New psychoactive and illicit substances (“legal highs”) are synthetic substances designed to mimic the effects of other illicit drugs such as cocaine and ecstasy/MDMA and even prescription drugs. In addition, these substances also contain a variety of unknown chemicals that have not undergone the necessary tests to understand how they interact with the human brain and body. As such, these medications are associated with a variety of effects and symptoms that can vary depending on the type of so-called “legal high” you are addicted to, the amount of medication you have taken, as well as specific to each individual. While plant hallucinogens have been used entheogenically for millennia, the first synthetic and perhaps most notorious hallucinogen, lysergic acid diethylamide (LSD), was developed in 1938 by Swiss chemist Albert Hofmann. Since then, several chemists, including David E. Nichols and Alexander Shulgin, have developed a number of analogues and similar compounds that act by essentially the same primary mechanism of action as classical hallucinogens. Notable officers who currently have legal or semi-legal status are listed in Table 2. Currently, the complete pharmacological profiles of most hallucinogenic NPS remain incomplete, and their grouping is based on subjective descriptions of user experiences. It should also be noted that several agents that are primarily psychostimulants, including MDMA, mephedrone, and methcathinone, also act as agonists on the 5-HT2A receptor, either by direct agonism or by that of metabolites, resulting in some degree of coactivation of more psychedelic signaling pathways. To demonstrate this, Liechti and colleagues [Liechti et al.
2000] administered ketanserin, a selective 5-HT2A antagonist, as a pretreatment for MDMA to healthy volunteers, which was associated with significant attenuation of perceptual changes, emotional arousal, body temperature and adverse response, but not positive mood, extraversion and well-being. Although little pharmacological data is currently available, the popular 2-C series as well as the NBOMe series can fall between the hallucinogenic and psychostimulant categories and show subjective effects that are congruent with both groups, as described below. The newer cannabinoids mimic THC in that they primarily activate CB1, although there is also evidence of binding to CB2 receptors, albeit with different affinities and efficacy [Gurney et al. 2014; Pertwee, 2008], and the neuropharmacological effects of new drugs may differ considerably: an example of this is that several novel cannabinoids acting as complete agonists, such as JWH-018, have been identified. The first synthesized cannabinoids were derived from indole, many of which are known as the JWH series, named after their first synthesizer, John W. Huffman, and later the group was expanded to include pyrroles and indenes. There is now a wide range of synthetic cannabinoids that have been sold as legal highs, with Presley and colleagues [Presley et al. 2014] listing 10 chemical subfamilies, although their psychopharmacological properties have not yet been fully defined. In general, it appears that synthetic cannabinoids work as one would expect due to their affinity for CB1 receptors. In a neural model, JWH-018 was shown to decrease dose-dependent neurotransmitter release by activating CB1 activation [Atwood et al.
2010]. However, it has been found, for example, that halogenation of compounds has led to the development of new, more efficient analogues, such as AM-2201, which has a binding 10 times stronger to the CB1 receptor than its predecessor JWH-018 [Gurney et al. 2014]. While the first active ingredients were mainly produced by academic and pharmaceutical companies, increasingly, the active ingredients seem to come from DIY labs. For example, while UR-144 was first manufactured by Abbott Laboratories, its stronger halogenated analogue XLR-11, apparently named after rocket fuel, has an unknown source and was first found in legal mixtures with high smoke content [Gurney et al. 2014; Presley et al., 2014]. It is important to realize that without the help of a specialist, addiction to these substances can gradually worsen over time, affecting you mentally, socially and physically, and causing a whole host of long-term problems. In addition, an untreated “legal” addiction can also lead you down the destructive path of abuse of other addictive substances, such as alcohol or other drugs, or compulsive behaviors such as gambling. Regardless of the type of so-called “legal high” consumed, repeated abuse of these substances can lead to the development of dangerous addiction and a whole host of negative physical and psychological consequences.
New psychoactive and illicit substances are particularly dangerous for two main reasons: so-called “high legal” addiction can have a profound negative impact on all areas of your life, including your relationships with others, your performance at work, your health and your overall well-being. However, the good news is that these destructive addictions are treatable and it is possible for you to fully and permanently recover. Our specialist treatment team at Manor Clinic is committed to helping you every step of the way to overcome your addiction and get your life back on track. These drugs will often appear to be legal products; Often they are packaged to look like harmless candy, or marketed and sold as innocent-sounding substances such as incense or bath salts. This can often lull people into a false sense of security, as they are led to believe that these drugs are not dangerous. The growth of NPS in recent years has been enormous, with a parallel increase in media attention, and it is obvious that science has not yet caught up with these drugs. Most clinicians are familiar with NPS from the popular press, but many will likely feel an understandable sense of confusion about its legality, prevalence, impact on users, and potential for physical and psychological harm and toxicity. This article aims to provide a framework for examining the broad pharmacological domains and effects of the current major classes of NPS and to serve as a guide for the allocation and categorization of compounds that will undoubtedly be synthesized in the future.
The overall toxicity and harmfulness of NPS has been difficult to assess precisely: it is partly an inherent problem in drug work; And in part, as mentioned earlier, the science is incomplete. At present, much of the data, particularly deaths that were clearly induced by NPS, are based on case reports [e.g., Olives et al. 2012], the generalizability of which is still unclear. Undoubtedly, there are also problems with the accuracy of terms such as “legal highs,” and a more careful decoding of drug poisoning data mitigates more sensationalist media reporting [King and Nutt, 2014]. The abuse of new psychoactive and illicit substances (“legal high”) can lead to a variety of serious long-term problems that can wreak havoc in all areas of your life. Long-term consequences may include: Cannabis is the most commonly used illicit recreational substance [EMCDDA, 2014a]. Not surprisingly, synthetic cannabinoids (sometimes colloquially referred to as “noids”) that offer similar effects without the same risk of lawsuits are among the most popular NPSs, along with newer stimulants [UNODC, 2012]. Due to the perceived notoriety in the mainstream press, they have received a lot of attention in the scientific literature, and several reviews have been published on the topic: these are mentioned in this article when relevant to further guide the interested reader. Synthetic cannabinoids modulate the G protein-coupled receptors (GPCRs) of the endocannabinoid system, two of which have been identified: cannabinoid receptor 1 (CB1), which is largely found in neurons in the central nervous system; and the cannabinoid receptor 2 (CB2), which is mainly expressed on immune system cells such as microglia, although there is some overlap in expression.
The two best-known endogenous cannabinoids identified are anandamide and 2-arachidonoylglycycerol (2-AG), both of which are synthesized in response to high levels of postsynaptic intracellular calcium and can activate CB1 and CB2 receptors [Pertwee, 2008]. Activation of receptors inhibits the release of presynaptic neurotransmitters and therefore excessive synaptic activity, and one of the main functions of the endocannabinoid system appears to be the maintenance of neuronal homeostasis. Presynaptic CB1 receptors inhibit the flow of many excitatory neurotransmitters from the neuron into the synaptic cleft, including serotonin, dopamine, norepinephrine, acetylcholine, and glutamate.