Samidorphan is not addictive. It works by blocking opioid receptors in the brain rather than activating them, which means it does not produce the euphoria or reinforcing effects that drive addiction. The U.S. Drug Enforcement Administration (DEA) has formally determined that samidorphan does not meet the criteria for controlled substance scheduling, confirming its low potential for abuse.
How Samidorphan Works at Opioid Receptors
Samidorphan binds tightly to the three main types of opioid receptors in the brain: mu, kappa, and delta. At the mu receptor, which is the primary target responsible for the “high” from drugs like heroin or oxycodone, samidorphan acts as an antagonist. That means it attaches to the receptor and blocks it without switching it on. It actually binds more strongly than naltrexone, a well-known opioid blocker used in addiction treatment, making it a more potent antagonist.
At kappa and delta opioid receptors, samidorphan has partial agonist activity, meaning it can weakly activate these receptors. But partial activation of kappa and delta receptors does not produce the rewarding, euphoric sensations associated with addiction. Kappa receptor activation, in fact, tends to produce unpleasant rather than pleasurable effects.
What Abuse Potential Studies Found
Before a drug reaches the market, researchers test whether recreational drug users find it appealing compared to a placebo and known drugs of abuse. Samidorphan has been studied this way as part of its combination with buprenorphine (a partial opioid activator).
In a crossover study of 38 non-dependent, recreational opioid users, participants rated how much they “liked” each drug on a standardized scale. At the intended therapeutic dose (2 mg samidorphan paired with 2 mg buprenorphine), drug liking scores were essentially identical to placebo, with a median difference of just 2.5 points on a 100-point scale. Even at supratherapeutic doses of 8 mg and 16 mg, the combination scored significantly lower on drug liking than buprenorphine alone. Samidorphan effectively neutralized the pleasurable effects of the opioid it was paired with, rather than adding any of its own.
Why It Was Removed From the Controlled Substances List
Samidorphan was initially classified as a Schedule II controlled substance, the same category as oxycodone and fentanyl, purely because it can be chemically derived from opium alkaloids. This classification was based on its chemical origin, not on any evidence that people misused it.
After reviewing scientific and medical evaluations, the DEA conducted an eight-factor analysis covering pharmacology, abuse history, dependence liability, and public health risk. The conclusion: samidorphan does not meet the requirements for inclusion in any schedule. In April 2021, the DEA published a final rule formally removing it from Schedule II and eliminating all controlled substance restrictions on its manufacture, distribution, and prescribing. It now sits alongside other excluded opioid-derived compounds like naltrexone and naloxone, drugs widely recognized as non-addictive.
Its Role in Lybalvi
Samidorphan is currently available as one half of Lybalvi, an FDA-approved medication for schizophrenia and bipolar I disorder. The other half is olanzapine, an antipsychotic known to cause significant weight gain. Samidorphan was added specifically to reduce that weight gain by modulating opioid receptor activity involved in metabolic regulation. It was not included for any euphoric or mood-altering properties.
In the Phase 3 clinical trials (ENLIGHTEN-1 and ENLIGHTEN-2), researchers excluded participants with active substance use disorders and screened for opioid use. No reports of cravings, drug-seeking behavior, or addictive patterns related to samidorphan emerged from these trials.
Important Interactions With Opioids
Because samidorphan blocks opioid receptors so effectively, it creates a practical concern that is sometimes confused with addiction risk. If you take Lybalvi and then use opioid pain medications, the opioids will not work properly. Your pain relief will be reduced or absent because samidorphan is occupying the same receptors.
This creates a dangerous temptation to take higher doses of opioids to push past the blockade. If the samidorphan then clears your system (for example, if you stop taking Lybalvi), all that built-up opioid can suddenly hit unblocked receptors at once, potentially causing respiratory failure. This is a pharmacological interaction, not a sign that samidorphan itself is addictive.
For this reason, Lybalvi is contraindicated in people currently using opioids or undergoing opioid withdrawal. If you need opioid-based pain relief for a planned surgery, Lybalvi should be stopped at least five days beforehand. If you have been using short-acting opioids, you need to be opioid-free for at least seven days before starting Lybalvi. For long-acting opioids, the waiting period is 14 days.
How It Compares to Addictive Opioids
The key distinction is simple. Addictive opioids activate the mu receptor, flooding the brain’s reward system with dopamine and creating a cycle of craving and compulsive use. Samidorphan does the opposite: it blocks the mu receptor. Pharmacologically, it belongs in the same category as naltrexone, a medication literally prescribed to treat opioid and alcohol addiction. Both drugs occupy opioid receptors without triggering the reward response, and neither produces dependence, tolerance, or withdrawal symptoms of its own.