Understanding Drug Tolerance, Dependence and Addiction

If I rely on my pain medication to ease my chronic pain, and I now require two pills to get the same level of relief that I used to get from one, does this mean I’m addicted? Not necessarily. If I smoke weed (marijuana, cannabis) regularly, but not every single day, yet I feel super grumpy on the days I don’t have it, does this mean I’m addicted? Maybe. If I feel like I can’t go a day without at least one drink and I get the shakes and feel panicky when I try to do without my habitual alcohol, even though I can see it’s affecting my life, does this mean I’m addicted? Probably. When it comes to the use of alcohol and other drugs, people get confused about the distinctions surrounding tolerance, dependence and addiction. Many people believe these are just different words for the same thing — addiction. This is a common misconception. Here we aim to clear up the widespread misunderstanding about these terms. 

Tolerance Basics

Tolerance is the physical aspect of substance or drug dependence. A person has developed tolerance to a substance when their body no longer responds to the original dose, requiring a higher dose of the medication in order to get the effect they initially experienced with a lower dose. According to the National Institute on Drug Abuse (NIDA), the development of tolerance is not addiction, though many drugs that lead to tolerance have the potential to lead to addiction. With some prescription medications, tolerance develops very gradually over many months and is not necessarily a cause for concern if the doses remain reasonably low and the prescribing physician continues to monitor the patient and determines that the benefits outweigh the risks. However, some drugs can rapidly lead to tolerance, and if they are highly addictive, can lead to dependence that accelerates to addiction in a very short time — sometimes in a matter of days (i.e., opioid painkillers, morphine and heroin).

The Science of Tolerance

Several different body and brain mechanisms can contribute to the development of alcohol or drug tolerance, but with highly addictive substances, it happens at a cellular level. Morphine, for example, binds to and activates the nervous system’s opiate receptors, inhibiting an enzyme called adenylate cyclase. This inhibition causes several chemicals in the cell to maintain the firing of impulses. NIDA explains that “after repeated activation of the opiate receptors by morphine, the enzyme adapts so that the morphine can no longer cause changes in cell firing. Thus, the effect of a given dose of morphine is diminished.” In other words, the person has developed tolerance to morphine. Once a person has developed tolerance to a substance, their body and brain can become dependent on it.

Dependence Basics

NIDA describes drug dependence, or drug dependency, as “a state in which an organism functions normally only in the presence of a drug and manifests a physical disturbance when the drug is removed.” The “disturbance” referred to in NIDA’s definition is withdrawal, a component of dependence. A person will experience withdrawal symptoms (i.e., a sharp increase in pain if withdrawing from painkillers, for example) when they go too long between doses or suddenly reduce or quit the substance or medication on which they have become dependent. How does dependence happen? With repeated use and/or high dose levels. Depending on the substance and its addictive properties, dependence can sometimes happen after just a couple of uses or after just a few days of repeated use. Dependence can occur whether the substance is a prescribed medication (i.e., an opioid prescription painkiller like hydrocodone or oxycodone) or an illicit drug (i.e., cocaine or heroin).

The Science of Dependence

Alcohol and many other drugs affect your central nervous system, which includes nerve cells (neurons), your brain and its circuits and neurotransmitters. With repeated use of alcohol and/or certain drugs, the neurons will change, adapting to repeated substance exposure by altering the signals they send to other nerve cells, glands, muscles and the brain via neurotransmitters. According to neuroscientists at McGill University, our body and brain’s system of information transmission and feedback is precisely controlled to keep us in balance, in much the same way a thermostat regulates the temperature in a room. If substances we consume trigger a spike in a neurotransmitter (i.e., dopamine), this can overwhelm our system. We may feel good — perhaps a rush of excitement or a pleasurable relaxation — but behind the scenes, our brain and nervous system adapt by producing less of the natural form of this neurotransmitter in an effort to rebalance our system. If we continue taking the substance that triggers this physiological response, our body and brain will become dependent it and can only function normally when that substance is in our system. If we stop taking the substance after overuse, we will feel bad, because our natural neurotransmitter levels have been reduced and cannot compensate quickly enough. If we suddenly give up coffee, for example, we may get a headache and feel fatigued for several days. This is withdrawal. During withdrawal, our nervous system needs time to adjust while our neurotransmitters return to normal levels. Once we stop coffee, our neurotransmitters typically rebound in about two weeks. Once we give up alcohol or an opiate drug like heroin, our neurotransmitters need much longer to rebound and withdrawal symptoms are more dramatic and severe, and far more serious. Withdrawal from some substances is so painful or debilitating that the person uses the substance again just to relieve the withdrawal symptoms. In these cases, it is best to taper off the substance gradually while our system and neurotransmitter levels adjust, ideally with assistance from a medical professional.


According to addiction experts, addiction is defined as compulsive drug or alcohol use (or other compulsive or addictive behavior) despite harmful or negative consequences. Addiction is further characterized by behavior that is reward- or pleasure-seeking, in that pleasurable feelings a person experiences after using a substance provide positive reinforcement (i.e., reduction of pain or an effect of relaxation, excitement or euphoria) that motivates the behavior to be repeated. A key feature of addiction is a loss of control in regard to limiting intake and an inability to stop even when the addiction interferes with work, relationships, family obligations and other responsibilities.

The Science of Addiction

It is generally accepted that addiction is influenced by genetic, environmental and physiological factors. Understanding how addiction happens requires an understanding of these factors, as well as a basic understanding of the brain’s reward center, circuit, or pathway, and how this pathway responds to addictive substances or behaviors. Research shows that the physical process of addiction is neurobiological, with biochemical, cellular and molecular components. There are natural rewards (i.e., food, water, nurturing and sex) that stimulate the neurons in our central nervous system to send signals to the brain along a series of channels, telling it to activate or release “feel-good” neurotransmitters like dopamine or endorphins. The activation of the neurotransmitters in the brain’s reward center leads to pleasurable feelings, reinforcing the motivation to repeat the behavior. Our brain’s reward circuit or pathway is wired this way for our survival and, under normal conditions, this information and feedback system works well. Then there are artificial rewards in the form of psychoactive substances, such as alcohol, tobacco and certain drugs, which overstimulate or short-circuit the central nervous system by activating the brain’s pleasure pathway or circuit directly, triggering an overabundance of dopamine to be released — leading to a more intense sensation of pleasure or reward that motivates a person to repeat the experience. If it is repeated, this can lead to dependence that can lead to cravings, which can lead to addiction. The overactivation of the neurotransmitter dopamine is a key aspect in the process of addiction, and it can also be activated through process addictions or behavior addictions, such as gambling and sex addiction. In summary, repeated use or overuse of certain substances with addictive properties —substances that range from coffee and tobacco to alcohol, some prescription medications (i.e., opioid painkillers, benzodiazepines) and certain illicit drugs (i.e., heroin, cocaine) — can result in dependency, and the release of the neurotransmitter dopamine in the brain’s reward center is a key aspect of the addiction process. Certain behaviors can also lead to the overactivation of dopamine, leading to behavioral addiction. While several theories on addiction continue to be discussed within the research and medical communities, the process of addiction is generally understood to begin with initial pleasure (or relief) that can advance to dependence, then tolerance and withdrawal, that can progress to full-blown addiction. Once the addiction threshold has been crossed, it is usually necessary to receive professional addiction treatment that often begins with medically-supervised detox to flush the substance of abuse from the system, and continues with rehabilitation (including therapy and training in coping strategies) to help a person attain and learn to sustain recovery, with the understanding that addiction is a chronic disease that cannot be cured, only managed.


The Neurobiology of Drug Addiction: Definition of tolerance. National Institute on Drug Abuse (NIDA), 2007. https://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-iii-action-heroin-morphine/6-definition-tolerance The Neurobiology of Drug Addiction: Definition of dependence. National Institute on Drug Abuse (NIDA), 2007. https://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-iii-action-heroin-morphine/8-definition-dependence The Neurobiology of Drug Addiction: Definition of addiction. National Institute on Drug Abuse (NIDA), 2007. https://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-ii-reward-pathway-addiction/5-addiction The Brain from Top to Bottom; Drug Consumption; When the Reward Circuit Gets Overheated. McGill University. https://thebrain.mcgill.ca/ https://www.blog-thebrain.org/beginner/2012/04/30/theories-on-drug-addiction/ https://thebrain.mcgill.ca/flash/a/a_03/a_03_p/a_03_p_par/a_03_p_par.html Supplement on Addiction. Nature, International Weekly Journal of Science. Nature Outlook, Vol. 522, No. 7557_supp ppS52-S94, June 2015. https://www.nature.com/nature/outlook/addiction/index.html?foxtrotcallback=true https://www.nature.com/nature/outlook/addiction/pdf/NIDA_NIH.pdf

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