HORMONES & Cannabis studies completed


Hormones are special chemical messengers in the body that are created in the endocrine glands. These messengers control most major bodily functions, from simple basic needs like hunger to complex systems like reproduction, and even the emotions and mood. Hormones travel in your bloodstream to tissues or organs.

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Marijuana: interaction with the estrogen receptor


Crude marijuana extract competed with estradiol for binding to the estrogen receptor of rat uterine cytosol. Condensed marijuana smoke also competed with estradiol for its receptor. Pure delta 9-tetrahydrocannabinol, however, did not interact with the estrogen receptor. Ten delta 9-tetrahydrocannabinol metabolites also failed to compete with estradiol for its receptor. Of several other common cannabinoids tested, only cannabidiol showed any estrogen receptor binding. This was evident only at very high concentrations of cannabidiol. Apigenin, the aglycone of a flavinoid phytoestrogen found in cannabis, displayed high affinity for the estrogen receptor. To assess the biological significance of these receptor data, estrogen activity was measured in vivo with the uterine growth bioassay, using immature rats. Cannabis extract in large doses exhibited neither estrogenic nor antiestrogenic effects. Thus, although estrogen receptor binding activity was observed in crude marijuana extract, marijuana smoke condensate and several known components of cannabis, direct estrogenic activity of cannabis extract could not be demonstrated in vivo.

Articles citing this article

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Endocrine Effects of Marijuana


Todd T. Brown, MD, and Adrian S. Dobs, MD, MHS

 In the 35 years since the active compound of marijuana, 9-tetrahydrocannabinol, was isolated, the psychological and physiological impact of marijuana use has been actively investigated. Animal models have demonstrated that cannabinoid administration acutely alters multiple hormonal
systems, including the suppression of the gonadal steroids, growth hormone, prolactin, and thyroid hormone and the activation of the hypothalamic-pituitary-adrenal axis.

These effects are mediated by binding to the endogenous cannabinoid receptor in or near the hypothalamus. Despite these findings in animals, the effects in humans have been inconsistent, and discrepancies are likely due in part to the development of tolerance. The long-term consequences of marijuana use in humans on endocrine systems remain unclear. Journal of Clinical Pharmacology, 2002;42:90S-96S

  In the late 1960s, the dramatic increase in the casual use of marijuana raised questions about its potential adverse effects on health. In 1972, Harmon and Aliapoulios1 provided the first report of marijuana’s clinical impact on the endocrine system with the initial description of marijuana-associated gynecomastia.

Further investigation has demonstrated that marijuana and its active component, Ä9 tetrahydrocannabinol (THC), have widespread effects on multiple hormonal systems, including gonadal, adrenal, prolactin, growth hormone, and thyroid hormone regulation in experimental
models. In addition, the effects on the neuroendocrine mechanism of feeding are being delineated.
Many of these acute effects, however, are transient as tolerance likely develops, and the long-term
impact of marijuana smoking on the endocrine systems in humans remains unclear. This review will outline the effects of cannabinoids on the various hormonal systems both in animals and in man and evaluate the evidence of possible clinical consequences on the endocrine system with marijuana use.

HYPOTHALAMICPITUITARY-GONADAL AXIS In both males and females, the secretion of sex hormones is directly controlled by the pituitary and indirectly influenced by the hypothalamus. From cells in the medial basal hypothalamus, gonadotropinreleasing hormone (GnRH) is secreted in a pulsatile fashion under the influence of a variety of other factors, including endogenous opiates, catecholamines, prolactin, corticotropin-releasing hormone (CRH), and neuropeptide Y. GnRH stimulates the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the anterior pituitary gonadotrophs. In both males and females, FSH and LH act on the gonads,
leading to the secretion of testosterone in males and estradiol and progesterone in females. These hormones feed back to the hypothalamus and anterior pituitary to modulate GnRH and gonadotropin release. Marijuana, Ä9-THC, and other cannabinoids acutely alter hypothalamic-pituitary-gonadal (HPG) integrity and affect reproductive function by acting at the hypothalamus either directly through GnRH or indirectly through other modulators (Figure 1).

These effects are
likely mediated by central cannabinoid (CB1) receptorsin the hypothalamus.2 CB1 receptors have also been found in the testes3 and the ovaries4 of experimental animals, suggesting a possible direct effect of cannabinoids on the gonads. In addition, marijuana condensate and Ä9-THC inhibit binding of dihydrotestosterone (DHT) to the androgen receptor,5 and noncannabinoid components of marijuana extract have been shown to bind to the estrogen receptor.6 The extent to which these non-CB1-mediated pathways contribute to marijuana’s effects on the HPG axis has not been clarified. HPG AXIS EFFECTS IN MALES LH stimulates the Leydig cells in the testes to produce testosterone, while FSH primarily acts on the Sertoli...read entire pdf



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Marijuana Effects on the Endocrine and Reproductive Systems

Monique C. Braude, Ph.D.
Jacqueline P. Ludford, M.S.
National Institute on Drug Abuse
NIDA Research Monograph 44
A RAUS Review Report
Public Health Service
Alcohol, Drug Abuse, and Mental Health Administration
National Institute on Drug Abuse
5600 Fishers Lane
Rockville, Maryland 20857Preface
The Research Analysis and Utilization System (RAUS) is designed to
serve four functions:
Collect and systematically classify the findings of all
intramural and extramural research supported by the
hational institute on Drug Abuse (NIDA);
Evaluate the findings in selected areas of particular
interest and formulate a state-of-the-art review by a
panel of scientific peers;
Disseminate findings to researchers in the field and to
administrators, planners, instructors, and other
interested persons;
Provide a feedback mechanism to NIDA staff and planners so
that the administration and monitoring of the NIDA
research program reflect the very latest knowledge gleaned
from research in the field.
Since there is a limit to the number of reseach findings that can
be intensively reviewed annually, four subject areas are chosen
each year to undergo a thorough examination. Distinguished
scientists in the selected field are provided with copies of
reports from NIDA-funded research and invited to add any
information derived from the literature and from their own research
in order to formulate a comprehensive vick of the field. Each
reviewer is charged with writing a state-of-the-art paper in his or
her particular subject area. These papers, together with a summary
of the discussions and recommendations which take place at the
review meeting, make up a RAUS Review Report in the NIDA Research
Monograph series.....read entire pdf


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Cannabis reward: biased towards the fairer sex?

Br J Pharmacol. 2007 November; 152(5): 562–564.

Published online 2007 September 24. doi: 10.1038/sj.bjp.0707469.
Copyright 2007, Nature Publishing Group
I S McGregor1* and J C Arnold2
1School of Psychology, University of Sydney, Sydney, Australia
2Department of Pharmacology, Bosch Institute, University of Sydney, Sydney, Australia
*Author for correspondence: [email protected]
Received August 21, 2007; Accepted August 28, 2007.

In contrast to drugs such as alcohol, amphetamine and cocaine, cannabis use in humans has proven difficult to model in laboratory animals. Recent breakthrough discoveries of intravenous THC self-administration in rhesus monkeys and self-administration of the synthetic cannabinoid agonist WIN 55,212-2 in rats have allowed new studies of the genetic, neural and environmental determinants of cannabis use. In the present issue of BJP, Fattore and colleagues further demonstrate genetic (strain) differences in WIN 55,212-2 self-administration in rats, with Long Evans (LE) and Lister Hooded (LH), but not Sprague–Dawley, rats self-administering this drug. They then show that female LE and LH rats self-administer more WIN 55,212-2 than male rats. Ovariectomy abolished this sex difference, suggesting a permissive role for oestrogen in cannabis reward. This accompanying Commentary reviews recent progress in animal models of cannabis use and highlights the role of genetic, developmental and endocrine factors in driving cannabis use and dependence.
Keywords: cannabis, reward, reinforcement, strain, self-administration, sex differences, oestrogen, oxytocin, rat
Cannabis is the most widely used illicit drug in the world and is generally considered to have only modest addictive potential compared to other drugs such as nicotine, heroin or methamphetamine. However, some users do become dependent on cannabis, consuming the drug in a compulsive fashion and experiencing dysphoria during abstinence. The factors determining vulnerability to cannabis dependence have proven difficult to untangle in human studies. In this issue of the British Journal of Pharmacology, Fattore et al. (2007), provide evidence from an animal model of hitherto unexpected sex differences in cannabinoid intake in rats.
Self-administration studies provide a superior animal model of human drug use with high face validity. The avid self-administration of alcohol, nicotine, cocaine and methamphetamine by rodents has been of great utility to addiction scientists. However, cannabis self-administration has proven notoriously difficult to obtain in laboratory animals. A breakthrough came in 2000, when Stephen Goldberg and colleagues at NIDA showed self-administration of the prototypical natural cannabinoid THC in squirrel monkeys (Tanda et al., 2000). The critical factor appeared to be the use of very low intravenous doses of THC, analogous to the doses present in a puff of cannabis smoke. Soon after this, Fattore et al. (2001) showed intravenous self-administration of low doses of the synthetic cannabinoid CB1 receptor agonist, WIN 55212-2 in rats, albeit with the limitation that rats must be chronically food restricted for this to occur.
Genes play a critical role in determining the proclivity towards cannabis consumption. Earlier studies involving intracranial self-stimulation and place preference models indicated that different genetic strains of rats had different motivational responses to cannabinoids, with Lewis and Long Evans (LE) but not Fischer 344 strain rats seen as ‘cannabis preferring' (Lepore et al., 1995; Gardner, 2002). Corresponding strain differences in cannabinoid-induced brain activation and mesolimbic dopamine release were also evident (Arnold et al., 2001). More recently, WIN 55212-2 self-administration was reported in Lister Hooded (LH) and LE rats, but not in Sprague–Dawley rats, who will not self-administer the drug (Deiana et al., 2007).
Cannabis has intake-limiting panic and anxiety-inducing properties in a subset of human users and has anxiogenic and aversive properties in rats (McGregor et al., 1996; Quinn et al., 2007). If such an aversive component could be minimized then the rewarding actions of cannabinoids might be unmasked. Accordingly, the apparently ‘reward-resistant' Sprague–Dawley strain, will self-administer THC directly into the nucleus accumbens and ventral tegmental area, presumably bypassing the aversive effects of cannabinoid stimulation of other brain sites that occur with systemic administration (Zangen et al., 2006).
A genetic predisposition towards or away from cannabis is also hinted at in human studies. A fascinating early study involving identical twins in New Zealand indicated that the extent to which cannabis is perceived as pleasurable or aversive appears at least partly genetically determined (Lyons et al., 1997). A more recent study showed that single-nucleotide polymorphisms in the cannabinoid receptor 1 gene can be associated with vulnerability towards cannabis dependence in cannabis-using adolescents (Hopfer et al., 2006).
What of the gender factor? In general, intravenous self-administration studies show female rats outstripping males in their acquisition of a drug taking habit and their overall drug intake, particularly with stimulants (Lynch, 2006). Fattore et al. (2007), now show that female LH and LE rats maintain a higher level of response for WIN 55212-2 than their male counterparts. On first glance these results deduced from rats seem to largely conflict with human population studies reporting higher rates of cannabis intake in males than females. However, societal factors contribute to such statistics (for example higher social disapproval of female drug use) which do not necessarily imply that females find cannabis less rewarding than males (Reed and Mowbray, 1999). Indeed, recent survey results indicate that adolescent females in the USA are now overtaking males in their rates of initiation of cannabis use (ONDCP, 2006). Other human research suggests that women progress through the various stages of drug addiction at an accelerated rate, entering treatment programmes earlier than men (Brady and Randall, 1999; Westermeyer and Boedicker, 2000).
The heightened cannabinoid self-administration seen in female rats is diminished by ovariectomy (Fattore et al., 2007). This oestrogenic modulation of the reinforcing effects of cannabinoids, mirrors that seen with stimulant drugs (Lynch, 2006). Oestrogen has powerful anxiolytic effects in rats that involves endocannabinoids (Hill et al., 2007). Thus oestrogen may minimize the aversive effects of cannabinoids, unmasking a euphorogenic effect. In addition, CB1 receptors and oestrogen receptors interact in the mesolimbic dopamine system (Freund et al., 2003; Weiser et al., 2007), with administration of THC increasing dopamine activity in this system in an oestrogen-sensitive fashion (Bonnin et al., 1993). Recent findings indicate that adolescent rats find cannabinoids less aversive than adult rats, and it is conceivable that a hormonal influence is also at play here (Quinn et al., 2007).
Humans of course are not ‘large rats' and the behavioural influence of oestrogen is generally far more pronounced in female rats than in female humans. Indeed, one important study found that cannabis intake in women does not vary across menstrual cycle phases (Griffin et al., 1986). Another caveat is that higher rates of self-administration in rats can sometimes reflect lower rewarding efficacy (that is more drug is self-administered to compensate for diminished rewarding effects): it would be reassuring to see these sex differences in rats extended using other complementary animal models of drug reward.
Finally, recent research indicates that repeated cannabinoid exposure can have lasting adverse residual effects on social behaviour, emotionality and cognitive function in rats (Quinn et al., 2007) and such effects may be more pronounced in adolescent female rats (O'Shea et al., 2004). Human studies also highlight adolescent female populations as particularly prone to anxiety and depressive disorders when cannabis is used heavily (Patton et al., 2002). Oxytocin, a neuropeptide strongly linked to oestrogen, is downregulated in mesolimbic sites by chronic cannabinoid exposure (Butovsky et al., 2006), and this may play a critical role in cannabis-withdrawal symptoms (Cui et al., 2001). Exploration of an oestrogen and oxytocin-linked component in the negative lasting impacts of chronic cannabis use would therefore appear a worthwhile avenue for future research.
This work was supported by Australian Research Council and NH & MRC grants to ISM and JCA.
LELong Evans
LHLister hooded
NIDANational Institute on Drug Abuse
WIN 55,212-2(R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]- pyrrolo[1,2,3-de]-1,4 benzoxazinyl]-(1-naphthalenyl)-methanone mesylate]

Conflict of interest
The authors state no conflict of interest.

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Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women

Drug Alcohol Depend. 1991 Aug;28(2):121-8.


Department of Anesthesia, College of Medicine, University of Iowa, Iowa City 52242.


To investigate possible effects of chronic marijuana use on reproductive and stress hormones, we assayed testosterone, luteinizing hormone, follicle stimulating hormone, prolactin, and cortisol in 93 men and 56 women with a mean (+/- S.E.) age of 23.5 +/- 0.4 years. Hormone values were compared among groups of subjects stratified according to frequency of marijuana use (frequent, moderate and infrequent; N = 27, 18, and 30, respectively) and non-using controls (N = 74). Chronic marijuana use showed no significant effect on hormone concentrations in either men or women.




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