, with strains that contain more innate psilocin tending to have a faster onset, since it doesn't need to waste as much time converting to psilocin first.
4) Active metabolites. On a similar vein, some drugs are precursors to active compounds, but are still themselves also psychoactive. This could lead to a potentially polyphasic response where one type of high comes on quicker, while a different high comes on later on in the experience. Tramadol is a good example of this. By itself, tramadol is mostly an SNRI (serotonin, norepinephrine reuptake inhibitor) with some mild opioid activity. However, its active metabolite O-DSMT is a mu-opioid receptor full agonist with some NRI (norepi reuptake inhibition) effects. This could lead to the first half of a tramadol experience being more stimulating with the latter half being more like a traditional opioid experience. Higher doses of tramadol (note: taking a very high dose of tramadol is risky and could potentially lead to life threatening seizures) also tend to have more of an opioid like effect than lower dosages, however this has a ceiling effect due to saturating your body's ability to metabolize tramadol into o-dsmt. Like before, staggering also works for tramadol, and taking a bit at a time would generally lead to a more opioid like experience than taking a bunch at once.
Weed is another interesting one. Orally, the primary active psychoactive ingredient is delta 9-THC (typically known as just "THC"). However, with an oral route of administration, the delta 9-THC gets metabolized into 11-HO-delta 9-THC. 11-HO-THC is more potent than delta 9-THC and helps to account for edible's much stronger effect compared to vaping / smoking mg for mg. This process takes time (about 30 minutes to 2 hours), which explains the potentially slow onset of edibles. This also explains why very quickly after eating edibles you'll start experiencing a mild high that plateaus until about an hour in when the full experience hits you. This could potentially be due to you first getting high from the THC, and then later getting even more high once it has fully converted to 11-HO-THC.
5) Food. Especially important for oral, how much you've had to eat usually has a big impact on time of onset (and sometimes intensity of experience). For drugs that require digestion, having food already in your stomach makes it take longer before your GI tract gets to work on the drugs. Hormonal balance / circadian rhythm also play a role in this as well.
An extreme example of food impacting the drug experience is with phenibut and to a lesser degree pregabalin. Not only does taking phenibut on a full stomach could potentially delay the onset (not unusual to delay the onset by 9+ hours or more), it could also completely nullify the peak, leading to a longer lasting but much milder experience. I'm not actually too sure on the exact pharmacokinetics behind why phenibut is uniquely sensitive to a full stomach. The fact that the drug innately has a very slow come up (3-6 hours) and a relatively long half life (5+ hours, leading to an average experience lasting 24-48 hours depending on dosage) potentially has something to do with it.
On the flip side, some drugs require a certain amount of fat to be absorbed by the body, and in which case coadministration with fatty foods might make it impact faster. Also enzymes and terpenes in certain foods such as grapefruit and mango can also potentiate the effects of some drugs or speed up / slow down metabolism / absorption of certain compounds.
6) Metabolic enzymes. For drugs that require metabolism (such as the ones mentioned above), they typically depend on a certain set of enzymes. The most prolific among these is CYP2D6, which is responsible for the metabolism of about 25% of all clinical drugs [https://pubmed.ncbi.nlm.nih.gov/19645588/]. Individual variations in CYP2D6 enzyme is encoded for by the CYP2D6 gene. Both the amount of enzyme present, and the efficiency of these enzymes vary from individual to individual, leading to potentially vastly different experiences. If you are a CYP2D6 hypermetabolizer, for example, it would mean that you would have a faster onset and more intense peak for drugs that are inactive prodrugs, but would have a shorter high for drugs that are metabolized into inactive waste products. There are numerous other enzymes / gene pairs that all contribute to metabolism rate and efficiency of various compounds in various ways. A gene sequencing service can usually give you information about your genotype, but due to the vast number possible genetic variations paired with a large number of total enzymes / genes, it is not simple to map from a genotype straight to a predictable drug effect.
7) Neurotransmitter precursors. Some drugs operate by activating pathways to release specific endogenous (your body's own natural) neurotransmitters. Most psychoactive Amphetamines, for example, tend to operate as monoamine triple releasers: releasing large amounts of Dopamine, Serotonin, and Norepinephrine. The exact ratio between these three depend on the exact compound itself. These drugs signal neurons to release the monoamines into the synaptic cleft, but these neurons can only achieve this if there are enough building materials to construct them. Long term use of high doses of serotonin releasers (such as MDMA), for example, is well known to potentially lead to serotonin depletion. Further usage of serotonin releasers would have a muted effect due to your body lacking enough serotonin and 5-hydroxy-tryptophan and potentially tryptophan itself. A common post-roll supplement people take is 5-htp (5-hydroxy-tryptophan), which is the direct precursor to serotonin. Ingesting the precursors enables the proper neurons to generate more of the relevant neurotransmitter. This strategy is also used in the management of disorders with dopaminergic deficiencies such as parkinsons: L-dopa (the precursor to dopamine) is a standard medicine for parkinsons.
8) Neurotransmitter transport protein balance. Psychoactive drugs and endogenous neurotransmitters are released into the synaptic cleft (small gap between two neurons where information can be exchanged via chemical signals aka neurotransmitters) in order to impart their effect by binding to receptors on the downstream neuron. Specialized proteins such as the serotonin transporter (SERT), the dopamine transporter (DAT), and the norepinephrine transporter (NET), are responsible for movement of these signatory chemicals. One of their primary roles is "recycling" neurotransmitters that have served their function to be used for future uses, and also to prevent overly activating the intended receptors. There are drugs that bind to and inhibit the actions of these transporters, which typically leads to a heightened levels of the corresponding neurotransmitter, since your body can no longer as effectively recycle them once they are done being used. These neurotransmitters stay in the synapse for longer, potentially agonizing / antagonizing the receptors many more times than it would have. Co-administration of a reuptake inhibitor with a releaser could potentially impact the onset, duration, and intensity of the experience. In reverse too, some drugs depend on certain transporter enzymes to make it into the synapse. MDMA, for example, effectively cannot function without a working serotonin transporter. Despite the outdated knowledge that MDMA + SSRI = serotonin syndrome risk, the reality is actually quite the opposite. If you are on a high enough dose of SSRIs, MDMA's effects get completely neutered, and even fatal level doses would potentially present itself as simply a very mild dopamine high. (Do not try this at home, even if the SSRI blocks the effects, oding off MDMA is very dangerous. But for an anecdote from a dumber period of my life. I was on 300mg daily venlafaxine and 1 whole gram of MDMA gave me nothing more than a mild high comparable to a couple bumps of some low quality coke.) However, if you are not an SSRI, but instead take an SSRI after the peak effects of MDMA have hit, it would work to heighten the serotonergic effects of the roll, and is indeed a high risk for overheating and serotonin syndrome.
9) Ability to cross blood brain barrier. This is somewhat of a subpoint to 2), since inability to cross the BBB is one of the many ways a drug can have a low bioavailability. Some drugs struggle to make it into the brain, and could either take a long time to onset, or have mild to no effects. GABA pills for example, although many swear by them, they are mildly effective at best. GABA has difficulty crossing the blood brain barrier effectively (though not impossible), and is generally not super effective when taken directly. Picamilon is an attempt to circumvent this. Picamilon is a GABA molecule attached to a niacin (also known as vitamin B3). This configuration grants it much more ease in crossing the blood brain barrier, and consequentially, picamilon has a higher bioavailability. This means faster onset and stronger effects.
10) Dosage. Since binding is probabilistic, the more molecules of a given substance that was ingested, the more likely it is that any given molecule finds its way into the correct receptor. A higher dosage, thus, means shorter time delay before enough molecules bounded to enough receptors that you'd start to notice it. A higher dose does not necessarily reach its peak in any shorter time (despite a faster onset, theres also a higher peak to reach), but you will definitely notice threshold effects much quicker than if a lower dose was taken.
11) Luck. This is a relatively minor factor, but still probably worth stating. Most psychoactive compounds work by binding to certain receptors, causing it to activate (agonism) or deactivate (antagonism) one or other downstream pathways. Compounds bind to receptors by simply floating around aimlessly until it happens to bump into a receptor that happens to somewhat fit. It's a completely probabilistic process that relies on random chance. However, due to the law of large numbers, there's relatively low variation in onset time.
Note: Despite common community knowledge saying otherwise, exercise actually seems to have minimal impact on the speed of onset of orally ingested drugs:
