Psychoactive drugs chemically alter the brain and change the way we feel, think, perceive and understand our world. They are ubiquitous: alcohol, cannabis, opioids, tobacco, stimulants, sedatives and hallucinogens, to name a few. Some occur naturally—nature’s contribution to our bodies and psyches—and some are synthesized in labs to impact the same brain receptors as do those found in forests, deserts and open fields.

We are in a psychoactive drug epidemic in our country, most notably the opioids, because of their tragic death toll.

We need solutions to the epidemic to save lives, families and communities—and government treasuries. But if we focus only on the drug itself, whatever it may be, we will miss what really matters when it comes to how human beings respond to psychoactive agents.

Here are nine things that matter when it comes to drugs:

1. Age. It’s one thing to start drinking or smoking dope when you are 21. It is very different when at 12 or 13 or 15, even 18. That’s because the human brain is still under construction until well into the 20s, later for males than females. It takes almost three decades for the brain to fully lay down the fatty substance, myelin, that surrounds the nerve connections and permits reflection and controls impulsive action, for the cortex to stand a chance against the drive centers deeper in the brain. Repetitive or high doses of psychoactive drugs like cannabis, alcohol and hallucinogens interfere with the normal development of the brain. Not a good thing, and cause for controls on the access youth can have to substances.

Teens who smoke by the age of 18 are far more likely to be smokers as adults. Early drinking, by age 12, 13 or younger, is a marker of biological susceptibility to alcohol. By the way, the aging brain is also highly vulnerable to psychoactive drugs, and small amounts are like large amounts when a person is in the seventh and eighth decades of life.

Age counts.

2. Set and Setting. Set means the unique biological, neurological, psychological and experiential qualities of the user. Set creates a personal vulnerability and selective responsivity to substances.

Biologically, a person’s genetics (inherited DNA), as well as current brain neurochemistry or entire body physiology, can significantly influence the action of a psychoactive drug. The same quantity of drug may have orders of magnitude, more or less, in its impact. Moreover, repetitive use of a substance can produce central nervous system hyper- or hypo-reactivity to that agent.

Psychologically and experientially, a history of trauma (from abuse, neglect, violence and torture, forced immigration, and natural disaster) induces great brain (and emotional) reactivity to many things, including drugs. Temperamental aspects of a personality—particularly a tendency to externalize, to hold others responsible for whatever, as well as dimensions of personality, such as passive or active, rebellious or conforming, the capacity to experience feelings or not, and accepting or denying reality—all influence the action of a substance.

Set matters. The person is an active ingredient in their reaction to a drug.

A historical story reveals what setting means. At the height of the Vietnam War, the Department of Defense came to realize that 20 percent of the soldiers were frequent users of the potent heroin they had easy access to. The DoD feared that upon their return they would continue their use, join the already too large population in the U.S. of those addicted to heroin.

Norman Zinberg (a former colleague, now deceased) and his colleague Lee Robins were dispatched to Vietnam to assess the problem and try to predict the future for these soldiers. They were proven to be correct when they forecast a no greater rate of heroin use or dependence than existed in those who did not go to war.

It was the soldiers’ setting—battling in a fierce, deadly, unpredictable guerrilla war in a country that did not want them and with little support from Americans back home, with ready access to cheap, powerful heroin to make the unbearable bearable—that led to their high rates of use.

Today’s analogue, if only partial, is Iraq and Afghanistan, where studies show that as many of 30 percent of combat veterans return with PTSD, depression or traumatic brain injury (TBI). Their setting is inducing high rates of alcoholism and drug dependence.

The setting a person is in matters.

3. Route of Administration. How fast a substance gets to and bathes our neurons with its receptor-loving chemical configuration makes a big difference. The faster the arrival, the more likely it is to be habit-forming. Most people think the most rapid route to the brain is intravenously (or intra-arterially if you’re in intensive care): a push on the syringe and a bam in the brain. Turns out the speediest route is inhalation. A venous load of a drug, like heroin, has to first work its way back to the heart, then go by pulmonary artery to the lungs, then by carotid artery to the brain. It’s quick, for sure, but that first venous pass from the body to the heart is bypassed when a drug is inhaled.

Our brains give top priority to getting oxygen. Without it, we are dead in just a few minutes. A drug that can accompany oxygen, right from the lungs, will be the first to arrive and do its job.

Some believe this is the reason that cigarettes (or vapes) are the most addictive of substances, harder to quit than heroin. It is why cocaine that is smoked (crack) is more habit-forming than cocaine that is snorted. And why methedrine in tablet form or applied to the mucosa of the mouth or nose does not have the power of sucking in a hit of crystal meth from a pipe.

If you want fast and furious, and you’re not talking about an action movie, inhale deeply and you are there.

4. Purity. It makes both common and pharmacological sense that how pure a substance is makes a big difference. Heroin is often mixed with talcum powder, strychnine or other chemicals that reduce its purity, and that happens at about every step of the supply chain to boost profit—from the boat that smuggles it in to the gangs that distribute it to the regional, local and street dealers. It is why people who are dependent on high doses of heroin often find a fix inadequate to even abate their withdrawal, much less get them high.

The same, of course, applies to cocaine and methedrine.

One exception is cannabis: plants are now far purer, genetically bred to be up to 60 times more powerful than they were decades ago.

Heroin, on the other hand, is terribly diluted by the time it enters a user’s bloodstream. This is in part why deaths from opioid overdose keep growing: dealers are mixing it with fentanyl (and its cousins) to give the user a far more powerful hit. Fentanyl is 50–100 time more potent than morphine. A quantity as small as one or two grains of salt can kill a lot of people. Pure heroin, or morphine, is far safer, and why some countries have adopted the harm reduction strategy of making these opioids legal.

The purer the drug, the fewer its contaminants, the greater its impact on our central nervous system.

5. Potency. The more potent the drug, the more it takes us down its neurochemical journey. A host of different psychoactive substances (including heroin, cocaine, meth, even alcohol—the least understood and most used substance around) produce the release of dopamine, especially in a section of the brain called the nucleus accumbens, which is a small but critical nerve complex deep in the brain, involved in pleasure, reward and aversion.

The more potent the drug, the greater its kick.

Potency counts. Yet we hardly ever know the potency of a drug bought on the street or the dark web.

6. Half-Life. Consider Xanax (alprazolam), sometimes called Vitamin X, which was introduced for public consumption in the U.S. in 1969. I used to prescribe it, especially for patients with disabling anxiety or insomnia related to a clinical depression, for the several weeks it took for the antidepressant I had also prescribed began to work. But I soon learned that its rapid and effective action began to fade in a matter of hours, leaving patients feeling awful or awakening at night, craving more of the drug. That’s why it has largely been replaced by longer-acting agents.

The half-life of a drug is the time it takes for the blood level of the substance to reduce by 50 percent. Xanax’s half-life was officially 11 hours, on average, but patients told me they could feel it wearing off more rapidly than that. They could feel it wearing off, reaching its half-life, in a few hours. A single drink of an alcoholic beverage taken by an adult has a half-life of about half an hour. Methedrine has a half-life ranging from six to 12 or more hours, depending on the individual.

A drug’s half-life, therefore, influences the time to craving for more of its desired action, and how soon a person feels the pangs of withdrawal.

7. The Original Source. When a drug is derived from a plant rather than synthesized in a lab, the composition of the plant affects its psychoactive properties, use, and potential for dependence. Cannabis is a good example. It contains well over 60 cannabinoids, the active ingredients. The two principal ones are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC gets us high, but CBD has no psychoactive properties.

When I was smoking pot in college THC levels were low; it took a few good tokes to get a buzz. Today, thanks to sophisticated genetic modification of the plants, THC’s potency is often 60 times greater. That can be mitigated if CBD concentrations are also high: CBD serves to protect users—especially young people, or people with a vulnerability to psychosis, from experiencing psychotic symptoms (which can persist in some users even after the drug is gone from the blood). Research is under way to see if CBD can lead to a new antipsychotic medication. CBD has already been approved for the treatment of an infant onset intractable seizure disorder.

The complexity of plant organisms influences their actions, both desired and adverse.

8. Refinement and Extraction. The coca leaf, simply harvested and chewed, is far milder in its effects than cocaine, which is refined to have a higher percentage of the plant’s active psychoactive ingredient. Crack is even more refined, making for an even more powerful drug.

Similarly, the psychedelic drug mescaline is extracted and refined from a cactus native to Mexico and parts of Texas. And any number of plants can be refined, fermented and aged to produce distilled spirits such as vodka, whiskey, scotch, tequila and more.

What matters is not just the plant, but how humans process it.

9. The Drug/Social Forces Ratio. This speaks to the interplay of the drug, the person and the social setting in which it is used.

The prescription of opioid agonists—medications like buprenorphine and methadone—has been proven to reduce relapse in people dependent on opioids. But if a person receiving medication-assisted treatment (MAT) spends time with people who are still using opioids, or is battered with cues about opioids on TV, social media and in music, these social forces can lead to relapse.

When LSD first became popular in the 1960s, urban, hospital emergency departments regularly saw patients in the midst of a bad trip—in distress or even panic from frightening hallucinations. But bad trips eventually became less frequent, because users began to understand that taking the drug in a calm setting with the support of an experienced guide would prevent them.

With all drugs, we need to appreciate that the setting in which a drug is consumed, and the user’s expectations of what will come, can influence the action of a substance, for better or for worse.

In other words, drugs and their uses are complex. They all contain psychoactive ingredients. But it’s the other “ingredients”—who we are; how old we are; where, when and with whom we take the drugs; how pure or impure they are; how fast they reach the brain and long they last—that determine what the experience will be like.