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Brain Sciences 2018, 8(3), 43; doi:10.3390/brainsci8030043

Review
Mood Fluctuation and Psychobiological Instability: The Same Core Functions Are Disrupted by Novel Psychoactive Substances and Established Recreational Drugs
Andrew C. Parrott 1,2
1
Department of Psychology, Swansea University, Swansea SA2 8PP, South Wales, UK; Tel.: +44-(0)-1792-295271
2
Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC 3122, Australia
Received: 30 January 2018 / Accepted: 6 March 2018 / Published: 13 March 2018

Abstract

:
Many novel psychoactive substances (NPS) have entered the recreational drug scene in recent years, yet the problems they cause are similar to those found with established drugs. This article will debate the psychobiological effects of these newer and more traditional substances. It will show how they disrupt the same core psychobiological functions, so damaging well-being in similar ways. Every psychoactive drug causes mood states to fluctuate. Users feel better on-drug, then feel worse off-drug. The strength of these mood fluctuations is closely related to their addiction potential. Cyclical changes can occur with many other core psychobiological functions, such as information processing and psychomotor speed. Hence the list of drug-related impairments can include: homeostatic imbalance, HPA axis disruption, increased stress, altered sleep patterns, neurohormonal changes, modified brain rhythms, neurocognitive impairments, and greater psychiatric vulnerability. Similar patterns of deficit are found with older drugs such as cocaine, nicotine and cannabis, and newer substances such as 3,4-methylenedioxymethamphetamine (MDMA), mephedrone and spice. All psychoactive drugs damage human well-being through similar basic neuropsychobiological mechanisms.
Keywords:
amphetamine; cocaine; mephedrone; cannabis; spice; drug; mood; homeostasis

1. Mood State Fluctuations

Psychoactive drugs, by definition, cause mood states to change and fluctuate. Hence an important factor for drug-induced distress is mood instability. This is found with sedative drugs such as alcohol or cannabis, and stimulant drugs such as cocaine or methamphetamine [1,2,3,4,5,6]. Indeed, the main reason that psychoactive drugs are used recreationally is for their “positive” mood effects, such as feelings of relaxation and pleasure [4]. Novel psychoactive substances (NPS) such as mephedrone and spice cannabinoids are very similar in this regard [6,7,8,9]. Although one of the paradoxes of drug taking is that many of the apparent mood gains represent the reversal of unpleasant abstinence feelings. Nicotine is a prime example of this pattern [10,11,12], although it also occurs with other substances [4].
Psychoactive drugs can also produce undesirable mood state changes. For instance, recreational cannabis, whether herbal or spice, can lead to feelings of tension and suspiciousness [2,13]. Stimulants such as cocaine, methamphetamine and mephedrone can also lead to feelings of anxiety and paranoia [1,14,15]. The acute mood effects of all psychoactive drugs can be highly variable and may differ considerably between individuals. On alcohol some users become happy and jovial, while others become moody and aggressive, especially after excess levels of consumption [5,16,17]. In a similar way, Le Strat et al. [18] documented a wide range of responses to an acute dose of cannabis. Furthermore, those with positive initial mood reactions were most likely to become regular cannabis users, whereas those with negative or neutral mood reactions to cannabis tended not to persevere with its usage. Similar differences in mood response have also been empirically demonstrated with the methamphetamine derivative MDMA (3,4-methylenedioxymethamphetamine or “Ecstasy”). This drug is often described as the most euphoriant of all the recreational stimulants. Yet acute MDMA can release a wide range of feelings and cognitions-both positive and negative. Liechti et al. [19] found that an acute dose of MDMA in the laboratory led to significant increases in feelings of both introversion and extraversion, while feelings of happiness and depression were also significantly intensified. In a comprehensive review of the acute-dose MDMA mood literature, it was found that a wide range of positive and negative psychological material could be released/intensified [20]. For instance, psychotherapists who have incorporated MDMA into their therapy sessions have noted that the emergent psychological material can be difficult and stressful for the client to handle, although its release may also be important for potential therapeutic gains [20,21,22,23,24]. In positive environmental situations, the positive mood effects of MDMA predominate, whereas in neutral situations its mood effects can be more variable and less positive [14,15]. These adverse mood abreactions to MDMA can be more frequent than is commonly portrayed. In an article entitled: “Hug drug or thug drug”, Reid et al. [25] noted that MDMA often generated feelings of anger and aggression. Rugani et al. [26] noted that acute psychotic patients who had used MDMA for recreational purposes demonstrated heightened levels of hostility, physical violence, and verbal aggression than non-users. The authors noted that this finding “surely runs counter to the expected entactogenic effects of Ecstasy” (for further debate, see [27]).
In a large Internet study of mephedrone and MDMA users, the acute mood effects of each drug were broadly similar, although some intriguing differences in pharmacodynamic tolerance were apparent [9]. A mixture of positive and negative mood changes is also found with established recreational stimulants such as cocaine [28], and laboratory doses of methamphetamine [14,15]. The effects of high doses of amphetamine and cocaine can be very strong, with reports of a physical rush or hit. These high doses can lead to intensely negative moods, with very severe feelings of suspiciousness, or clinical paranoia. Spice cannabinoids can also have far stronger effects that herbal cannabis, in both positive and negative ways [29]. The more extreme mood reactions of the more powerful drugs can lead to changeable and unpredictable patterns of behavior. However, these abreactions can occur with any psychoactive drug, irrespective of whether they are established or novel.

1.1. Drug Withdrawal and Repetitive Mood Vacillation

One of the main problems with every psychoactive drug is that the brief period of on-drug mood gains is followed by a period of neurochemical depletion afterwards, when the opposite mood states develop. These rebound moods are typically negative and aversive, and are readily reversed by taking the drug again. Hence every mood-altering drug has addiction potential. Indeed, the essence of addiction is these repetitive mood vacillations [4,30]. This pattern can be illustrated by legal stimulants such as nicotine, illicit drugs such as cocaine, or novel substances such as MDMA or mephedrone. The former two drugs have been extensively studied, with nicotine showing many pharmacokinetic and pharmacodynamic similarities to cocaine [31]. Both drugs are powerful Central Nervous System (CNS) stimulants, with the first cigarette of the day increasing heart rate substantially [32,33], which is one of the reasons tobacco smokers develop hypertension. In mood terms, tobacco smokers feel more alert after the first cigarette of the day, but soon this activation is lost, and after 20–60 min the regular smoker needs yet another cigarette. This mood fluctuation repeats over the rest of the day and recurs every day for the rest of their lives—until they quit or prematurely die [10,11,34].
Similar patterns of mood fluctuation occur with cocaine, since nasal snorting leads to a rapid hit, followed by a low-mood comedown, and the urgent need for another drug hit. Cocaine therefore displays high addiction potential, with crack cocaine being even more troublesome and addictive, due its extreme rapidity of action [4,35,36]. Khat leaf chewing occurs in many countries around the Horn of Africa [37,38], with cathinone being slowly released into the systemic circulation. Cathinone displays weaker stimulant properties than cocaine. Yet Khat chewers also report acute mood gains, followed by negative moods on withdrawal, in a pattern identical to that found with other stimulants [37]. This is also evident with MDMA, although over a longer time period. Hence the acute moods peak after a couple of hours, while the recovery period can last for several days [28,39,40,41,42]. This long pharmacodynamic profile explains why Ecstasy/MDMA is only taken intermittently and displays lower addiction potential than most other stimulants [43,44].
Cannabis may be a sedative drug, but it shows a similar pattern of mood vacillation to the stimulant drug nicotine. Vandrey et al. [45] compared the mood changes found during withdrawal from cannabis and tobacco, and concluded that they were very similar. For instance, the unpleasant mood effects of cannabis withdrawal could include feelings of irritability, anger, and depression (i.e., very similar to tobacco), along with other problems such as impaired sleep, altered circadian rhythms, changed appetite, and drug cravings [45,46]. These symptoms of cannabis withdrawal have been formalized in standardized questionnaires such as the Cannabis Withdrawal Discomfort Scale [47], and the Marijuana Craving Questionnaire [48]. The high addictiveness of cannabis does make it difficult to understand current movements to make its usage legal [49].

1.2. Related Psychobiological Problems

Many other psychological skills and abilities may also fluctuate during drug stimulation and drug withdrawal. For instance, tobacco smokers display worse memories than non-smokers [50]. The reason for this is that new information is being laid down in memory and is being stored under a constantly changing background of nicotine levels. Hence memory storage and retrieval are both adversely affected by nicotine addiction [12]. Sleep is also adversely affected by nicotine addiction, while it improves to normal following smoking cessation [12]. The many psychobiological problems found in recreational stimulant users have been described in numerous comprehensive reviews [1,3,36,51,52].
Similarly, the addictiveness of herbal cannabis was noted earlier, while the stronger skunk varieties of herbal cannabis display greater potential [53]. Artificial spice cannabinoids are even stronger, and hence more damaging. Some of the artificial spices are full agonists for the cannabinoid receptor, whereas herbal cannabis is a weak partial agonist [54]. Hence spice displays far greater addictiveness, with some users committing suicide when they cannot access their normal drug supplies [6,29,55,56,57,58]. The practical consequences of cannabis dependency can be severe [49]. In the USA around 300,000 individuals approach professional drug addiction services for cannabis dependency every year [59]. Clinically disabling dependency occurs in around 10% of those who have ever tried the drug [60], while 65% of cannabis ever-users report some aspects of drug dependency [61], with young initiates the most vulnerable [62]. In summary, the core problems related to drug dependency are similar for stimulants and depressant drugs, and for older and newer psychoactive substances.

2. Homeostasis

One fundamental index of psychological balance and health is homeostasis. When the organism is well adapted to its environment, its daily rhythms of behavioral and physiological activity occur smoothly and efficiently. Selye [63] noted that disruption to homeostasis led to psychological imbalance, increased bio-physiological stress, and led to excessive energy expenditure. Furthermore, the repeated experience of acute stress led to cumulative chronic stress and this caused physical and psychological ill-health. Selye [63] showed that the Hypothalamic-Pituitary-Adrenal (HPA) axis was crucial for psychophysiological stability, with cortisol being the key neurohormone for maintaining homeostatic balance [64]. Healthy individuals showed regular circadian rhythms of cortisol secretion, and this master hormone helped to maintain the optimal secretion patterns for other important neurohormones [63,65,66].
Many psychoactive drugs affect neurohormonal secretions acutely, and when these drugs are taken repeatedly, they can lead to chronic stress. This may be illustrated with the recreational stimulant MDMA [65,66]. In placebo-controlled laboratory trials, an acute dose of MDMA can generate a cortisol increase of around 150% [67]. Recreational Ecstasy/MDMA users show peak cortisol increases of around 800%, probably due to the combined effects of taking a stimulant drug in a stimulating environment [42,68]. The Cortisol Awakening Response can also be affected in recreational Ecstasy/MDMA users [69], with around 70% of recreational users complaining of disrupted sleep, even when drug-free [70]. Body temperatures can also change, with MDMA showing well-documented patterns of thermal change [71,72,73]. Synthetic cannabinoids such as AKB48 can induce hypothermia [74], while synthetic cathinones such as mephedrone can also affect thermal reactivity [75]. Returning to chronic stress, regular MDMA users show strong longer-term neurohormonal changes. When cortisol was measured in 3-month hair samples, the regular Ecstasy/MDMA users displayed 400% higher cortisol levels than non-user controls, while the light Ecstasy/MDMA users showed intermediate cortisol values [76]. MDMA is not the only recreational drug which can affect cortisol. Raganathan et al. [77] showed that acute tetrahydrocannabinol (THC) led to a significant increase in cortisol secretion. King et al. [78] found that chronic cannabis users had significantly higher salivary cortisol levels than non-user controls. Currently there is a paucity of empirical evidence on the neurohormonal effects of Novel Psychoactive Substances, and empirical studies in this area are therefore needed.

Psychiatric Aspects

All psychiatric disorders are dimensional, with symptoms ranging on a continuum from low to high. This core notion may seem rather obvious, but it needs to be stated since it can help explain how psychoactive drugs contribute to mental distress. The core processes described earlier, of mood state vacillation and homeostatic imbalance, can each contribute to mental instability, while those individuals with a predisposition to mental distress may be particularly vulnerable to the destabilizing effects of psychoactive drugs. For an example of this interactive psychiatric model applied to recreational MDMA, see Parrott [79].
The first written report of psychiatric problems being caused by any psychoactive drug were present in the world’s oldest pharmacopoeia, attributed to Emperor Shen Nung in bronze-age China. This noted that when cannabis was taken in excess, it could produce “visions of devils” [80]. Modern research has confirmed that cannabis may cause a form of psychosis, with many similarities to classic schizophrenia [13]. Hence an acute dose of cannabis can induce bizarre thoughts and cognitions [81]. D’Souza and colleagues [82] administered THC and placebo to recreational cannabis users without any prior psychiatric history. The active cannabis condition led to significant increases in scores on the Positive and Negative Symptom Scale (PANSS), the standard rating scale for clinical symptoms of schizophrenia. Individual subjective experiences under the acute influence of THC included the following: “I thought I could see into the future” … “I thought you were trying to program me” … “I thought you could read my mind” … “I thought I was god”. These delusional thoughts as measured by raised PANSS positive symptom scores, can also correlate with changed patterns of brain activity [83].
When used regularly, cannabis can lead to both clinical psychosis, and other forms of psychiatric disorder [84]. The Swedish Conscript study was the first prospective investigation to demonstrate an association between cannabis and schizophrenia [85]. This finding has been replicated in further prospective studies, where regular cannabis use led to an increased risk of psychotic breakdown in later years. Le Bec et al. [86] undertook a comprehensive review and concluded that every published study showed a significant link between recreational cannabis and the later emergence of psychosis. One crucial factor is that the drug needs to be taken repeatedly and regularly. In one prospective study, Henquet et al. [87] found that occasional cannabis users showed no increase in risk, weekly-users showed a slightly increased risk, while daily-cannabis users showed a highly significant increase in later psychosis. Regular cannabis use is also associated with an increased risk for other mental health problems, such as depression and mania [88,89].
Recreational CNS stimulants can also cause greater psychiatric distress. Feyissa and Kelly [90] noted that Khat chewing could lead to a range of mental health problems including depression and hypomania; hence even weaker drugs such as cathinone can lead to psychiatric problems, while regular users of stronger stimulants such as amphetamine, cocaine or methamphetamine can experience a wide range of problems, including psychosis, depression, paranoia, psychomotor tics/tremors, eating disorders, and aggression [1,3,4,35,51,91]. Recreational MDMA is also associated with a wide range of adverse psychiatric consequences, such as clinical depression, aggression, problems with weight control, eating/food intake, and some of these issues may endure for years after drug cessation [26,76,92,93,94,95,96,97,98,99].

3. Neurocognitive Deficits

Cognitive skills are an important focus for most areas of applied psychology, and psychopharmacology is no exception. The extensive empirical literature demonstrates both acute and chronic drug influences. By definition, any drug which is psychoactive will affect not only mood states (see Section 1), but many other psychological functions including neurocognition. CNS stimulants such as cocaine or mephedrone will speed information processing, but also increase errors through increased carelessness and impulsivity. CNS depressants will generally lengthen reaction times but may increase errors through reduced alertness and vigilance/attention. When combined with drug-induced feelings of confidence, these changes can make any psychoactive drug dangerous for practical skills such as car driving [4,55,100]. Their chronic use can also be damaging. In an extensive review, Cruickshank and Dyer [1] noted that methamphetamine led to impairments in executive functioning, learning, memory, and motor skills. Other reviews have generated similar lists of neurocognitive impairments following other stimulants such as cocaine [52,101], or Ecstasy/MDMA [27,44,102,103,104,105,106,107,108]. Cannabis can lead to acute deficits in memory, learning, sustained attention, and higher cognitive skills, while its chronic use can lead to a wide range of cognitive deficits, even including a decline in general intelligence, with reduced IQ test scores [109,110,111,112,113,114]. Neuroimaging studies of regular cannabis users indicate deficits in various brain regions, such as the hippocampus and amygdala [114], with white matter degeneration and de-myelination [115].

4. Final Overview

Psychoactive drugs can damage human well-being simply by being psychoactive! In acute terms they may boost activity for a short period, but this is soon followed by a period of neurochemical recovery, when the opposite psychological states develop. These psychological fluctuations are readily seen in mood state changes of daily tobacco smokers (see Figure 1 in Parrott, [10]). However, moods and feelings provide just one index for other more general changes in psychological status. Many different psychological functions can be affected—in different ways by different drugs. They also affect many different neurotransmitter systems. Yet despite the multitude and variety of their neurotransmitter actions, in psychobiological terms these drugs all display the same underlying pattern of disrupted balance and equilibrium [4,11,30,38]. These core biological factors also explain why every psychoactive drug displays addiction potential. Regular users suffer from negative states off-drug, and feel better when on-drug, hence the “need” to take the drug repeatedly [10]. As novice users, the more they succumb to their new habit, the stronger their drug dependency becomes.
Psychoactive drugs also affect the HPA axis, causing hormonal dysregulation, and increasing the susceptibility for stress [4,66]. The healthy human organism displays a natural balance between sympathetic and parasympathetic nervous system activity. So, when humans take recreational drugs, they disturb this natural balance, and this leads to adverse consequences [4]. Proponents for drug use typically only talk about the short-term drug gains, and with this narrow focus, any psychoactive drug can be miss-described as beneficial. It is only by covering all aspects of their acute and chronic usage that a more complete picture of their damaging effects can emerge.

Conflicts of Interest

The author declares no conflicts of interest.

References

  1. Cruickshank, C.C.; Dyer, K.R. A review of the clinical pharmacology of methamphetamine. Addiction 2009, 104, 1085–1099. [Google Scholar] [CrossRef] [PubMed]
  2. Hall, W. What has research over the past two decades revealed about the adverse health effects of recreational cannabis use? Addiction 2015, 110, 19–35. [Google Scholar] [CrossRef] [PubMed]
  3. Panenka, W.K.; Procyshyn, R.M.; Lecomte, T.; MacEwan, G.W.; Flynn, S.W.; Honer, W.G.; Barr, A.M. Methamphetamine use: A comprehensive review of molecular, preclinical and clinical findings. Drug Alcohol Depend. 2013, 129, 167–179. [Google Scholar] [CrossRef] [PubMed]
  4. Parrott, A.C. Why all stimulant drugs are damaging to recreational users: An empirical overview and psychobiological explanation. Hum. Psychopharmacol. 2015, 30, 213–224. [Google Scholar] [CrossRef] [PubMed]
  5. Parrott, A.; Morinan, A.; Moss, M.; Scholey, A. Understanding Drugs and Behaviour; John Wiley & Sons: Chichester, UK, 2004. [Google Scholar]
  6. Schifano, F.; Albanese, A.; Fergus, S.; Stair, J.L.; Deluca, P.; Corraza, O. Mephedrone (4-methylmethcathinone; ‘meow meow’): Chemical, pharmacological and clinical issues. Psychopharmacology 2011, 214, 593–602. [Google Scholar] [CrossRef] [PubMed]
  7. Freeman, T.P.; Morgan, C.J.A.; Vaughn-Jones, J.; Hussain, N.; Karimi, K.; Curran, V.H. Cognitive and subjective effects of mephedrone and factors influencing use of a new ‘legal high’. Addiction 2011, 107, 792–800. [Google Scholar] [CrossRef] [PubMed]
  8. Gurney, S.M.; Scott, K.S.; Kacinko, S.L.; Presley, B.C.; Logan, B.K. Pharmacology, Toxicology, and Adverse Effects of Synthetic Cannabinoid Drugs. Forensic. Sci. Rev. 2014, 26, 53–78. [Google Scholar] [PubMed]
  9. Jones, L.; Reed, P.; Parrott, A.C. Mephedrone and MDMA: A comparison of their acute and chronic effects, as described by young recreational polydrug users. J. Psychopharmacol. 2016, in press. [Google Scholar]
  10. Parrott, A.C. Individual differences in stress and arousal during cigarette smoking. Psychopharmacology 1994, 115, 389–396. [Google Scholar] [CrossRef] [PubMed]
  11. Parrott, A.C. Does cigarette smoking cause stress? Am. Psychol. 1999, 54, 817–820. [Google Scholar] [CrossRef] [PubMed]
  12. Parrott, A.C. Nicotine psychobiology: How chronic-dose prospective studies can illuminate some of the theoretical issues from acute-dose research. Psychopharmacology 2006, 184, 567–576. [Google Scholar] [CrossRef] [PubMed]
  13. Volkow, N.D.; Baler, R.D.; Compton, W.M.; Weiss, S.R.B. Adverse Health Effects of Marijuana Use. N. Engl. J. Med. 2014, 370, 2219–2227. [Google Scholar] [CrossRef] [PubMed]
  14. Kirkpatrick, M.G.; Gunderson, E.W.; Perez, A.Y.; Haney, M.; Foltin, R.W.; Hart, C.L. A direct comparison of the behavioral and physiological effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 2012, 219, 109–122. [Google Scholar] [CrossRef] [PubMed]
  15. Parrott, A.C.; Gibbs, A.; Scholey, A.B.; King, R.; Owens, K.; Swann, P.; Ogden, E.; Stough, C. MDMA and methamphetamine: Some paradoxical negative and positive mood changes in an acute dose laboratory study. Psychopharmacology 2011, 215, 527–536. [Google Scholar] [CrossRef] [PubMed]
  16. Murgraff, V.; Parrott, A.C.; Bennett, P. Risky single occasion drinking amongst young people: Definition, correlates, policy and intervention. A broad overview of research findings. Alcohol Alcohol. 1998, 33, 3–14. [Google Scholar] [CrossRef]
  17. Parrott, A.C.; Drayson, R.; Henry, L.A. Alcohol: Drink less and live more. J. Alcohol Drug Depend. Subst. Abuse 2016, 2, 4. [Google Scholar]
  18. Le Strat, Y.; Ramoz, N.; Horwood, J.; Falissard, B.; Hassler, C.; Romo, L.; Gorwood, P. First positive reactions to cannabis constitute a priority risk factor for cannabis dependence. Addiction 2009, 104, 1710–1717. [Google Scholar] [CrossRef] [PubMed]
  19. Liechti, M.E.; Gamma, A.; Vollenweider, F.X. Gender differences in the subjective effects of MDMA. Psychopharmacology 2001, 154, 161–168. [Google Scholar] [CrossRef] [PubMed]
  20. Parrott, A.C. The psychotherapeutic potential of MDMA (3,4-methylenedioxymethamphetamine): An evidence-based review. Psychopharmacology 2007, 191, 181–193. [Google Scholar] [CrossRef] [PubMed]
  21. Bouso, J.C. Using MDMA in the treatment of post-traumatic stress disorder. In Ecstasy: The Complete Guide; Holland, J., Ed.; Park Street Press: Rochester, NY, USA, 2001. [Google Scholar]
  22. Greer, G.; Tolbert, R. Subjective reports of the effects of MDMA in a clinical setting. J. Psychoact. Drugs 1986, 18, 319–327. [Google Scholar] [CrossRef] [PubMed]
  23. Parrott, A.C. MDMA assisted psychotherapy—A psychobiological perspective and critique. In International Handbook of Psychobiology; Murphy, P., Ed.; Routledge: Abingdon-on-Thames, UK, 2018. [Google Scholar]
  24. Parrott, A.C. The potential dangers of using MDMA for psychotherapy. J. Psychoactive Drugs 2014, 46, 37–43. [Google Scholar] [CrossRef] [PubMed]
  25. Reid, L.W.; Elifson, K.W.; Sterk, C.E. Hug drug or thug drug? Ecstasy use and aggressive behavior. Violence Vict. 2007, 22, 104–119. [Google Scholar] [CrossRef] [PubMed]
  26. Rugani, F.; Bacciardi, S.; Rovai, L.; Pacini, M.; Maremmani, A.G.I.; Deltito, J.; Dell’Osso, L.; Maremmani, I. Symptomatological features of patients with and without ecstasy use during their first psychotic episode. Int. J. Environ. Res. Pub. Health 2012, 9, 2283–2292. [Google Scholar] [CrossRef] [PubMed]
  27. Parrott, A.C. Human psychobiology of MDMA or ‘Ecstasy’: An overview of 25 years of empirical research. Hum. Psychopharmacol. 2013, 28, 289–307. [Google Scholar] [CrossRef] [PubMed]
  28. Parrott, A.C.; Evans, L.J.; Howells, J.; Robart, R. Cocaine versus Ecstasy/MDMA: Comparative effects on mood and cognition in recreational users. Open Addict. J. 2011, 4, 36–37. [Google Scholar] [CrossRef]
  29. Seely, K.A.; Lapoint, J.; Moran, J.H.; Fattore, L. Spice drugs are more than harmless herbal blends: A review of the pharmacology and toxicology of synthetic cannabinoids. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2012, 39, 234–243. [Google Scholar] [CrossRef] [PubMed]
  30. Parrott, A.C. Drug taking–for better or for worse? Psychologist 2008, 21, 924–927. [Google Scholar]
  31. Mello, N.K. Hormones, nicotine, and cocaine: Clinical studies. Hormones Behav. 2010, 58, 57–71. [Google Scholar] [CrossRef] [PubMed]
  32. Mangan, G.L.; Golding, J.F. The Psychopharmacology of Smoking; Oxford University Press: Oxford, UK, 1986. [Google Scholar]
  33. Parrott, A.C.; Winder, G. Nicotine chewing gum (2 mg, 4 mg) and cigarette smoking: Comparative effects upon vigilance and heart rate. Psychopharmacology 1989, 97, 257–261. [Google Scholar] [CrossRef] [PubMed]
  34. Parrott, A.C. Nesbitt’s Paradox resolved? Stress and arousal modulation during cigarette smoking. Addiction 1998, 93, 27–39. [Google Scholar] [CrossRef] [PubMed]
  35. Cadet, J.L.; Krasnova, I.; Jayanthi, S.; Lyles, J. Neurotoxicity of substituted amphetamines: Molecular and cellular mechanisms. Neurotox. Res. 2007, 11, 183–202. [Google Scholar] [CrossRef] [PubMed]
  36. Carvalho, M.; Carmo, H.; Costa, V.M.; Capela, J.P.; Pontes, H.; Remiao, F. Toxicology of amphetamines: An update. Arch. Toxicol. 2013, 86, 1167–1231. [Google Scholar] [CrossRef] [PubMed]
  37. Aden, A.; Dimba, E.A.; Neola, U.M.; Chindia, M.L. Socio-economic effects of khat chewing in north eastern Kenya. East Afr. Med. J. 2006, 83, 69–73. [Google Scholar] [PubMed]
  38. Parrott, A.C. Drug related harm: A complex and difficult concept to scale. Hum. Psychopharmacol. 2007, 22, 423–425. [Google Scholar] [CrossRef] [PubMed]
  39. Curran, H.V.; Travill, R.A. Mood and cognitive effects of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”): Weekend “high” followed by mid-week “low”. Addiction 1997, 92, 821–831. [Google Scholar] [PubMed]
  40. Curran, H.V.; Rees, H.; Hoare, T.; Hoshi, R.; Bond, A. Empathy and aggression: Two faces of ecstasy? A study of interpretive cognitive bias and mood change in ecstasy users. Psychopharmacology 2004, 173, 425–433. [Google Scholar] [CrossRef] [PubMed]
  41. Parrott, A.C.; Lasky, J. Ecstasy (MDMA) effects upon mood and cognition; before, during, and after a Saturday night dance. Psychopharmacology 1998, 139, 261–268. [Google Scholar] [CrossRef] [PubMed]
  42. Parrott, A.C.; Lock, J.; Conner, A.C.; Kissling, C.; Thome, J. Dance clubbing on MDMA and during abstinence from Ecstasy/MDMA: Prospective neuroendocrine and psychobiological changes. Neuropsychobiology 2008, 57, 165–180. [Google Scholar] [CrossRef] [PubMed]
  43. Parrott, A.C. Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy. J. Psychopharmacol. 2005, 19, 71–83. [Google Scholar] [CrossRef] [PubMed]
  44. Parrott, A.C. MDMA, serotonergic neurotoxicity, and the diverse functional deficits of recreational ‘Ecstasy’ users. Neurosci. Biobehav. Rev. 2013, 37, 1466–1484. [Google Scholar] [CrossRef] [PubMed]
  45. Vandrey, R.G.; Budney, A.J.; Moore, B.A.; Hughes, J.R. A cross-study comparison of cannabis and tobacco withdrawal. Am. J. Addict. 2005, 14, 54–63. [Google Scholar] [CrossRef] [PubMed]
  46. Budney, A.J.; Hughes, J.R.; Moore, B.A.; Novy, P.L. Marijuana abstinence effects in marijuana smokers maintained in their home environment. Arch. Gen. Psychiatry 2001, 58, 917–924. [Google Scholar] [CrossRef] [PubMed]
  47. Budney, A.J.; Novy, P.L.; Hughes, J.R. Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction 1999, 94, 1311–1322. [Google Scholar] [CrossRef] [PubMed]
  48. Heishman, S.J.; Singleton, E.G.; Liguori, A. Marijuana Craving Questionnaire: Development and initial validation of a self-report instrument. Addiction 2001, 96, 1023–1034. [Google Scholar] [CrossRef] [PubMed]
  49. Parrott, A.C.; Hayley, A.; Downey, L. Recreational stimulants, herbal and spice cannabis: The core psychobiological processes that underlie their damaging effects. Hum. Psychopharmacol. 2017, 32, E2594. [Google Scholar] [CrossRef] [PubMed]
  50. Heffernan, T.M.; Ling, J.; Parrott, A.C.; Buchanan, T.; Scholey, A.B.; Rodgers, J. Self-rated everyday and prospective memory abilities of cigarette smokers and non-smokers: A web based study. Drug Alcohol Depend. 2005, 78, 235–241. [Google Scholar] [CrossRef] [PubMed]
  51. Glasner-Edwards, S.; Mooney, L.J. Methamphetamine psychosis: Epidemiology and management. CNS Drugs 2014, 28, 1115–1126. [Google Scholar] [CrossRef] [PubMed]
  52. Soar, K.; Mason, C.; Potton, A.; Dawkins, L. Neuropsychological effects associated with recreational cocaine use. Psychopharmacology 2012, 222, 633–643. [Google Scholar] [CrossRef] [PubMed]
  53. Copeland, J.; Clement, N.; Swift, W. Cannabis use, harms and the management of cannabis use disorder. Neuropsychiatry 2014, 4, 55–63. [Google Scholar] [CrossRef]
  54. De Luca, M.A.; Castelli, M.P.; Loi, B.; Porcu, A.; Martorelli, M.; Miliano, C.; Kellett, K.; Davidson, C.; Stair, J.L.; Schifano, F.; et al. Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135. Neuropharmacology 2015, 105, 630–638. [Google Scholar] [CrossRef] [PubMed]
  55. Downey, L.A.; Verster, J.C. Cannabis Concerns: Increased potency, availability and synthetic analogues. Curr. Drug Abuse Rev. 2014, 7, 67–68. [Google Scholar] [CrossRef] [PubMed]
  56. Papanti, D.; Schifano, F.; Botteon, G.; Bertossi, F.; Mannix, J.; Vidoni, D.; Bonavigo, T. “Spiceophrenia”: A systematic overview of “Spice”-related psychopathological issues and a case report. Hum. Psychopharmacol. 2013, 28, 379–389. [Google Scholar] [CrossRef] [PubMed]
  57. Schifano, F.; Orsolini, L.; Papanti, G.D.; Corkery, J. Novel psychoactive substances of interest for psychiatry. World Psychiatry 2015, 14, 15–26. [Google Scholar] [CrossRef] [PubMed]
  58. Zimmermann, U.S.; Winklemann, P.R.; Pilhatsch, M.; Nees, J.A.; Spanagel, R.; Schulz, K. Withdrawal phenomena and dependence syndrome after the cousumption of “spice gold”. Dtsch. Arztebl. Int. 2009, 106, 464–467. [Google Scholar] [PubMed]
  59. Herrmann, E.S.; Weerts, E.M.; Vandrey, R. Sex differences in cannabis withdrawal symptoms among treatment-seeking cannabis users. Exp. Clin. Psychopharmacol. 2015, 23, 415–421. [Google Scholar] [CrossRef] [PubMed]
  60. Wagner, F.A.; Anthony, J.C. From First Drug Use to Drug Dependence–Developmental Periods of Risk for Dependence upon Marijuana, Cocaine, and Alcohol. Neuropsychopharmacology 2002, 26, 479–488. [Google Scholar] [CrossRef]
  61. Terry, P.; Wright, K.A.; Cochrane, R. Factors contributing to changes in frequency of cannabis consumption by cannabis users in England: A structured interview study. Addict. Res. Theory 2007, 15, 113–119. [Google Scholar] [CrossRef]
  62. Silins, E.; Horwood, L.J.; Patton, G.C.; Fergusson, D.M.; Olsson, C.A.; Hutchinson, D.M.; Mattick, R.P. Young adult sequelae of adolescent cannabis use: An integrative analysis. Lancet Psychiatry 2014, 1, 286–293. [Google Scholar] [CrossRef]
  63. Selye, H. The Stress of Life; McGraw Hill: New York, NY, USA, 1956. [Google Scholar]
  64. Lovallo, W.R. Stress and Health: Biological and Psychological Interactions; Sage: Kern County, CA, USA, 1997. [Google Scholar]
  65. Parrott, A.C. Cortisol and MDMA (3,4-methylenedioxymethamphetamine): Neurohormonal aspects of bioenergetic-stress in Ecstasy users. Neuropsychobiology 2009, 60, 148–158. [Google Scholar] [CrossRef] [PubMed]
  66. Parrott, A.C. Oxytocin, cortisol and MDMA (3,4-methylenedioxymethamphetamine): Neurohormonal aspects of recreational ‘Ecstasy’. Behav. Pharmacol. 2016, 27, 649–658. [Google Scholar] [CrossRef] [PubMed]
  67. Harris, D.S.; Baggott, M.; Mendelson, J.H.; Mendelson, J.E.; Jones, R.T. Subjective and hormonal effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 2002, 162, 396–405. [Google Scholar] [CrossRef] [PubMed]
  68. Parrott, A.C.; Adnum, L.; Evans, A.; Kissling, C.; Thome, J. Heavy Ecstasy/MDMA use at cool house parties: Substantial cortisol release and increased body temperature. J. Psychopharmacol. 2007, 21, 35. [Google Scholar]
  69. Wetherell, M.A.; Montgomery, C. Basal functioning of the hypothalamic-pituitary-adrenal (HPA) axis and psychological distress in recreational ecstasy polydrug users. Psychopharmacology 2013, 231, 1365–1375. [Google Scholar] [CrossRef] [PubMed]
  70. Ogeil, R.P.; Rajaratnam, S.M.; Broadbear, J.H. Male and female ecstasy users: Differences in patterns of use, sleep quality and mental health outcomes. Drug Alcohol Depend. 2013, 132, 223–230. [Google Scholar] [CrossRef] [PubMed]
  71. Freedman, R.R.; Johanson, C.E.; Tancer, M.E. Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 2005, 183, 248–256. [Google Scholar] [CrossRef] [PubMed]
  72. Parrott, A.C. MDMA and temperature: A review of the thermal effects of ‘Ecstasy’ in humans. Drug Alcohol Depend. 2012, 121, 1–9. [Google Scholar] [CrossRef] [PubMed]
  73. Parrott, A.C.; Young, L. Saturday night fever in ecstasy/MDMA dance clubbers: Heightened body temperature and associated psychobiological changes. Temperature 2015, 3, 1–6. [Google Scholar] [CrossRef] [PubMed]
  74. Canazza, I.; Ossato, A.; Trapella, C.; Fantinati, A.; De Luca, M.A.; Margiani, G.; Vincenzi, F.; Rimondo, C.; Di Rosa, F.; Gregori, A. Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on “tetrad”, sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies. Psychopharmacology 2016, 233, 3685–3709. [Google Scholar] [CrossRef] [PubMed]
  75. Alsufyani, H.A. Cardiovascular and Temperature Actions of Cathinones. Ph.D. Thesis, Royal College of Surgeons in Ireland, Dublin, Ireland, 2017. [Google Scholar]
  76. Parrott, A.C.; Sands, H.R.; Jones, L.; Clow, A.; Evans, P.; Downey, L.; Stalder, T. Increased cortisol levels in hair of recent Ecstasy/MDMA users. Eur. Neuropsychopharmacol. 2014, 24, 369–374. [Google Scholar] [CrossRef] [PubMed]
  77. Ranganathan, M.; Braley, G.; Pittman, B.; Cooper, T.; Perry, E.; Krystal, J.; D’Souza, D.C. The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology 2009, 203, 737–744. [Google Scholar] [CrossRef] [PubMed]
  78. King, G.R.; Ernst, T.; Deng, W.; Stenger, A.; Gonzales, R.M.K.; Nakama, H.; Chang, L. Effects of chronic active cannabis use on visuomotor integration, in relation to brain activation and cortisol levels. J. Neurosci. 2011, 31, 17923–17931. [Google Scholar] [CrossRef] [PubMed]
  79. Parrott, A.C. MDMA in humans: Factors which affect the neuropsychobiological profiles of recreational ecstasy users, the integrative role of bio-energetic stress. J. Psychopharmacol. 2006, 20, 147–163. [Google Scholar] [CrossRef] [PubMed]
  80. Nung, S. The Divine Farmer’s Materia Medica Classic; Blue Poppy Press: Boulder, CO, USA, 1998. [Google Scholar]
  81. Ashton, C.H. Pharmacology and effects of cannabis: A brief review. Br. J. Psychiatry 2001, 178, 101–106. [Google Scholar] [CrossRef] [PubMed]
  82. D’Souza, D.C.; Perry, E.; MacDougall, L.; Ammerman, Y.; Cooper, T.; Yu-Te, W.; Krystal, J.H. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: Implications for psychosis. Neuropsychopharmacology 2004, 29, 1558–1572. [Google Scholar] [CrossRef] [PubMed]
  83. Nottage, J.; Stone, J.; Murray, R.; Sumich, A.; Bramon-Bosch, E.; Ffytche, D.; Morrison, P. Delta-9-tetrahydrocannabinol, neural oscillations above 20 Hz and induced acute psychosis. Psychopharmacology 2015, 232, 519–528. [Google Scholar] [CrossRef] [PubMed]
  84. Paparelli, A.; Di Forti, M.; Morrison, P.D.; Murray, R.M. Drug-induced psychosis: How to avoid star gazing in schizophrenia research by looking at more obvious sources of light. Front. Behav. Neurosci. 2011, 5. [Google Scholar] [CrossRef] [PubMed]
  85. Andréasson, S.; Engström, A.; Allebeck, P.; Rydberg, U. Cannabis and schizophrenia: A longitudinal study of Swedish conscripts. Lancet 1987, 330, 1483–1486. [Google Scholar] [CrossRef]
  86. Le Bec, P.Y.; Fatséas, M.; Denis, C.; Lavie, E.; Auriacombe, M. Cannabis and psychosis: Search of a causal link through a critical and systematic review. L'Encephale 2009, 35, 377–385. (In French) [Google Scholar] [CrossRef] [PubMed]
  87. Henquet, C.; Krabbendam, L.; Spauwen, J.; Kaplan, C.; Lieb, R.; Wittchen, H.-U.; Van Os, J. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. Br. Med. J. 2005, 330, 11. [Google Scholar] [CrossRef] [PubMed]
  88. Bovasso, G.B. Cannabis abuse as a risk factor for depressive symptoms. Am. J. Psychiatry 2014, 158, 2033–2037. [Google Scholar] [CrossRef] [PubMed]
  89. Richardson, T. Cannabis use and mental health: A review of recent epidemiological research. Int. J. Pharmacol. 2010, 6, 796–807. [Google Scholar] [CrossRef]
  90. Feyissa, A.M.; Kelly, J.P. A review of the neuropharmacological properties of khat. Prog. Neuro Psychopharmacol. Biol. Psychiatry 2008, 32, 1147–1166. [Google Scholar] [CrossRef] [PubMed]
  91. Vearrier, D.; Greenberg, M.I.; Miller, S.N.; Okaneku, J.T.; Haggerty, D.A. Methamphetamine: History, pathophysiology, adverse mental health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine. Dis. Mon. 2012, 58, 38–89. [Google Scholar] [CrossRef] [PubMed]
  92. Brière, F.N.; Fallu, J.S.; Janosz, M.; Pagani, L.S. Prospective associations between meth/amphetamine (speed) and MDMA (ecstasy) use and depressive symptoms in secondary school students. J. Epidemiol. Community Health 2012, 66, 990–994. [Google Scholar] [CrossRef] [PubMed]
  93. MacInnes, N.; Handley, S.L.; Harding, G.F. Former chronic methylenedioxymethamphetamine (MDMA or ecstasy) users report mild depressive symptoms. J. Psychopharmacol. 2001, 15, 181–186. [Google Scholar] [CrossRef] [PubMed]
  94. Parrott, A.C.; Montgomery, C.A.; Wetherell, M.A.; Downey, L.A.; Stough, C.; Scholey, A.B. MDMA, cortisol, and heightened stress in recreational Ecstasy/MDMA users. Behav. Pharmacol. 2014, 25, 458–472. [Google Scholar] [CrossRef] [PubMed]
  95. Parrott, A.C.; Milani, R.M.; Parmar, R.; Turner, J.J.D. Recreational Ecstasy/MDMA and other drug users form the UK and Italy: Psychiatric symptoms and psychobiological problems. Psychopharmacology 2001, 159, 77–82. [Google Scholar] [CrossRef] [PubMed]
  96. Schifano, F.; Di Furia, L.; Forza, G.; Minicuci, N.; Bricolo, R. MDMA (‘ecstasy’) consumption in the context of polydrug abuse: A report on 150 patients. Drug Alcohol Depend. 1998, 52, 85–90. [Google Scholar] [CrossRef]
  97. Scholey, A.B.; Owen, L.; Gates, J.; Rodgers, J.; Buchanan, T.; Ling, J.; Heffernan, T.; Swan, P.; Stough, C.; Parrott, A.C. Hair MDMA samples are consistent with reported Ecstasy use: Findings from an internet study investigating effects of Ecstasy on mood and memory. Neuropsychobiology 2011, 63, 15–21. [Google Scholar] [CrossRef] [PubMed]
  98. Taurah, L.; Chandler, C.; Sanders, G. Depression, impulsiveness, sleep and memory in past and present polydrug users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Psychopharmacology 2014, 231, 737–751. [Google Scholar] [CrossRef] [PubMed]
  99. Turner, J.J.D.; Singer, L.T.; Moore, D.G.; Min, M.O.; Goodwin, J.; Fulton, S.; Parrott, A.C. Psychiatric profiles of mothers who take Ecstasy/MDMA during pregnancy: Reduced depression one year after giving birth and quitting Ecstasy. J. Psychopharmacol. 2014, 28, 55–66. [Google Scholar] [CrossRef] [PubMed]
  100. Downey, L.A.; Tysse, B.; Ford, T.C.; Samuels, A.C.; Wilson, R.P.; Parrott, A.C. Psychomotor tremor and proprioceptive control problems in current and former stimulant drug users: An accelerometer study of heavy users of amphetamine, MDMA, and other recreational stimulants. J. Clin. Pharmacol. 2017, 57, 1330–1337. [Google Scholar] [CrossRef] [PubMed]
  101. Vonmoos, M.; Hulka, L.M.; Preller, K.H.; Jenni, D.; Baumgartner, M.R.; Stohler, R.; Bolla, K.I.; Quednow, B.B. Cognitive dysfunction in recreational and dependent cocaine users: Role of attention-deficit hyperactivity disorder, craving and early age at onset. Br. J. Psychiatry 2014, 203, 35–43. [Google Scholar] [CrossRef] [PubMed]
  102. Fisk, J.E.; Montgomery, C.; Wareing, M.; Murphy, P.N. Reasoning deficits in ecstasy (MDMA) polydrug users. Psychopharmacology 2005, 181, 550–559. [Google Scholar] [CrossRef] [PubMed]
  103. Fox, H.; Parrott, A.C.; Turner, J.J.D. Ecstasy/MDMA related cognitive deficits: A function of dosage rather than awareness of problems. J. Psychopharmacol. 2001, 15, 273–281. [Google Scholar] [CrossRef] [PubMed]
  104. Fox, H.C.; McLean, A.; Turner, J.J.D.; Parrott, A.C.; Rogers, R.; Sahakian, B.J. Neuropsychological evidence of a relatively selective profile of temporal dysfunction in drug-free MDMA (“ecstasy”) polydrug users. Psychopharmacology 2002, 162, 203–214. [Google Scholar] [CrossRef] [PubMed]
  105. Laws, K.R.; Kokkalis, J. Ecstasy (MDMA) and memory function: A meta-analytic update. Hum. Psychopharmacol. 2007, 22, 381–388. [Google Scholar] [CrossRef] [PubMed]
  106. Montgomery, C.; Hatton, N.P.; Fisk, J.E.; Ogden, R.S.; Jansari, A. Assessing the functional significance of ecstasy-related memory deficits using a virtual reality paradigm. Hum. Psychopharmacol. 2010, 25, 318–325. [Google Scholar] [CrossRef] [PubMed]
  107. Parrott, A.C.; Lees, A.; Garnham, N.J.; Jones, M.; Wesnes, K. Cognitive performance in recreational users of MDMA or “ecstasy”: Evidence for memory deficits. J. Psychopharmacol. 1998, 12, 79–83. [Google Scholar] [CrossRef] [PubMed]
  108. Parrott, A.C.; Downey, L.A.; Roberts, C.A.; Montgomery, C.; Bruno, R.; Fox, H.C. Recreational 3.4-methylenedioxymethamphetamine or ‘ecstasy’: Current perspective and future research needs. J. Psychopharmacol. 2017, 31, 959–966. [Google Scholar] [CrossRef] [PubMed]
  109. Bolla, K.I.; Brown, K.; Eldreth, D.; Tate, K.; Cadet, J.L. Dose-related neurocognitive effects of marijuana use. Neurology 2002, 59, 1337–1343. [Google Scholar] [CrossRef] [PubMed]
  110. Grant, I.; Gonzalez, R.; Carey, C.L.; Natarajan, L.; Wolfson, T. Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study. J. Int. Neuropsychol. Soc. 2003, 9, 679–689. [Google Scholar] [CrossRef] [PubMed]
  111. Jager, G.; Block, R.I.; Luijten, M.; Ramsey, N.F. Cannabis use and memory brain function in adolescent boys: A cross-sectional multicenter fMRI study. J. Am. Acad. Child Adolesc. Psychiatry 2010, 49, 561–572. [Google Scholar] [CrossRef] [PubMed]
  112. Meier, M.H.; Caspi, A.; Ambler, A.; Harrington, H.; Houts, R.; Keefe, R.S.E.; Moffitt, T.E. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc. Nat. Acad. Sci. USA 2012, 109, E2657–E2664. [Google Scholar] [CrossRef] [PubMed]
  113. Pope, H.G.; Gruber, A.J.; Hudson, J.I.; Huestis, M.A.; Yurgelun-Todd, D. Neuropsychological performance in long-term cannabis users. Arch. Gen. Psychiatry 2001, 58, 909–915. [Google Scholar] [CrossRef] [PubMed]
  114. Yücel, M.; Solowij, N.; Respondek, C.; Whittle, S.; Fornito, A.; Pantelis, C.; Lubman, D.I. Regional brain abnormalities associated with long-term heavy cannabis use. Arch. Gen. Psychiatry 2008, 65, 694–701. [Google Scholar] [CrossRef] [PubMed]
  115. Mandelbaum, D.E.; de la Monte, S.M. Adverse structural and functional effects of marijuana on the brain: Evidence reviewed. Pediatric Neurol. 2017, 66, 12–20. [Google Scholar] [CrossRef] [PubMed]

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