Opioids

Opioids are based upon morphine and opium-like structures. They work via their similar chemical structures to the endogenous opioids in the body. Morphine derived opioids, known as morphinans, contain a benzene ring attached to two partially unsaturated cyclohexane rings (phenanthrene) and a 4th nitrogenous ring attached to the core at carbons 9 and 13. There are several classes of opioids which differ greatly in structure from each other. For example, fentanyl and its analogues are structurally unique from morphinans and tramadol derivatives.

Opioids are known to mimic endogenous endorphins. Endorphins are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement. This mimicking of natural endorphins results in the drug's euphoric, analgesic (pain relief) and anxiolytic (anti-anxiety) effects.^[5]

Receptor types

Opioids act on the three main classes of opioid receptor in the nervous system, μ, κ, δ (mu, kappa, and delta).^[6] Each opioid is measured by its agonistic or antagonistic effects towards the receptors, with the responses to the different receptor sub-types (e.g., μ1 and μ2) providing even more effects. Opioid receptors are found mainly within the brain, but also within the spinal cord and digestive tract.^[7]

Delta (δ)

The delta receptor is responsible for the analgesia, antidepressant and convulsant effects as well as physical dependence.^[6]

Kappa (κ)

The kappa receptor is responsible for the analgesia, anticonvulsant, dissociative and deliriant effects as well as dysphoria, neuroprotection and sedation.^[6]

Mu (μ)

The mu receptor is responsible for analgesia, physical dependence, respiratory depression, euphoria, and possible vasodilation.^[6]

Agonists of mu opioid receptors produce sedative, euphoric, and anxiolytic effects largely through the interaction of the mu receptors with serotonin, dopamine, and norepinephrine. Activation of mu receptors allows for the disinhibition of serotonin and dopamine neurons by blocking the inhibitory effects of GABA on serotonin and dopamine neurons, thus increasing activity and release of serotonin and dopamine.^[8] Mu receptors additionally inhibit the activity of norepinephrine neurons, leading to sedation, anxiolysis, and respiratory depression.^[9]

Nociceptin

The nociceptin receptor is responsible for anxiety, depression, appetite and development of tolerance to μ agonists.^[10][11]

Zeta (ζ)

The zeta opioid receptor, also known as opioid growth factor receptor (OGFr) is responsible for tissue growth, neural development, and is further implicated in the development in some cancers.^{[12][13][14][15][16][17]} The endogenous ligand for OGFr is met-enkephalin, which is also a powerful endogenous delta opioid receptor agonist.^[18]

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.

It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.

The short-term non-chronic use of opioids is not associated with any physical or neurological toxicity.^{[citation needed]}

Long term effects

The long-term use of opioids causes hormonal imbalance in both men and women.^[19] In men, this opioid-induced androgen deficiency results in abnormally low levels of sex hormones, particularly testosterone.^[20]

This negative change in endocrine function in males can lead to: reduced libido, erectile dysfunction, fatigue, depression, reduced facial and body hair, decreased muscle mass, and weight gain.

Another often observed long-term effect is hyperalgesia, an increase in the pain sensitivity of the person. This is specially seen in chronic pain patients on high dose opioid regimes. There is some evidence that NMDA antagonists like ketamine and opoids that are also weak NMDA antagonist such as methadone, levorphanol and tramadol may help delay the onset of hyperalgesia or even revert it.^[21]

It is strongly recommended that one use harm reduction practices when using this class of substances.

Tolerance and addiction potential

Due to the highly euphoric nature of these substances, the recreational use and abuse of opioids has an extremely high rate of addiction and dependence. This is combined with a tolerance which builds up quickly, necessitates that the user take increasingly high dosages in order to get the same effects.

The risk of fatal opioid overdoses rise sharply after a period of cessation and relapse, largely because of reduced tolerance.^[22] To account for this lack of tolerance, it is safer to only dose a fraction of one's usual dosage if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the drug in contrast to a familiar environment.^[23]

Dangerous interactions

Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).

Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.

• Alcohol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Place affected patients in the recovery position to prevent vomit aspiration from excess. Memory blackouts are likely
• Stimulants - Stimulants increase respiration rate which allows for a higher dose of opiates than would otherwise be used. If the stimulant wears off first then the opiate may overcome the user and cause respiratory arrest.
• Benzodiazepines - Central nervous system and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position blackouts/memory loss likely.
• DXM - Generally considered to be toxic. CNS depression, difficulty breathing, heart issues, and liver toxicity have been observed. Additionally if one takes DXM, their tolerance of opiates goes down slightly, thus causing additional synergistic effects.
• GHB/GBL - The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position
• Ketamine - Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
• MAOIs - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases.
• MXE - MXE can potentiate the effects of opioids but also increases the risk of respiratory depression and organ toxicity.
• Nitrous - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are common.
• PCP - PCP may reduce opioid tolerance, increasing the risk of overdose.
• Tramadol - Increased risk of seizures. Tramadol itself is known to induce seizures and it may have additive effects on seizure threshold with other opioids. Central nervous system- and/or respiratory-depressant effects may be additively or synergistically present.
• Grapefruit - While grapefruit is not psychoactive, it may affect the metabolism of certain opioids. Tramadol, oxycodone, and fentanyl are all primarily metabolized by the enzyme CYP3A4, which is potently inhibited by grapefruit juice^[24]. This may cause the drug to take longer to clear from the body. it may increase toxicity with repeated doses. Methadone may also be affected^[24]. Codeine and hydrocodone are metabolized by CYP2D6. People who are on medicines that inhibit CYP2D6, or that lack the enzyme due to a genetic mutation will not respond to codeine as it can not be metabolized into its active product: morphine.

• Responsible use
• Depressant
• Kratom
• Codeine
• Oxycodone

• Opioid (Wikipedia)
• Opiates (Erowid Vault)
• List of benzimidazole opioids (Wikipedia)