Clonidine

In the early 1960s, the medicinal chemist Helmut Stähle was tasked by Boehringer Ingelheim with synthesizing a peripherally active a-adrenergic compound that would be useful for nasal decongestion as simple nose drops. A locally acting a-adrenergic vasoconstrictor agent was expected to provide relief from the symptoms of the common cold by shrinking the swollen nasal membranes and producing an unobstructed air passage.^[2]

The synthetic design of clonidine was achieved when Stähle had the idea of substituting two chlorine groups on the phenyl group of the imidazoline structure, which most of the newer decongestive agents at the time were derived from. At that time, a double halogen substitution was still unusual for pharmaceuticals, and the prevailing opinion was that compounds with several halogen atoms would at best be useful as pesticides. Despite this, clonidine was pursued and discovered to have a remarkably high vasoconstrictive and decongestive effect at an unusually low dosage level.^[2]

The decongestive effects were then determined by nasal cavity tests on anesthetized dogs. After the first trial in humans, it became clear that clonidine's decongestant properties were far less interesting than its potent anti-hypertensive effects. The compound was then developed for this new indication and was introduced into therapy in 1966 under the trade name Catapres, where it saw widespread use.^[2]

With the discovery of clonidine, the central a-adrenergic receptors first became known to chemists, pharmacologists and physicians. It has been an important pharmacological tool in researching the role of central α-adrenoceptors in the physiology of central blood pressure regulation and nervous system function.^[2]

In the 2010s, the US Food and Drug Administration (FDA) approved clonidine, both alone or with stimulants, for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric and adult patients. In Australia, clonidine is an accepted but not approved use for ADHD by the TGA.^[13]

Clonidine, or 2-[(2,6-Dichlorophenyl)imino]imidazoline, is a compound of the imidazoline chemical class. Imidazolines are substituted amidines in which the amidine function is incorporated into an imidazoline ring. This portion is connected to an aromatic nucleus by way of a methylene bridge.

Additionally, two chlorine atoms are substituted in the 2- and 6-positions of the phenyl ring. This addition has the critical effect of making the molecule sufficiently lipophilic to penetrate the blood-brain barrier.^{[citation needed]}

Other compounds of this class include the a-adrenergic agents tolazoline, naphazoline, and phentolamine. The a-adrenergic effects of clonidine and other imidazolidine compounds may be explained on the basis of a structural overlap between clonidine and norepinephrine.

Pharmacodynamics

Clonidine is an agonist for the α₂ adrenergic receptor. When α₂ receptors in the brain are stimulated, peripheral vascular resistance decreases, resulting in lowered blood pressure. It has specificity towards the presynaptic α₂ receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels and inhibits the release of norepinephrine (NE). The net effect is a decrease in sympathetic nervous system tone.^[14]

Three G-protein coupled α2-receptor subtypes have been identified: α_2A, α_2B, and α_2C. Each subtype has a unique pattern of tissue distribution in the central nervous system and peripheral tissues. The α2A-receptor is widely distributed throughout the central nervous system; it is found in the locus coeruleus, brain stem nuclei, cerebral cortex, septum, hypothalamus, and hippocampus. α_2A receptors are also expressed in the kidneys, spleen, thymus, lung and salivary glands. The α_2C-receptor is primarily expressed in the central nervous system, including the striatum, olfactory tubercle, hippocampus and cerebral cortex. The α_2B receptor is located primarily in the periphery (kidney, liver, lung and heart).^{[citation needed]}

The α_2A- and α_2C receptors are located presynaptically and inhibit the released of noradrenaline from sympathetic nerves. Stimulation of these receptors decreases sympathetic tone, resulting in decreases in blood pressure and heart rate. Sedation and analgesia is mediated by centrally located α_2A receptors, while peripheral α_2B receptors mediate constriction of vascular smooth muscle. α_2A receptors also mediate essential components of the analgesic effect of nitrous oxide in the spinal cord. Clonidine stimulates all three α₂ receptor subtypes with similar potency.^{[citation needed]}

Clonidine also has peripheral α₁ agonist activity.^{[citation needed]}

Clonidine is also an agonist for the imidazoline I₁ receptor.^[15] This has been proposed to be responsible for the antihypertensive effects.^[16]

Pharmacokinetics

Clonidine is rapidly absorbed from the gastrointestinal tract and has excellent CNS penetration because of lipid solubility.^{[citation needed]} Peak plasma concentrations are reached 3-5 hours after a single oral dose.^{[citation needed]} No known pharmacologically active metabolites exist.^{[citation needed]} Plasma half-life is 12-16 hours, with the antihypertensive effects occurring within 30-60 minutes of ingestion. Clonidine is excreted unchanged in the urine and is metabolized by the liver.^{[citation needed]}

''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 ☠.''

Experience reports

There are currently 1 anecdotal reports which describe the effects of this compound within our experience index.

• Experience:17mg 3-MeO-PCP & Cannabis oil - Terrifying confusion

Additional experience reports can be found here:

• Erowid Experience Vaults: Clonidine

At therapeutic doses (0.2-0.9 mg/d), clonidine is commonly associated with adverse effects such as dry mouth, sedation, dizziness, and constipation. While generally safe, at toxic doses clonidine can cause serious cardiopulmonary instability and central nervous system (CNS) depression in children and adults. Caution should be used when clonidine is taken with other depressants.

It is strongly recommended that one use harm reduction practices when using this substance.

Lethal dosage

The oral LD₅₀ for clonidine in mice is 206 mg/kg and for rats, 465 mg/kg.^{[citation needed]} In humans, lethality is rare with a small number of reported deaths. Morbidity, in terms of cardiorespiratory and CNS dysfunction, generally tends to be more severe in young persons than in adults.^{[citation needed]}

Overdose

Symptoms of clonidine overdose include constriction of pupils of the eye, drowsiness, high blood pressure followed by a drop in pressure, irritability, low body temperature, slowed breathing, slowed heartbeat, slowed reflexes, and weakness.^{[citation needed]}

There are case reports that show naloxone may be a useful antidote in treating clonidine overdoses. However, this is not in widespread clinical use.^[22]

Tolerance and addiction potential

Clonidine is not addictive and has a low potential for abuse. The chronic use of clonidine can produce physical dependence and withdrawal symptoms if one suddenly stops their usage. Clonidine therapy should generally be gradually tapered when discontinuing therapy to avoid rebound hypertension from occurring.

Although clonidine is not considered to be addictive, cases of misuse have been documented among certain groups with pre-existing substance use disorders. It is sometimes used in combination with opiates to extend and potentiate their effects.^[23] This practice may increase the risk of oversedation and respiratory depression associated with opioid use.

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.

• Depressants (1,4-Butanediol, 2M2B, alcohol, benzodiazepines, barbiturates, GHB/GBL, methaqualone, opioids) - This combination potentiates the muscle relaxation, amnesia, sedation, and respiratory depression caused by one another. At higher doses, it can lead to a sudden, unexpected loss of consciousness along with a dangerous amount of depressed respiration. There is also an increased risk of suffocating on one's vomit while unconscious. If nausea or vomiting occurs before a loss of consciousness, users should attempt to fall asleep in the recovery position or have a friend move them into it.
• Dissociatives - This combination can unpredictably potentiate the amnesia, sedation, motor control loss and delusions that can be caused by each other. It may also result in a sudden loss of consciousness accompanied by a dangerous degree of respiratory depression. If nausea or vomiting occurs before consciousness is lost, users should attempt to fall asleep in the recovery position or have a friend move them into it.
• Stimulants - Stimulants mask the sedative effect of depressants, which is the main factor most people use to gauge their level of intoxication. Once the stimulant effects wear off, the effects of the depressant will significantly increase, leading to intensified disinhibition, motor control loss, and dangerous black-out states. This combination can also potentially result in severe dehydration if one's fluid intake is not closely monitored. If choosing to combine these substances, one should strictly limit themselves to a pre-set schedule of dosing only a certain amount per hour until a maximum threshold has been reached.

• Germany: Clonidine is prescription medicine, according to Anlage 1 AMVV.^[24]
• Switzerland: Clonidine is listed as a "Abgabekategorie B" pharmaceutical, which requires a prescription.^{[citation needed]}
• United States: Clonidine is only available with a prescription.^[25]

• Responsible use
• Depressant
• Adrenaline (Epinephrine)
• Noradrenaline (Norpinephrine)

• Clonidine (Wikipedia)
• Clonidine (Erowid Vault)
• Clonidine (TiHKAL / Isomer Design)
• Clonidine (Drugs-Forum)

• Stähle, H. (2000). A historical perspective: development of clonidine. Best Practice & Research Clinical Anaesthesiology, 14(2), 237-246. https://doi.org/10.1053/bean.2000.007