• Archives of Pharmacal Research
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• 제28권12호
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• pp.1365-1375
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• 2005

The antiestrogenic effects of marijuana smoke condensate (MSC) and three major cannabinoids, i.e., $\bigtriangleup^{9}$-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), were evaluated using in vitro bioassays, viz., the human breast cancer cell proliferation assay, the recombinant human estrogen receptor (ER) competitive binding assay, and the reporter gene assay. The inhibitory effects on estrogen were also examined using the ethoxyresorufin-O­deethylase (EROD) assay, the aromatase assay, and the 17$\beta$-estradiol ($E_{2}$) metabolism assay. The results showed that MSC induced the antiestrogenic effect via the ER-mediated pathway, while THC, CBD, and CBN did not have any antiestrogenic activity. This suggests that the combined effects of the marijuana smoke components are responsible for the antiestrogenicity of marijuana use. In addition, MSC induced the CYP1A activity and the $E_{2}$ metabolism, but inhibited the aromatase activity, suggesting that the antiestrogenic activity of MSC is also related to the indirect ER-dependent pathway, as a result of the depletion of the in situ $E_{2}$ level available to bind to the ER. In conclusion, pyrogenic products including polycyclic aromatic hydrocarbons (PAHs) in the non-polar fraction, which is the most biologically active fraction among the seven fractions of MSC, might be responsible for the antiestrogenic effect.

• 대한의생명과학회지
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• 제5권2호
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• pp.167-179
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• 1999

냉동생물학 연구분야 중 동면의 기전은 미래의 우주과학과 저온생물학이 풀어야 될 중요한 과제로서, 박쥐를 비롯한 동면동물을 사용하는 응용과학에서 가장 주목을 받아 오고 있다. 동면동물의 동면돌입 현상이 체온하강과 함께 뇌 전도상 전간발작 (epileptic seizure)을 유도시킨다는 가설을 검증하기 위하여 여러 가지 박쥐를 포함하는 동면동물을 대상으로 박쥐의 정상 동면돌입과정과 전간발작유발인자인 tetrahydrocannabinol (THC), pentylenetetrazol (metrazol), intermittent light stimulation (ILS)이 박쥐의 체온 (Tb), 심박률 (HR), 뇌전도 (EEG), 뇌영상 (brain mapping) 등에 미치는 영향을 관찰하여 다음과 같은 결과를 얻었다. 정상 동면돌입과정에 있어서는 안주애기박쥐는 1∼2개의 고평부를 형성하지만 대체로 2시 간 후에 동면에 안정 (심박률 15회/분)되었고 작은갈색박쥐는 2시간 30분에 동면온도에서 안정되었다. THC는 햄스터의 체온을 감소시켰고, pentylenetetrazol (metrazol)의 유의한 체온하강효과는 볼 수 없었으나, ILS는 긴가락박쥐, 쇠박쥐의 체온과 심박률을 하강시켰으며, 문둥이박쥐는 정상적으로 동면돌입시 뇌전도상 epileptic seizure시 나타나는 뇌파 (3 spikes and wave/sec)를 나타내었으며, 사람의 경우 ILS 자극 (Intensity 4∼8, 20 flashes/sec)을 받은 9명 중 1명에서 epileptic seizure시의 EEG상의 뇌영상 (brain map) (우측 후두엽의 일부만이 활성)으로 추측되는 소견을 볼 수 있었다. 이상의 실험결과는, 북부 온대지방의 동면동물인 박쥐와 햄스터의 경우 동면돌입과 체온하강 및 전간발작과 상당한 관련성이 있음을 암시한다고 사료된다.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2007년도 Proceedings of The Convention
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• pp.57-64
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• 2007

Metabolic interactions of the three major cannabinoids, ${\Delta}^9$-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) with steroid hormones were investigated. These cannabioids concentration-dependently inhibited $3{\beta}$-hydroxysteroid dehydrogenase and $17{\alpha}$-hydroxylase in rat adrenal and testis microsomes. CBD and CBN were the most potent inhibitors of $3{\beta}$-phydroxysteroid dehydrogenase and progesterone $17{\alpha}$-hydroxylase, respectively, in rat testis microsomes. Three cannabinoids highly attenuated hCG-stimulated testosterone production in rat testicular interstitial cells. These cannabinoids also decreased in levels of mRNA and protein of StAR in the rat testis cells. These results indicate that the cannabinoids could interact with steroid hormones, and exert their modulatory effects on endocrine and testicular functions. Metabolic interaction of a THC metabolite, $7{\beta}$-hydroxy-${\Delta}^8$-THC with steroids is also investigated. Monkey liver microsomes catalyzed the stereoselective oxidation of $7{\beta}$-hydroxy-${\Delta}^8$-THC to 7-oxo-${\Delta}^8$-THC, so-called microsomal alcohol oxygenase (MALCO). The reaction is catalyzed by CYP3A8 in the monkey liver microsomes, and required NADH as well as NADPH as an efficient cofactor, and its activity is stimulated by some steroids such as testosterone and progesterone. Kinetic analyses revealed that MALCO-catalyze reaction showed positive cooperativity. In order to explain the metabolic interaction between the cannabinoid metabolite and testosterone, we propose a novel kinetic model involving at least three binding sites for mechanism of the metabolic interactions.

• Biomolecules & Therapeutics
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• 제29권4호
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• pp.384-391
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• 2021

Currently, the expanding recreational use of synthetic cannabinoids (SCBs) threatens public health. SCBs produce psychoactive effects similar to those of tetrahydrocannabinol, the main component of cannabis, and additionally induce unexpected pharmacological side effects. SCBs are falsely advertised as legal and safe, but in reality, SCB abuse has been reported to cause acute intoxication and addictive disorders. However, because of the lack of scientific evidence to elucidate their dangerous pharmacological effects, SCBs are weakly regulated and continue to circulate in illegal drug markets. In the present study, the intravenous self-administration (IVSA) paradigm was used to evaluate the abuse potential of three SCBs (AM-1248, CB-13, and PB-22) in rats. All three SCBs maintained IVSA with a large number of infusions and active lever presses, demonstrating their reinforcing effects. The increase of active lever presses was particularly significant during the early IVSA sessions, indicating the reinforcement-enhancing effects of the SCBs (AM-1248 and CB-13). The number of inactive lever presses was significantly higher in the SCB groups (AM-1248 and CB-13) than that in the vehicle group, indicating their impulsive effects. In summary, these results demonstrated that SCBs have distinct pharmacological properties and abuse potential.

• Journal of Dental Anesthesia and Pain Medicine
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• 제21권6호
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• pp.479-506
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• 2021

Background: Chronic neuropathic pain (NP) presents therapeutic challenges. Interest in the use of cannabis-based medications has outpaced the knowledge of its efficacy and safety in treating NP. The objective of this review was to evaluate the effectiveness of cannabis-based medications in individuals with chronic NP. Methods: Randomized placebo-controlled trials using tetrahydrocannabinol (THC), cannabidiol (CBD), cannabidivarin (CBDV), or synthetic cannabinoids for NP treatment were included. The MEDLINE, Cochrane Library, EMBASE, and Web of Science databases were examined. The primary outcome was the NP intensity. The risk of bias analysis was based on the Cochrane handbook. Results: The search of databases up to 2/1/2021 yielded 379 records with 17 RCTs included (861 patients with NP). Meta-analysis showed that there was a significant reduction in pain intensity for THC/CBD by -6.624 units (P < .001), THC by -8.681 units (P < .001), and dronabinol by -6.0 units (P = .008) compared to placebo on a 0-100 scale. CBD, CBDV, and CT-3 showed no significant differences. Patients taking THC/CBD were 1.756 times more likely to achieve a 30% reduction in pain (P = .008) and 1.422 times more likely to achieve a 50% reduction (P = .37) than placebo. Patients receiving THC had a 21% higher improvement in pain intensity (P = .005) and were 1.855 times more likely to achieve a 30% reduction in pain than placebo (P < .001). Conclusion: Although THC and THC/CBD interventions provided a significant improvement in pain intensity and were more likely to provide a 30% reduction in pain, the evidence was of moderate-to-low quality. Further research is needed for CBD, dronabinol, CT-3, and CBDV.

• Biomolecules & Therapeutics
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• 제22권4호
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• pp.363-369
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• 2014

Synthetic cannabinoids (CBs) such as the JWH series have caused social problems concerning their abuse liability. Because the JWH series produces euphoric and hallucinogenic effects, they have been distributed illegally under street names such as "Spice" and "Smoke". Many countries including Korea have started to schedule some of the JWH series compounds as controlled substances, but there are a number of JWH series chemicals that remain uncontrolled by law. In this study, three synthetic CBs with different binding affinities to the $CB_1$ receptor (JWH-073, 081, and 210) and ${\Delta}^9$-tetrahydrocannabinol (${\Delta}^9$-THC) were evaluated for their potential for psychological dependence. The conditioned place preference test (unbiased method) and self-administration test (fixed ratio of 1) using rodents were conducted. $K_i$ values of the three synthetic cannabinoids were calculated as supplementary data using a receptor binding assay and overexpressed $CB_1$ protein membranes to compare dependence potential with $CB_1$ receptor binding affinity. All mice administered JWH-073, 081, or 210 showed significantly increased time spent at unpreferred space in a dose-dependence manner in the conditioned place preference test. In contrast, all tested substances except ${\Delta}^9$-THC showed aversion phenomenon at high doses in the conditioned place preference test. The order of affinity to the $CB_1$ receptor in the receptor binding assay was JWH-210 > JWH-081 >> JWH-073, which was in agreement with the results from the conditioned place preference test. However, no change in self-administration was observed. These findings suggest the possibility to predict dependence potential of synthetic CBs through a receptor binding assay at the screening level.

• 한국작물학회지
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• 제51권3호
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• pp.187-190
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• 2006

저 마약형 대마 품종이 육성되지 않았을 경우 그 대안으로서 섬유용 대마의 THC 함량을 낮추기 위해 저 마약형 도입 유전자원중 경장은 작지만 개화기가 재래종과 비슷한 IH3 과 재래종 종자를 1:1, 2:1, 3:1로 혼합하여 채종시험을 실시하고 각 혼합비율별로 채종한 종자를 섬유용으로 재배하여 종실용 및 섬유용 대마 생육특성과 수량, 그리고 cannabinoid 함량분포를 검정한 결과를 요약하면 다음과 같다. 채종시험에서 IH3 의 비율이 클수록 천립중은 무거웠으나 종실수량은 100 kg/10a 내외로 차이가 없었다. 혼합비율별로 집단 채종한 종자를 섬유용으로 재배하였을 때 섬유수량은 $193{\sim}198kg/10a$로 비슷하였으나 THC 함량은 종자 IH3 혼합비율이 클수록 낮아져 3:1 에서는 0.39%이었다. THC 및 CBD 함량분포에서도 IH3 혼합비율이 높을수록 마약형 및 중간형 비율이 낮아졌고 저 마약형 비율은 증가하였다.

• 한국약용작물학회지
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• 제13권4호
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• pp.190-193
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• 2005

종실의 유분함량이 많아 유료작물로 전용이 가능한 대표적인 섬유작물인 대마 종실의 지방산조성의 분석을 통하여 감마리놀렌산 함유여부 및 함량과와 품종간 차이를 조사하였다. 45 수집종의 대마 종실에는 감마리놀렌산의 경우 평균 2.1% 함유되어 있었으며 이중 IH4 등 7 품종이 $3.1%{\sim}3.8%$로 높으면서 경장이 $31{\sim}122\;cm$로 작아 종실용 품종 육성재료로 유망시 되었다. 도입된 대마의 지방산 조성 변이에서 감마리놀렌산 비율 범위 및 변이계수는 각각 $0.8%{\sim}3.8%$, 42.9%로 품종간 변이가 가장 컸으나 리놀레산은 각각 $51.4%{\sim}61.8%$, 4.2%로 가장 적었다 개화일수와 경장간에는 고도의 정의 상관이었고, 개화일수와 알파리놀렌산 비율 및 경장과 감마리놀렌산 비율간에는 부의 상관이었으며 환각성분인 THC와 다른 형질들 간에는 유의적인 상관이 없었다. 팔미트산과 감마리놀렌산 비율간에는 부의상관, 올렌산과 알파리놀렌산 그리고 리놀레산과 알파리놀렌산은 고도의 부의 상관을 나타내었다. 감마리놀렌산 함량이 높은 도입종들은 대체로 수집지가 중앙러시아 등 유럽이었고 개화일수가 $29{\sim}44$일로 짧았다.

• 생물정신의학
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• 제21권3호
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• pp.99-106
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• 2014

Objectives Previous studies suggest that the cannabinoid receptor 1 (CNR1) gene could be an important candidate gene for schizophrenia. According to linkage studies, this gene is located on chromosome 6q14-q15, which is known to harbor the schizophrenia susceptibility locus (locus 5, SCZ5, OMIM 803175). The pharmacological agent delta-9-tetrahydrocannabinol (${\Delta}$-9-THC) seems to elicit the symptoms of schizophrenia. The association between CNR1 polymorphisms and schizophrenia is actively being investigated, and some studies have linked the AAT-trinucleotide repeats in CNR1 to the onset of schizophrenia. In this study, we have investigated the association between the AAT-trinucleotide repeats in CNR1 and schizophrenia by studying schizophrenia patients and healthy individuals from Korea. Methods DNA was extracted from the blood samples of 394 control subjects and 337 patients diagnosed with schizophrenia (as per the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria). After polymerase chain reaction amplification, a logistic regression analysis, with age and gender as the covariates, was performed to study the variations in the AAT-repeat polymorphisms between the two groups. Results In total, 8 types of trinucleotide repeats were identified, each containing 7, 8, 10, 11, 12, 13, 14, and 15 repeats, respectively. $(AAT)_{13}$ allele was most frequently observed, with a frequency of 33.6% and 31.6% in the patient and control groups, respectively. The frequency of the other repeat alleles in the patient group (in the decreasing order) was as follows : $(AAT)_{13}$ 33.6%, $(AAT)_{14}$ 21.6%, $(AAT)_{12}$ 18.5%, and $(AAT)_{7}$ 11.1%. The frequency of the repeat alleles in the control group (in the decreasing order) was as follows : $(AAT)_{13}$ 31.6%, $(AAT)_{14}$ 24.5%, $(AAT)_{12}$ 17.2%, and $(AAT)_{7}$ 11.6%. However, there were no significant differences in the AAT-repeat polymorphisms of the CNR1 gene between the patient group and the control group. Conclusions Although our study revealed no significant association of the AAT-repeat polymorphism of the CNR1 gene with schizophrenia, it will serve as a good reference for future studies designed to examine the cannabinoid hypothesis of schizophrenia.