Nevertheless, this study was among participants in young adulthood . Contrastingly, among HIV+ men in our study, we found no significant association between cumulative marijuana-use-years and rate of decline across all cognitive function measure. One other study that assessed associations of lifetime exposure to marijuana and cognitive function in HIV+ individuals found similar findings. In a cross-sectional analysis of 215 HIV+ adults with substance use disorder, lifetime marijuana use, was defined as the number of years marijuana was used ≥3 times per week. Although they did not assessed cognitive processing speed or flexibility, they authors found no significant association between lifetime marijuana use and worse memory and attention assessed using the Montreal Cognitive Assessment . These findings lend support to the literature on residual effects of marijuana exposure on cognitive function, which suggest that cognitive deficits dissipate following abstinence periods that span 25 days . It is unclear why cumulative exposure to marijuana was significantly associated with slowed processing speed in the HIV- men in our study, but not in the HIV+ men. As noted earlier and similar to our findings for current marijuana use, all of the coefficients for cumulative marijuana-use-years and cognitive function outcomes, were very small, falling below Cohen’s f 2 small effect size,hydroponics flood table indicating that our findings are likely not clinically meaningful. Further, our study did not find evidence that cognitive function outcome may be worse in HIV+ individuals with disease progression.
Our additional analysis found no significant interaction between current and cumulative marijuana-use-years with viral load detectability and CD4 counts. This contrasts with one early study published over 13 years ago that found pronounced memory impairment in subjects with symptomatic HIV infection . One likely explanation is that the men in our sample were medically stable as nearly all were receiving HAART and about half had CD4 counts greater than 500 copies with undetectable viral load at baseline.Readers should interpret our results in light of some limitations. Marijuana use in this study was obtained via self-report and no biological marker was used to confirm self-reported use. Related to this issue is that our method for calculating cumulative marijuana use may have been imprecise. For example, there is the possibility for significant data loss in average number of days of marijuana use for participants who use marijuana more than weekly but less than daily . Second, we were not able to account for exposures to marijuana prior to enrollment in the MACS; including data on age of first use. Studies have previously demonstrated that early initiation of marijuana may confer profound cognitive impairments – via its effect on the developing adolescent brain . Thirdly, selective attrition was likely a concern in this study as participants who dropped out or died during follow-up performed worse on the cognitive function measures at baseline than those who survived and remained in the study. Participants who reported substance use, including marijuana use, were more likely to drop out or die during follow-up , and this trend was greater in HIV+ compared to HIV– participants. We note however, that our analyses employed inverse probability of attrition weights, but this approach may not have completely accounted for these attrition effects, thus our estimates of cognitive decline may have been underestimated.
Fourth, our study did not adjust for additional covariates that may confound the associations between marijuana use and cognitive function including psychiatric illness and use of psychotropic medications. Psychiatric illness is prevalent in HIV+ individuals and can interfere with cognitive function . This leaves open the possibility that our significant results for current monthly and daily marijuana use and slowed processing speed in HIV+ men may explained by the presence of psychiatric illness and other unmeasured confounds . Fifth, our study only focused on two domains of cognitive function . Future investigations of current and the long-term impact of marijuana use on other aspects of cognitive function including executive function, attention and motor functions is warranted. In addition, participants in our study comprised men who have sex with men, majority of whom were non-Hispanic whites with relatively high educational accomplishment and thus our study findings may be less generalizable to other populations . Finally, our study did not distinguish between the THC/cannabidiol content of the marijuana consumed. There is some evidence that CBD – which does not have psychoactive properties – may confer neuroprotective effects against the negative effects of THC . Notwithstanding, our study has many strengths including among the first studies utilizing a sample size this large, with longitudinal data on marijuana exposure and cognitive function assessments for over a 17-year period. The consumption of psychoactive natural products predates recorded history.For millennia, our ancestors subsisted by consuming materials foraged from the natural world.
Over time, innumerable person-hours of trial and error resulted in a keen understanding of the expected physiological and psychological effects upon ingestion of specific plants, animals, and fungi. This information propagated initially as traditional knowledge, forming the basis of valuable cultural practices and efficacious traditional medicine.The myriad of ethical concerns around the appropriation of indigenous knowledge, exploitation of slave labor, as well as inequitable access to natural product cultivation, sale, and use, typically go unanswered by mainstream science, and we encourage the reader to consult a selection of responsibly written articles on these subject matters. Scientists are beginning to recognize that natural products have mediated intimate evolutionary relationships between plants, animals, and fungi.For instance, over centuries, winemakers selected grapes harboring high-alcohol producing Crabtree-positive yeast, enabling the co-domestication of a plant fungal symbiont pair.An additional, highly speculative example known as the “Stoned Ape Hypothesis” posits that the consumption of psychedelic mushrooms may have played a role in rapid increase of brain size in early hominids.This push-pull relationship of humans with natural products continues to this day, as the adoption of single molecule constituents by Western culture has triggered the expansion of traditional cultivation practices to meet global demands.Isolation of and characterization of organic plant extracts marked the beginnings of both organic chemistry and Western medicine. Prior to 20th century prohibition,hydroponic stands efforts towards the total synthesis of commodified natural products provided a foundation for generations of organic chemists. Sir Robert Robinson’s 1917 route to the cocaine precursor tropinone is widely lauded as a classic in total synthesis,while Woodward’s innumerable contributions to the field of natural product total synthesis included a route to the lysergic acid diethylamide precursor lysergic acid.Incorporation of this knowledge into semi-syntheses prompted researchers to think of biological materials as chemical factories, and beg the question: how do organisms synthesize natural products? Extraordinary progress has been made in the elucidation of the metabolic pathways underpinning the chemical composition of psychoactive substances. In the field of natural product biosynthesis, scientists investigate the bio-synthetic logic that enables Nature to synthesize psychoactive natural products with high efficiencies and selectivities.Identification and reconstitution of key enzymatic steps uncovers Nature’s synthetic schema towards complex molecular scaffolds from simple metabolic precursors. The accumulation of such bio-synthetic information is driven in part by advancements in synthetic biology; emerging bio-technologies promise to outperform traditional synthetic methods in cost, safety, efficiency, and sustainability. Thus, significant achievements have been made in the heterologous expression of natural product pathways towards consumer products. Only in the last half of a century have scientists begun to investigate the molecular mechanisms of psychoactivity – the alterations in perception, consciousness, and behavior, associated with such small molecules.Prior to the 1950s, most scientists believed that synaptic activity was dictated entirely through electrical impulses, and little evidence existed on the role of chemical signaling.
Our current understanding of psychopharmacology has been directly facilitated by the use of natural products. The extraordinary protein receptor binding affinities of psychoactive natural products allowed scientists to deduce the role of neurotransmitters in the central nervous system.We now know that neuroreceptors are the key signal transducers able to integrate chemical signals into biological systems. It is the selective receptor binding and activation by native and non-native chemical ligands that causes modulation of neural pathways, resulting in altered perception.These receptors are differentially expressed in different populations of neurons, and may exist as splice variants or exhibit single-nucleotide polymorphisms between individuals.Further, differential activation of receptor subtypes by a given ligand makes it difficult to categorize psychoactive drugs based strictly on the physiological target. For example, activation of μ- opioid receptors by agonists like morphine results in analgesia and sedation,whereas activation of κ-opioid receptors by the potent ligand salvinorin A results in dissociation.Thus, while formally an opioid, the consumer of Salvia divinorum would classify the shrub as a bona fide hallucinogen based on perceived psychological effect. As a result, psychoactive drugs have traditionally been categorized based simply on the experience of the user, as opposed to complex molecular mechanisms of psychoactivity. The natural products discussed herein fall within one of four well-recognized classes: hallucinogens, stimulants, cannabinoids, and opioids . The utility of psychoactive natural products, if used safely, cannot be questioned. Selective, potent binding of a ligand to a target is a hallmark feature of a pharmaceutical agent. While immense pharmaceutical potential has been ascribed to many psychoactive natural products, evidence-based drug development campaigns are largely hindered by regulatory statusNatural products in the Schedule I Controlled Substance category have been designated as having no accepted medical use, hindering clinical trials, even though many compounds on the list exhibit great potential for clinical success. For example, evidence implicates psilocybin as a promising candidate for treatment-resistant depression and posttraumatic stress disorderwhereas the alkaloid ibogaine has undergone development as anti-addictive agentMeanwhile, a recent meta-analysis concluded that the natural product derivative lysergic acid diethylamide has strong potential in the treatment of alcoholism.These three compounds fall into the category of hallucinogenic natural products, invoking psychedelic, introspective effects. Alkaloidal stimulants are also of great societal value, and include the world’s most widely consumed psychoactive drug, caffeine. Nicotine and cocaine, two other well-known alkaloidal stimulants, exhibit high potential for dependence, but are each approved for specific medicinal indications.While the legal status of Cannabis is currently in flux, the primary constituents tetrahydrocannabinol and cannabidiol are FDA approved medications.State-by-state deregulation has resulted in the ongoing cannabinoid boon driving academia and industry to discover additional applications for THC, CBD, and other rare cannabinoids. Finally, opioid analgesics are included on the World Health Organization’s List of Essential Medicines. Despite the ongoing opioid crisis, morphine plays a critical role in pain management and palliative care.Kratom, which contains the potent MOR agonist mitragynine, has emerged recently as an alternative to opium-derived substances. Given its potential for abuse, additional epidemiological studies of kratom are warranted.As opioid dependence soars, public health organizations have described the importance of research into pain management and addiction. We advocate for an unbiased, evidence-based evaluation of the risks and benefits of psychoactive natural product use in order to maximize societal value. As with most natural products isolated from microorganisms and plants, the psychoactive compounds discussed in this review are biosynthesized from simple, primary metabolites such as acetate, isoprene, and amino acids.With the exception of cannabinoids and a few others, most of the compounds covered are alkaloids derived from the decarboxylation of a small set of amino acids. For example, L-tryptophan is the precursor to ibogaine and psilocybin; L-tyrosine is the precursor to mescaline and morphine; while the nonproteinogenic amino acid L-ornithine is the precursor to nicotine and cocaine. The decarboxylation of amino acids is catalyzed by an enzyme family known as amino acid decarboxylase , which uses pyridoxal-5’-phosphate as a cofactor. A few of the compounds contain isoprenoid building blocks, such as the C5 prenyl unit in lysergic acid and the C10 geranyl unit in cannabinoids . The C–C bonds between the isoprenes and the rest of the molecules in these compounds are catalyzed by a group of enzymes known as prenyltransferases. Prenyltransferases are one type of group transfer enzyme used by nature to transfer functional groups from thermodynamically activated carriers to natural product bio-synthetic intermediates. Other group transfer enzymes include acyltransferases and S-adenosylmethionine dependent methyltransferases, which are frequently found in bio-synthetic pathways.The enzymes catalyzing these reactions are collectively referred to as oxidoreductases, and include examples such as cytochrome P450s, ketoreductases and amine oxidases.