Samidorphan (, ) is an

opioid antagonist An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors. Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to ...

that in the form of olanzapine/samidorphan (sold as Lybalvi) is used in the treatment of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

and

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

. Samidorphan reduces the

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...

associated with

olanzapine Olanzapine, sold under the brand name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. It is also sometimes used off-label for treatment of chemotherapy-induced nausea and vomitin ...

. Samidorphan is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Samidorphan was under development as a standalone medication for various indications but has been discontinued. Buprenorphine/samidorphan for the treatment of

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

was rejected by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) due to insufficient evidence of effectiveness, but remains in preregistration as of September 2021. Development of

baclofen Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity, such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life, and ...

/samidorphan has also been discontinued.

Development

Samidorphan has been investigated for the treatment of

alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...

and

cocaine addiction Cocaine dependence is a neurological disorder that is characterized by withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by persistent use of ...

by its developer, Alkermes, showing similar efficacy to

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been ...

, but possibly with reduced side effects. It has attracted much more attention as part of the combination product ( buprenorphine/samidorphan), where samidorphan is combined with the mixed

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

(MOR) weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

and

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four re ...

(KOR) antagonist

buprenorphine Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous a ...

, as an

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

. Buprenorphine has shown antidepressant effects in some human studies, thought to be because of its antagonist effects at the KOR, but has not been further developed for this application because of its MOR agonist effects and consequent

abuse potential Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions ...

. By combining buprenorphine with samidorphan to block the MOR agonist effects, the combination acts more like a selective KOR antagonist, and produces only antidepressant effects, without typical MOR effects such as

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

substance dependence Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has develop ...

being evident. Samidorphan was also studied in combination with

, ( olanzapine/samidorphan), for use in

. A Phase III study found that the addition of samidorphan to olanzapine significantly reduced weight gain compared to olanzapine alone, and the combination was approved for the treatment of schizophrenia and

by the FDA in May 2021, under the brand name Lybalvi.

Side effects

Side effects of samidorphan include

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

and gastrointestinal disturbances among others.

Pharmacology

Pharmacodynamics

Samidorphan acts primarily as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the

(MOR) and to a lesser extent as a

of the

(KOR) and

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi alpha subunit, Gi/G0 and has enkephalins as it ...

(DOR). In accordance with this profile, samidorphan has been observed to produce some

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s that are potentially consistent with activation of the KOR such as

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, and

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

s in some patients in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

Pharmacokinetics

The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of samidorphan is 7 to 9 hours.

Chemistry

Samidorphan has its origins in

academia An academy (Attic Greek: Ἀκαδήμεια; Koine Greek Ἀκαδημία) is an institution of tertiary education. The name traces back to Plato's school of philosophy, founded approximately 386 BC at Akademia, a sanctuary of Athena, the go ...

where 8-carboxamidocyclazocine and

were utilized in its design and synthesis.

References

External links

Buprenorphine/samidorphan (ALKS-5461 - AdisInsight

Olanzapine/samidorphan (ALKS-3831) - AdisInsight
{{Opioid receptor modulators Abandoned drugs Cyclopropyl compounds Delta-opioid receptor agonists Kappa-opioid receptor agonists Ketones Morphinans Mu-opioid receptor antagonists Salicylamides Synthetic opioids