The Legal Highs of Novel Drugs of AbuseMay 02, ; Accepted Date: May 31, gigh Published Date: The abuse of drugs is dbol safe widespread and growing issue, both in United States and Europe, as a number of synthetic drugs have raised popularity legal high sp bt the past years for recreational use. Moreover, the nature of addiction is often debated as either a lifestyle choice that may underline a physiological vulnerability, and achievements in neuroscience identified addiction as a chronic brain disease with remarkable epigenetic, neurodevelopmental and sociocultural components. Consciousness and treatment of new drugs of abuse give challenges for health care practitioners legl due to a lack of quantitative reports. Also, a major problem ap tracking these drugs is that legal high sp bt are easily available through head shops, the web and other sources, therefore giving rise to a high risk of suspected intoxication.
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May 02, ; Accepted Date: May 31, ; Published Date: The abuse of drugs is a widespread and growing issue, both in United States and Europe, as a number of synthetic drugs have raised popularity over the past years for recreational use.
Moreover, the nature of addiction is often debated as either a lifestyle choice that may underline a physiological vulnerability, and achievements in neuroscience identified addiction as a chronic brain disease with remarkable epigenetic, neurodevelopmental and sociocultural components.
Consciousness and treatment of new drugs of abuse give challenges for health care practitioners primarily due to a lack of quantitative reports. Also, a major problem in tracking these drugs is that they are easily available through head shops, the web and other sources, therefore giving rise to a high risk of suspected intoxication. Drugs of abuse are currently a growing problem, especially in the most westernized countries, whereas novel drugs have become increasingly popular.
Drug addiction is described as a progression from impulsive to compulsive behavior, ending in chronic, relapsing drug taking. Patients with impulse control disorders experience an increasing sense of tension or arousal before committing an impulsive act; pleasure, gratification or relief at the time of committing the act; and then regret, selfreproach or guilt after the act [ 1 ].
The nature of addiction is often debated as either a lifestyle choice that may underline a physiological vulnerability. A brief description of the mechanisms of action through which drugs of abuse exert their reinforcing effects is that they trigger supraphysiologic surges of dopamine in the nucleus accumbens that activate the direct striatal pathway vias Dopamine 1 D1 receptors and inhibit the indirect striato-cortical pathway via Dopamine D2 D2 receptors [ 3 ].
Drugs modulate the expression of genes involved in neuroplasticity via epigenetic and RNA modifications, thus altering intracellular cascades and the neuronal circuits whose dysfunction have been implicated in the long-lasting changes associated with addiction [ 4 , 5 ].
Patient management is primarily driven by the symptoms and basic laboratory screenings are important to help diagnosis and organ damage [ 6 ]. Many of these novel drugs have similar effects and respond well to careful supportive management. On the other hand, typical toxic symptoms are not precipitated equally by many of these agents, because most new designer drugs are not detected with conventional drug testing.
On the other hand, an estimated 23,9 million Americans 12 years old or older are currently under illicit abuse drugs. In this case the illicit drugs routinely surveyed include hashish, cocaine, hallucinogens, marijuana [ 8 ].
So far with the most known abuse substances, but there is an increasing evidence of a over-the-counter drug abuse and misuse, such as weight control drugs some of them may contain pseudoephedrine, banned by the WADA World Antidoping Agency [ 9 ]. The majority of the new drugs are synthetic cannabinoids, amphetamine-like stimulants, opioidlike substances, or hallucinogens [ 10 , 11 ].
In this article the pharmacology and clinical effects of these drugs are described. Currently, these compounds can not be considered drugs of abuse per se, but the popularity and the repetitive use, especially among athletes, may eventually lead to tolerance and addiction with consumption at higher doses.
Performance-enhancing drugs, whether they are prescription-based such as anabolic steroids or growth hormone or sold in sport nutrition shops, are becoming more popular among athletes as pre and post-workout supplements, based upon the drive and incentive to perform at always higher levels. They may then represent putative drugs of abuse, as long as they may exert reinforcing effect by activating reward circuits in the brain. Initial drug assumption is largely a voluntary behavior, but continued drug use may impair brain function by interfering with the capacity to exert self-control over drug-taking behavior, thus rendering the brain more sensitive to stress and eventually to negative moods [ 3 - 12 ].
Newer drugs, such as NBOMe have gained popularity over the past years. They are phenethylamine derivatives of the 2C group of hallucinogen. Administration route may include buccal, sublingual, nasal, oral, parenteral, rectal and inhalation [ 12 ]. They show both a stimulatory and hallucinogen clinical effect [ 16 , 17 ]. Their symptoms may include nausea, vomiting, dizziness, diarrhea, headaches, body aches, depression confusion and hallucination [ 18 ].
Also various "magic mushrooms" have also long been used for inducing hallucinations experiences and show a large variation in potency. Species of Psilocybe produce the alkaloid psilocybin 4-phosphoryloxy-N, Ndimethyltryptamine , which is hydrolysed to psilocin in the gut. This compound mimics a serotonin uptake inhibitor, invokes psychotropic experiences and have similar effects to DMT and other hallucinogenic compounds [ 20 ]. There are 22 species of mushrooms in the genus Psilocybe that contain psilocybin in the United States and Canada [ 21 ], as well as a number of species in other genera that contain psilocybin [ 22 ].
However it may be speculated that alcohol may enhance the adverse effects induced by "magic mushrooms". Infact both psilocine and psilocybine are rapidly inactivated by the enzyme MAO mono amine oxidase, which catalyses the oxidative deamination of biogenic amines.
Acetaldehyde, the primary metabolite of ethanol, reacts with endogenous biogenic amines thereby producing the MAO-inhibitors tetrahydroisoquinolines and b-carbolines tryptolines see review [ 23 ]. Also tobacco use is associated with lowered levels of MAO in the brain and peripheral organs [ 24 , 25 ]. Tobacco smokers may therefore experience more pronounced desired and adverse effects of magic mushrooms compared to non-smoker see review [ 23 ].
Stimulants are a variety of substances able to enhance focus and wakefulness, mood, and ultimately decrease ingestive behavior. Well known are nicotine, methylxanthines and amphetamines.
More recently, cathinones, also known as bath salts, have been added. Their mechanism of action is similar to other stimulants, therefore changing monoamine transporters through which serotonin, dopamine and norepinephrine are taken from central synaptic clefts, resulting in increased postsynaptic neurotransmission [ 27 ].
They are found in the leaves of the khat plant Catha edulis which also contains norephedrine [ 28 , 29 ]. Many are the routes of administration for bath salts, varying from insufflating snorting to oral ingestion, but also intravenous, intramuscular and perrectum administration [ 30 - 32 ]. Stimulants are strongly searched after as they show psychoactive effects such as increased energy, decreased appetite and decreased sleep. Therefore, their use could be as rewarding as drinking caffeine or chewing khat or coca leaves for cognitive enhancing performaces, but it may also result in severe addiction or psychiatric disorders, especially paranoia and hallucinations [ 33 , 34 ].
Cardiovascular effects may also be related to the stimulant effects of cathinones, with symptoms including chest pain, palpitations, hypertension and tachycardia [ 30 , 31 ]. Furthermore, long-term effects of bath salts are still unknown. Synthetic cannabinoids SC refer to a growing of man made chemicals and represent one the most illicit substances both worldwide and in the United States, that are either sprayed on dried, shredded plant material, so they can be smoked as herbal incense or sold in liquid form to be vaporized and inhaled in e-cigarettes [ 35 ].
They act through cannabinoid receptors with a large number of biologic targets. A high density of CB1 receptors are present in the brain and modulate gamma-aminobutyrric acid GABA and glutamate transmission, whereas CB2 receptors are found in the CNS and in peripheral tissues spleen and immune cells and mediate immunosuppression [ 26 - 40 ].
Onset and duration appear to be similar to marijuana but vary based on the product ingested [ 41 ]. Other effects are on metabolism and hyperthermia, tolerance, withdrawal and dependence.
Adverse effects include anxiety, paranoia, hallucinations, sedation, psychosis and seizures [ 26 - 39 ]. Cardiovascular effects include hypertension and tachycardia [ 42 , 43 ]. Other adverse effects may include nausea, vomiting, and acute kidney injury [ 44 - 46 ]. Longterm and chronic effects of SC use are difficult to characterize and unknown. Nevertheless, long-term users may be at increased risk for new-onset and relapse of psychosis and reduced brain volume and emotional processing [ 47 , 48 ].
Moreover, cognitive deficits and memory impairment were reported with chronic marijuana use [ 49 ]. Gabapentin was approved in the United States in for the treatment of seizure disorder, but since that time, it has increasingly been prescribed for a number of other conditions.
Nevertheless, blockinging voltage-dependent calcium channels, Gabapentin results to affect CNS [ 50 ]. Because of its CNS effects, recent findings have shown that Gabapentin might become a drug of abuse. So far, it may have benefit for some anxiety disorders and has clearer efficacy for alcohol craving and withdrawal symptoms and may play a role in adjunctive treatment of opioid dependence.
It is apparently effective and safe, but comes with the potential for misuse and negative sequelae Joseph Insler, Medscape Medical News. Eight case reports show the abuse and dependence of gabapentin, occurring in patients with a previous history of drug abuse or dependence [ 51 ]. Also it has been demonstrated that abuse of gabapentin is associated with opioid addiction [ 52 ].
Further research is required to better clarify the association with abuse. Kratom is an opioid-like tropical tree from Southest Asia, traditionally used by dwellers from Thailand and Malaysia to alleviate musculoskeletal pain and to increase energy, appetite, sexual desire [ 53 , 54 ].
Other claimed beneficial effects of Kratom include antipyretic antihypertensive, antinflammatory, antidiarrheal and hypoglicemic effects [ 26 ]. Kratom is readily available on the Internet and gained popularity in its use and abuse [ 56 ]. Most commonly it is use for the hallucinogenic effects but also, to a lesser extend, for management of opioid withdrawal. Kratom contains more than 40 alkaloids that interact with opioid and monoaminergic receptors, even though it is not related to opioids [ 57 ].
Mitragynine is responsible for its opioid-like effects [ 55 ]. The drug is usually smoked, but it can also be ingested after being brewed into a tea. Onset of effect occurs min after assumption and it lasts for about 2 to 5 h [ 58 , 59 ].
Toxicological effects are rare and only occurs in high dosages [ 55 ]. Adverse effects are similar to opioids and include nausea, vomiting, constipation, respiratory depression, itching, dry mouth, increased urination, anorexia and palpitations [ 53 ]. Acetyl fentanyl N-[1-phenethylpiperidinyl]-Nphenylacetamide is one of countless novel psychoactive substances that have been linked to several recent deaths in Rhode Island, Pennsylvania, North Carolina, and Louisiana [ 60 , 61 ].
This drug is an opioid analgesic, chemically similar to the medicinally used fentanyl, but it is not approved for therapeutic uses. Studies suggest that it is 5 to 15 times more potent than heroin [ 62 ], approximately 6 times as potent as morphine [ 63 ].
Although the pharmacological effects of Acetyl Fentanyl have not been specifically investigated clinically in humans, fentanyl-like substances have been generally associated with euphoria, altered mood, drowsiness, miosis, cough suppression, constipation and respiratory depression [ 64 ]. Moreover Fentanyl and its analogs are typically lipophilic, readily cross the blood—brain barrier and accordingly, display a rapid onset of analgesic effects [ 65 ].
Acetyl fentanyl is typically administered in transdermal patch or intravenous injectable formulations, as a direct substitute or mixed with heroin or other substances among dependent users [ 64 ]. However, acetyl fentanyl exists in a legal gray area: In comparison with traditional drugs of abuse, medical doctors have greater difficulty with the diagnosis. In fact clinicians should suspect acetyl fentanyl was the causal agent if a patient unresponsive to standard naloxone doses was revived by a megadose or responds to naloxone but screens negative for heroin [ 67 ].
Salvia is derived from the ethnomedical plant Salvia divinorum. Recently it has become more readily available to consumers due to distribution through head shops and the Internet. It is endorsed with potent hallucinogen properties in humans. The active compound, salvironin A is a selective high efficacy kappa-opioid receptor KOPr agonist, including mu-opioid receptor MOPr , the target of opioid alkaloids, such as morphine [ 68 , 69 ] and it is pharmacologically distinct from other known hallucinogens in humans.
Salvinorin A causes sedative-like and locomotordecreasing effects in rodent and non-human primate models including unresponsiveness to environmental stimuli [ 70 - 72 ].
These effects are qualitatively similar to those of synthetic KOPr agonists, and are sensitive to KOPr antagonism [ 70 - 72 ]. Salvironin A also results in anhedonia in intracranial self-stimulation ICSS assays and depressant-like effects in the forced swin test, similarly to synthetic KOPr agonists [ 77 , 78 ].
These findings may explain that prolonged high efficacy signaling, through KOPr, results in behavioral and neurobiological effects associated with human neuropsychiatric conditions, especially depression-like and anxiety-like states, and specific addictions.
Carefully controlled studies in human, initially experienced hallucinogen or Salvia Divinorum users, characterized the effects of salvinorin A smoking 0, Under these carefully monitored conditions, volunteers reported robust hallucinogenic-like effects, depersonalization and derealization, but no robust dysphoria or aversion [ 79 ].
It is unknown if effects in a different population i. A separate study with smoked salvinorin A in volunteers with previous self-exposure to Salvia divinorum reported dose-dependent and reversible psychomimetic effects, dissociation, and neuroendocrine effects increases in serum cortisol and prolactin [ 84 ].
A further study examined the effects of Salvia divinorum smoking, and characterized subjective experiences including cognitive alterations, which were also robust and time-dependent [ 85 ].