The vast majority of adult smokers began smoking during adolescence. Each day, approximately 2,000 youth smoke their first cigarette and over 300 become daily smokers. Previous studies have shown that the younger people are when they begin using tobacco products, the more likely they are to develop nicotine dependence and other substance use disorders. It has also been shown that adolescents can become nicot inedependent very quickly, even after occasional intermittent use. Furthermore, a meta analysis of longitudinal studies confirms that ENDS use is associated with an increased likelihood of future cigarette smoking. Although the percentage of teen ENDS use had been consistently increasing over the years, the percentage of high school seniors vaping nicotine actually decreased from 34.5% in 2020 to 26.6% in 2021 during the COVID-19 pandemic in the US. This decrease in adolescent drug use was surprisingly consistent across many substances, including alcohol and opioids. This phenomenon could possibly be attributed to limited access to drugs during government ‘stay at home’ orders, reduced in person peer pressure, increased messaging of the harmful effects of drug products targeted at youth, and/or potential survey response biases as adolescents are likely responding in the presence of a parent or guardian at home. According to the World Health Organization, cannabis, also known as weed or marijuana, is the most abused illicit drug. As of 2021,air racking only eight countries have at least partially legalized cannabis for recreational use, but approximately 200 million people report using cannabis worldwide.
Cannabis is derived from the Cannabis plant which contain over 100 compounds called phytocannabinoids, with Δ9-tetrahydrocannabinol and cannabidiol being the most well-characterized. Cannabis use may induce sensations of euphoria, altered sense of time, distorted sensory/body perception, and mood changes. THC is the main psychoactive component in cannabis and can result in feeling ‘high’, along with increased anxiety and paranoia, altered perception, impaired working memory, slower movements, and cognitive deficits, depending on the dose. Among youth, smoking cannabis appears to be becoming somewhat less prevalent, but this downward trend has been paralleled by a general upward trend in consumption of edibles and use of THC vapes. Of concern, high frequency adolescent cannabis use has been linked to deficits in attention, learning, and memory, as well as mental health issues including increased depression, anxiety, suicidal ideation and schizophrenia. Similar to nicotine, however, in correlation to the COVID-19 pandemic, there was a decrease in the percentage of adolescents who report using cannabis in 2021. Interestingly, there is evidence that low doses of THC in older mice may help restore cognitive function. Similarly, in older humans , short-term low-dose cannabis consumption does not seem to have adverse effects on cognition and can aid in pain management. THC can be also used to help counteract weight loss in HIV/AIDS patients and to alleviate nausea for patients undergoing chemotherapy. Synthetic cannabinoids are those created in a laboratory and fall under the drug classification ‘New Psychoactive Drugs’. Examples include WIN 55,212-2 and CP- 55,940 – which are compounds that can be used in the street drug termed ‘spice’.
Some forms of spice are created by spraying synthetic cannabinoids onto shredded plant material, with users smoking the resulting combination like a joint. However, it has more intense psychoactive and physiological effects than THC. Synthetic cannabinoids were initially created for pharmaceutical research and were not intended for human consumption. However, because synthetic cannabinoids have similar physiological effects as THC and were not federally illegal, they have been sold in US and European street drug markets since the early 2000s. Further, these synthetic cannabinoids are not typically tested for during routine drug screens and often remain undetected when law enforcement or hospitalization is involved. Synthetic cannabinoids induce many more intense effects than merely altering one’s mood and perceptions, such as tachycardia, psychosis, hallucinations, respiratory distress, and in some cases, death. In 2012, 26 different formulations of spice were banned with the Synthetic Drug Abuse Prevention Act in the US, classifying them as Schedule I drugs. Nevertheless, as different versions of these synthetic compounds become illegal, new modified versions created by underground chemists consistently reappear in the market. They have not yet been classified as illegal, but still can be quite harmful. Drug co-use is also of concern, given the potential synergistic effects on the user. For instance, a study in youth aged 12-17 found that those who used cannabis were more likely to use nicotine products at the same time, or initiate nicotine consumption within one year. Daily cannabis use has also been associated with co-use of opiates, cocaine, and/or inhalants, and approximately half of young cannabis users report simultaneously consuming alcohol and cannabis. Moreover, young adults co-using tobacco and cannabis were more likely to use nicotine ENDS, cocaine, and greater amounts of cannabis than those that just consumed cannabis alone. In older adults, using cannabis is associated with an increased likelihood of being diagnosed with a substance use disorder for either nicotine, alcohol, or cannabis.
Thus, the drug co-use condition represents a significant health concern among various age groups. When inhaled, nicotine readily enters the bloodstream through the alveoli in the lungs and becomes absorbed into the brain within seconds. Nicotine selectively binds to nicotinic acetylcholine receptors , which are pentameric ligand-gated ion channels located on either the presynaptic or postsynaptic membrane. The nAChR subtype may be heteromeric or homomeric, containing a combination of a and b subunits or containing all the same subunit, respectively. The a subunits present in nine different types, a2 – a10; whereas the b subunits present in three different types, b2 – b4. Various combinations of these subunits result in diverse effects on the pharmacokinetics of the receptor with ligand binding. The a7, a4 and b2 subunits are the most prevalent in the central nervous system. The homomeric a7 nAChR has a relatively lower affinity for nicotine and is important for modulating inflammation. The a4 and b2 subunits combine to form a functional heteromeric receptor with a high affinity for nicotine; the a4b2 nAChR is involved in mediating nicotine’s reinforcing and rewarding properties through receptor localization in the mesolimbic circuit. Further, receptors containing the a5, a3 and b4 subunits have been shown to modulate aversive signaling that limits nicotine intake and aspects of the withdrawal syndrome via receptor localization in the habenulo-interpeduncular circuit. Like nicotine, when cannabis smoke is inhaled, active phytocannabinoids pass from the lungs into the bloodstream and are carried throughout the brain and body. THC acts on the cannabinoid 1 receptor and cannabinoid 2 receptor. In the brain, CB1Rs are mainly localized in neurons and astrocytes, whereas CB2Rs are primarily found on immune cells. In humans and rodents, CB1Rs are highly expressed on neurons in the neocortex, hippocampus, amygdala, cerebellum, and basal ganglia. Since endogenous cannabinoids engage in retrograde signaling from the cell body to the presynaptic axon terminal, activation of CB1Rs results in inhibition of presynaptic neurotransmitter release. CB1Rs are also located on postsynaptic membranes and astrocytes. Of note, THC is a partial agonist of the CB1Rs and CB2Rs, whereas synthetic cannabinoids are typically full agonists. Cannabinoids can also act on other receptors, including GPR55 and TRPV1, although the functional role of these receptors is lesser known. When individuals co-use nicotine and cannabinoids, one would expect activity at both the nAChRs and CB1Rs. Both of these receptor types exhibit overlapping expression patterns in drug addiction-associated brain regions, such as the prefrontal cortex, nucleus accumbens ,drying weed ventral tegmental area , and amygdala. In particular, the mesolimbic dopamine pathway, a circuit from the VTA to the NAc, controls reward processing and the reinforcement of natural rewards and most drugs of abuse. Mechanistically, as nicotine and cannabinoids bind to nAChRs and CB1Rs in the VTA, they increase the firing rate of dopamine neurons and trigger the release of dopamine to the NAc which subsequently reinforces the drug-taking behavior. Nicotine acts on the a4b2-containing nAChRs to mediate dopamine signaling via their locations on both dopaminergic and GABAergic neurons in the VTA and neuron terminals in the NAc . Due to a lack of CB1R expression on VTA dopamine neurons, cannabinoids likely act on this circuit indirectly. Through retrograde mechanisms, cannabinoid binding to presynaptic CB1Rs expressed on GABAergic presynaptic terminals decrease GABAergic inhibition, thereby increasing dopamine release in the NAc.
In addition, it is important to acknowledge the involvement of other neurotransmitters, such acetylcholine, glutamate, and serotonin in consideration of the intricate complexity of the projections among brain regions. Thus, nicotinic and cannabinoid signaling within reward-related brain regions may lead to interactions among signaling mechanisms that modulate various aspects of drug-taking behaviors.Approximately 20-30% of people who experiment with cigarettes will meet criteria for nicotine use disorder during their lifetime. Around 30% of cannabis users are anticipated to develop some degree of cannabis use disorder. Individuals who begin using cannabis prior to 18 years of age have a four to seven times increased likelihood of developing the use disorder. Moreover, as noted above, the co-use of both substances is quite frequent. Around 60% of cigarette smokers reported ever using cannabis, and 90% of cannabis users reported ever smoking cigarettes in their lifetime. While individual drug use has its own potential to develop into a substance use disorder, co-users of both substances are at an increased risk of developing both nicotine dependence and cannabis dependence. This increased risk is of further concern because adults with cooccurring cannabis use disorder and nicotine dependence are more likely to have bipolar, anxiety, and personality disorders than those with only nicotine dependence. Among youth and young adults, the concern of these co-occurring substance use disorders is also prevalent. Teens who vape nicotine or smoke hookah are four times more likely to start smoking cannabis within two years, and current adolescent tobacco smokers who frequently use cannabis are more likely to report nicotine dependence. Likewise, adolescents who use cannabis are more likely to become daily cigarette smokers and develop nicotine dependence. Additionally, a longitudinal study looking at the trajectories of nicotine and cannabis vaping from adolescence into early adulthood revealed that those who frequently vape were also very likely to be users of both substances. Adolescent and young adult cannabis and tobacco cigarette co-users exhibit increased cannabis use disorder symptoms including continued use despite negative consequences, developing a tolerance, and inability to reduce cannabis use, in comparison to those who only use cannabis. Moreover, young adults who co-use cannabis and nicotine together report consuming more cannabis and nicotine in the past year than those who only use one of the drugs. In sum, across age ranges, nicotine and cannabis co-use conditions increase the risk of individual drug use and the development of substance use disorders. Furthermore, sex differences have emerged with the prevalence and patterns of substance use disorders in the population. Adult men are more likely to initiate drug use, but adult women develop substance use disorders more rapidly. Interestingly, during adolescence, drug use is initiated at similar rates between sexes, but boys appear to escalate their drug use faster than girls. According to a recent report, men are more likely to smoke cigarettes, vape nicotine, use smokeless tobacco, and be daily cannabis users. Women with a history of cannabis use are four times more likely to become regular cigarette smokers and almost three times as likely to develop nicotine dependence. However, women report experiencing more intense nicotine withdrawal symptoms.While the above findings suggest an important role of age or sex in nicotine and cannabis co-use, many individual, societal, and familial factors also influence drug taking behaviors in humans, and as such, animal models are important to delineate the precise effects of such factors on drug taking behaviors. Findings from rodent models have established that cannabinoids and nicotine exert unique effects on drug-related behaviors based on the duration and timing of exposure, in addition to the animal’s sex. Interestingly, adolescent male and female rats will self administer greater amounts of nicotine than adults, and nicotine exposure during adolescence can lead to increased self-administration of other drugs of abuse, including alcohol, methamphetamine, and cocaine. Drug exposure during adolescence can also induce long-lasting effects on the animal into adulthood. Adolescent male rats exposed to THC were found to self-administer higher levels of the synthetic cannabinoid WIN or heroin in adulthood.